Clin Drug Investig DOI 10.1007/s40261-015-0283-9
ORIGINAL RESEARCH ARTICLE
Safety and Pharmacokinetics of Single and Multiple Ascending Doses of Avibactam Alone and in Combination with Ceftazidime in Healthy Male Volunteers: Results of Two Randomized, Placebo-Controlled Studies Henri Merdjan1 • Manickam Rangaraju2 • Antoine Tarral3
Ó Springer International Publishing Switzerland 2015
Abstract Background and Objective Avibactam is a novel non-blactam b-lactamase inhibitor effective against Ambler class A, C and some class D b-lactamases that is currently in clinical development in combination with ceftazidime for the treatment of serious Gram-negative infections. It restores the in vitro activity of a range of b-lactams, including ceftazidime, against extended-spectrum blactamase-producing pathogens. Two phase I studies assessed the safety and pharmacokinetics of avibactam in healthy subjects when administered alone or with ceftazidime. Methods The first study (NXL104-1001) was a placebocontrolled, single-ascending dose study assessing avibactam 50, 100, 250, 500, 1000, 1500 or 2000 mg given as a 30-min intravenous infusion. After a 7-day washout, subjects in the 250 and 500 mg dosing groups received a second avibactam dose with concomitant ceftazidime 1000 or 2000 mg, respectively. The second study (NXL104-
1002) was performed in two parts. Part 1 assessed multipleascending doses of avibactam. Subjects were randomized to receive avibactam 500, 750 or 1000 mg every 8 h (q8 h) over 5 days, or ceftazidime-avibactam 2000–500 mg q8 h over 10 days. Part 2 assessed bioavailability of avibactam after a single oral dose (500 mg) relative to a single 30-min intravenous infusion (500 mg). Results No serious or severe adverse events were reported in either study. Avibactam exposure generally increased proportionally to dose and there was no trend for accumulation after multiple doses. Almost all avibactam was excreted largely unchanged in the urine within the first 6 h. Concomitant ceftazidime did not affect avibactam’s safety and pharmacokinetic profile. Avibactam exposure after oral dosing was very low at 6.2 % of that observed after intravenous infusion. Conclusion Avibactam was generally well tolerated across all dosing regimens, when given alone or with ceftazidime. Avibactam exposure was dose related in both studies, and avibactam pharmacokinetics were linear and not affected by ceftazidime.
The authors were formerly employees of Novexel SA.
Electronic supplementary material The online version of this article (doi:10.1007/s40261-015-0283-9) contains supplementary material, which is available to authorized users. & Henri Merdjan [email protected] 1
Present Address: Pharsight Consulting Services Europe, Regus Business Centre, 37-39 Avenue Ledru Rollin, CS11237, 75570 Paris Cedex 12, France
2
Present Address: Polyphor Ltd, Allschwil, Switzerland
3
Present Address: DNDi Drugs for Neglected Diseases Initiative, Geneva, Switzerland
Key Points Avibactam is generally well tolerated in healthy subjects when administered alone or in combination with ceftazidime as single or multiple intravenous infusions, or when given orally. Avibactam pharmacokinetics are approximately dose proportional. Avibactam pharmacokinetics are not affected by the presence of ceftazidime.
H. Merdjan et al.
1 Introduction Infections caused by Gram-negative organisms are a major concern due to the increasing prevalence of multidrug-resistant pathogens, with limited treatment options available [1–4]. The proliferation of plasmids encoding extendedspectrum b-lactamases (ESBLs) has been responsible for the spread of resistance to extended-spectrum cephalosporins in organisms such as Klebsiella pneumoniae and Escherichia coli [3, 5]. Moreover, resistance to carbapenems, the current treatment of choice for ESBL-producing pathogens, is increasing due to the spread of carbapenemases, including K. pneumoniae carbapenemase (KPC) [6–8]. Avibactam is a novel non-b-lactam b-lactamase inhibitor, which binds covalently to Ambler class A b-lactamases, including KPCs, Ambler class C and some class D b-lactamases [9]. Avibactam has limited intrinsic antimicrobial activity but restores the in vitro activity of b-lactams including ceftazidime [10–13], ceftaroline, the active metabolite of ceftaroline fosamil [14, 15], and aztreonam [16] against ESBL-producing pathogens. Furthermore, in murine models of ceftazidime-resistant infection, avibactam restores the in vivo activity of ceftazidime resulting in effective bacterial clearance [17–19]. This report presents the results from the first phase I trials to assess avibactam in humans. The two studies evaluated the safety, tolerability and pharmacokinetics of avibactam alone and in combination with ceftazidime given as either single or multiple ascending doses in healthy male subjects.
2 Methods The first study (sponsor protocol number NXL104-1001) was a randomized, double-blind, placebo-controlled, single ascending dose (SAD) study in which avibactam was given as a single dose either alone or in combination with ceftazidime. The second study (sponsor protocol number NXL104-1002) was conducted in two parts. The first part was a multiple ascending dose (MAD) study in which multiple doses of avibactam were administered alone or with ceftazidime every 8 h (q8 h), over 5 days. The second part, conducted in a separate cohort of subjects, was a preliminary evaluation of the bioavailability of avibactam after a single oral dose. The study protocols were approved by an independent ethics committee (CPP Ile de France VIII) and were performed in accordance with the ethical principles of the Declaration of Helsinki and in compliance with Good Clinical Practice. All subjects provided written,
informed consent. The Investigator and Sponsor were blinded to treatment allocation throughout the trial. 2.1 Subjects In both studies, healthy adult male subjects aged 18–45 years were eligible for inclusion if they had a body mass index (BMI) of 18–27 kg/m2, negative serology for HIV antibody, hepatitis B surface antigen and hepatitis C antibody, and had a negative urine drug screen. In addition, subjects were required to have no history of hypersensitivity to any medications. No concomitant medications were permitted 14 days prior to first dose and for the duration of the study with the exception of 1–2 tablets (total dose B1000 mg) per day of paracetamol (acetaminophen) for headache. Exclusion criteria included electrocardiogram (ECG) abnormalities which may confound QT interval (QTc) analysis; clinically significant illness (mutually agreed by the Sponsor and the Investigator on a case-by-case basis) in the 3 months before the study; presence or sequelae of gastrointestinal, liver or kidney disease, or other conditions known to interfere with the absorption, distribution, metabolism or excretion of any drug; clinically significant abnormal vital signs including diastolic blood pressure [90 mmHg and/or systolic blood pressure [150 mmHg and pulse rate (as detailed in the supplemental material); smoker of [5 cigarettes/day in previous 3 months; history of drug abuse within 1 year of randomization; blood or plasma donation [500 mL during the 3 months prior to commencement of study; and consumption of grapefruit-containing products within 7 days of the first study dose. In addition, both the MAD and the oral bioavailability part of the second study excluded subjects with QTc C420 ms, pronounced sinus bradycardia (\40 beats per min) or hypokalemia (\3.5 mEq/L); or with a family history of long QT syndrome, unexplained sudden death, sick sinus syndrome or any clinically relevant cardiovascular disease. 2.2 Study Design 2.2.1 Study 1: Single Ascending Dose Study Subjects were assigned sequentially to one of seven dosing groups (n = 10 per group): avibactam 50, 100, 250, 500, 1000, 1500 or 2000 mg in 250 mL 5 % glucose solution. Once assigned to a dose group, subjects were randomized to receive a single 30-min intravenous infusion on Day 1 of placebo (n = 2 per group) or avibactam (n = 8 per group). After a 7-day wash-out, subjects in the 250 and 500 mg
Safety and Pharmacokinetics of Avibactam
dosing groups were given a second avibactam dose plus ceftazidime 1000 or 2000 mg, respectively (n = 8 per group) or a second placebo dose (n = 2 per group) (Supplemental Figure 1). Dosing started with the lowest dosing group and the decision to proceed to the next dose was based on safety and tolerability results and, where available, pharmacokinetic data. For pharmacokinetic analysis, two 5 mL blood samples were collected pre-dose, 10, 30, and 40 min after the start of infusion, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h after the start of infusion. Two 10 mL urine samples were collected for pharmacokinetic analysis pre-dose, and 0–6, 6–12, 12–24 and 24–48 h post-dose. 2.2.2 Study 2: Part 1: Assessment of Multiple Ascending Doses Subjects were assigned sequentially to one of four dosing groups (n = 10 per group): avibactam 500, 750 or 1000 mg alone in 250 mL 5 % glucose solution, or avibactam 500 mg in combination with ceftazidime 2000 mg in 250 mL 5 % glucose solution. Subjects were then randomized to receive a 30-min intravenous infusion of either placebo (n = 2 per group) or avibactam (n = 8 per group), q8 h over 5 days or, for subjects assigned to the avibactam plus ceftazidime group, over 10 days (Supplemental Figure 2). Testing started with the lowest dosing group and the decision to proceed to the next dose level was based on safety and tolerability results. Where possible, the decision to proceed to the next dose level was also based upon proportional increase in systemic exposure and, where available, pharmacokinetic data falling within the no-observed-adverse-effect level of exposure determined in animal studies [20]. For pharmacokinetic analysis, two 2 mL blood samples were collected pre-dose, 15, 30 and 45 min, and 1, 1.5, 2, 4, 6, 8, 8.5, 9 and 16 h after the start of the morning infusion on Days 1 and 5. On Day 3, two 2 mL blood samples were collected pre-dose, 30 min, 1, 8, 8.5 and 9 h after start of the morning infusion; and on Day 10 in the ceftazidime-avibactam dosing groups’ samples were collected 8 h post-last infusion. Two 10 mL urine samples were collected for pharmacokinetic analysis pre-dose and 0–8, 8–16 and 16–24 h after the first dose on Days 1 and 5; and for the avibactam 500 mg plus ceftazidime 2000 mg group on Day 10. 2.2.3 Study 2: Part 2: Assessment of Oral Bioavailability The absolute oral bioavailability part of the second study had an open, cross-over design in which eight subjects received a 30-min intravenous infusion of avibactam 500 mg in 250 mL 5 % glucose solution, or oral
administration of avibactam 500 mg in 5 % glucose solution. Treatment was administered in a randomized order, separated by a 7-day wash-out period. Two 2 mL blood samples were taken pre-dose, 15, 30 and 45 min, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h after start of infusion or oral dosing. Two 10 mL urine samples were obtained pre-dose, 0–6, 6–12 and 12–24 h post-dose. 2.3 Safety and Tolerability In both studies, safety and tolerability were assessed by adverse event (AE) monitoring coded using the Medical Dictionary for Regulatory Activities [version 7.1 (MedDRA MSSO, Chantilly, VA, USA)], local tolerability at injection site, 12-lead ECG, vital signs (blood pressure and heart rate), and clinical laboratory data (hematology, biochemistry and urinalysis). AEs were reported by the Investigator as mild, moderate or severe according to the classifications outlined in the supplemental material. Serious AEs were classified as such based on the outcome or action criteria usually associated with events that pose a threat to life or functioning. An AE was considered as a treatment-emergent AE (TEAE) if it started between the beginning of administration of the first dose of the study drug (intravenous or oral) and 48 h after the end of administration; or if it started before the start of administration of the first dose of the study drug and worsened in intensity after treatment administration. 2.4 Pharmacokinetic Analysis Blood and urine samples were collected in duplicate in both studies: one sample for analysis and the second for backup purposes. Concentrations of avibactam (sourced from MP5, Riom, France) and ceftazidime (sourced from Sandoz GmbH, Kundl, Austria) were determined separately using liquid chromatography-tandem mass spectrometry utilizing validated bioanalytical assays. The lower limit of quantification was 10 ng/mL in plasma, and 100 ng/mL in urine for avibactam, and 50 ng/mL in plasma and 100 ng/mL in urine for ceftazidime. Measurement of ceftazidime and avibactam plasma concentrations is described in the supplementary materials. Pharmacokinetic parameters determined in each study included: maximum observed plasma concentration (Cmax); time to maximum plasma concentration (tmax); terminal half-life (t); apparent volume of distribution at steady state (Vss); plasma clearance (CL); area under the plasma concentration–time curve (AUC) from time zero to time of last measurable plasma concentration (AUClast); on Day 1, AUC from time zero to infinity (AUC0–?); and on Day 5 and 10, AUC during the dosing interval (AUC0–s). Renal clearance (CLR), and urinary excretion and recovery were
H. Merdjan et al.
also determined. Additionally, in the MAD part of the second study, geometric mean accumulation ratio (RSS) and observed pre-dose plasma concentration (Ctrough) were calculated on Days 3 or 8, and 5 or 10; and in the oral bioavailability part of the second study absolute bioavailability, intravenous mean residence time, oral mean residence time and oral mean absorption time (MAT) were calculated. 2.5 Statistics These were the first studies to evaluate the safety and tolerability of avibactam in humans, therefore sample size was based on accepted industry standards for this type of investigation [21]. The safety population comprised all randomized subjects who received at least part of a dose of study drug. The pharmacokinetic-analysis population comprised only subjects receiving avibactam or ceftazidime-avibactam who had avibactam plasma concentrations considered interpretable by the investigator. Pharmacokinetic parameters were derived using WinNonlin software version 5.01 (Pharsight Corporation, Mountain View, CA, USA). Descriptive statistics comparing the pharmacokinetic parameters and safety analyses
were performed using SAS software version 8.2 (SAS Institute, Cary, NC, USA).
3 Results 3.1 Subjects In the SAD study, 56 subjects received a dose of avibactam (alone or in combination with ceftazidime) and 14 subjects received placebo. All subjects completed the study. The mean [standard deviation (SD)] age was 29.6 (6.9) years; body weight 73.03 (7.96) kg; BMI 23.32 (2.35) kg/m2. The majority of subjects (49; 70.0 %) were Caucasian; 13 (18.6 %) were Black, one (1.4 %) was Asian and seven (10.0 %) were of other ethnic origin. In the MAD part of the second study, 33 subjects received avibactam (alone or in combination with ceftazidime) and eight received placebo. One subject, randomized to avibactam 750 mg, discontinued on Day 1 due to personal reasons and is included in the safety but not the pharmacokinetic-analysis population. All other subjects completed the study. The mean (SD) age was 30.2 (6.7) years; body weight 74.95 (9.45) kg; BMI 23.51 (1.96) kg/m2.
Table 1 Summary of TEAEs by preferred terms after single ascending doses in the SAD study or multiple (three times daily) doses in the MAD part of the second study (safety population) SAD study
Total (n = 70)
Placebo (n = 14)
Avibactam 250 mg (n = 8)a
Avibactam 500 mg (n = 8)
Avibactam 2000 mg (n = 8)
Total number of TEAEs
6b
0
3
2
1
Number (%) of subjects reporting a TEAE
4 (5.7)
0
2 (25.0)
1 (12.5)
1 (12.5)
Abdominal pain
1 (1.4)
0
1 (12.5)
0
0
Sense of oppression
1 (1.4)
0
0
1 (12.5)
0
Somnolence
1 (1.4)
0
0
1 (12.5)
0
Anxiety
1 (1.4)
0
1 (12.5)
0
0
Postural dizziness
1 (1.4)
0
1 (12.5)
0
0
Orthostatic hypotension
1 (1.4)
0
0
0
1 (12.5)
Total (n = 41)
Placebo (n = 8)
Avibactam 500 mg (n = 8)
Avibactam 750 mg (n = 9)
Avibactam 1000 mg (n = 8)
Avibactam 500 mg ? ceftazidime 2000 mg (n = 8) 3 (37.5)
MAD study
c
Number (%) of subjects reporting a TEAE
5 (12.2)
1 (12.5)
0
1 (11.1)
0
Infusion site erythema
1 (2.4)
1 (12.5)
0
0
0
0
Injections site hematoma
2 (4.9)
0
0
0
0
2 (25.0)
Injections site inflammation
1 (2.4)
0
0
1 (11.1)
0
0
Arthralgia
1 (2.4)
0
0
0
0
1 (12.5)
AE adverse event, MAD multiple ascending dose, SAD single ascending dose, TEAE treatment-emergent adverse event a
Only avibactam dosing groups in which a TEAE was reported are displayed for the SAD study
b
Six AEs were reported in four subjects. One event of anxiety in one subject in the 250 mg group; one event of abdominal pain and one event of postural dizziness in one subject in the 250 mg group; and one event of a sense of oppression and one event of somnolence in one subject in the 500 mg group
c
No TEAEs were reported in the absolute oral bioavailability part of the second study (n = 8)
Safety and Pharmacokinetics of Avibactam
The majority of subjects (22; 53.7 %) were Caucasian, 11 (26.8 %) were Black, two (4.9 %) were Asian and six (14.6 %) were of other ethnic origin. In the absolute oral bioavailability part of the second study, eight subjects received avibactam and all completed the study. All were male with a mean (SD) age of 28.9 (8) years, two subjects were Caucasian (25 %), three were Black (37.5 %) and three were of other ethnic origin. 3.2 Safety There were no serious or severe AEs reported in either study and no subjects discontinued due to AEs. In the SAD study, six TEAEs were reported in four subjects (Table 1), of which five (anxiety in one subject in the 250 mg group; abdominal pain and postural dizziness in one subject in the 250 mg group; and sense of oppression and somnolence in one subject in the 500 mg group) were considered by the investigator to be related to the study treatment. The TEAE of orthostatic hypertension (one subject in the 2000 mg group) was considered to be probably unrelated. Five of the six TEAEs were of mild intensity and one was moderate and all resolved without corrective treatment. In the MAD part of the second study, five TEAEs (one during administration of placebo, one during administration of avibactam alone, and three during administration of ceftazidime-avibactam) were reported in five subjects (Table 1) all of which were considered probably not related to the study drug. All AEs resolved spontaneously with the exception of one event of moderate hematoma at the injection site, which was ongoing at the last observation 8 h after the end of the last infusion. There were no TEAEs in the oral bioavailability part of the second study. There were no clinically significant abnormal values reported for any of the ECG, vital signs, hematology, biochemistry and urinalysis parameters in either study. Serum creatinine and hepatic function laboratory values are reported in supplemental Tables 1–3. 3.3 Pharmacokinetics of Avibactam Following Single and Multiple Doses 3.3.1 Study 1: Single Ascending Dose Study After a single-intravenous dose, peak avibactam and ceftazidime concentrations were generally observed at the end of the infusion (at 30 min) (Table 2) followed by a rapid multi-exponential decline (bi- or triphasic) (avibactam, Fig. 1a; ceftazidime, data not shown). Avibactam geometric mean Cmax and AUC increased with increasing avibactam dose (Table 2). Avibactam exposure was approximately dose-proportional (Fig. 2), although this was not formally assessed. The arithmetic mean t was similar
across all doses (Table 2; Fig. 1a). Cmax and AUC of avibactam 250 or 500 mg alone were comparable with those of avibactam 250 or 500 mg co-administered with ceftazidime 1000 or 2000 mg, respectively (Table 2). Avibactam was excreted largely unchanged in the urine. Overall, 80–90 % of the dose was excreted in the first 6 h, with 85–100 % of the parent drug excreted over 48 h in all dose groups (Fig. 3). Ceftazidime was excreted extensively unchanged in the urine (96–108 % after 1000–2000 mg, respectively). 3.3.2 Study 2: Part 1: Assessment of Multiple Ascending Doses Peak avibactam and ceftazidime concentrations were generally observed at the end of the infusion (at 30 min) on Day 1, Day 5 and, in the case of ceftazidime-avibactam, Day 10, followed by a rapid decline at the end of each infusion (Table 3) (Avibactam, Fig. 1b, c; ceftazidime, data not shown). Avibactam plasma concentrations were still measurable in all subjects at the end of the 8 h dosing interval (Fig. 1b, c). Avibactam geometric mean Cmax increased with increasing dose (Table 3). The arithmetic mean t calculated over the dosing interval was comparable between Day 1 and Day 5 (Table 3). In addition, RSS was close to 1 for each dose, indicating that there was no trend for accumulation of avibactam over the 5 days of treatment (Table 3). Inter-individual variability [coefficient of variation (CV) %] of avibactam pharmacokinetic parameters was comparable across all dosing groups on Day 1, with the exception of Cmax in the 500 mg group where inter-individual variability reached 70 % (Table 3). This result could be ascribed to one subject whose individual Cmax value was approximately fourfold greater than the other subjects. When avibactam 500 mg was administered concomitantly with ceftazidime 2000 mg, all ceftazidime pharmacokinetic parameters remained comparable across Days 1, 5 and 10, with the exception of CLR (Table 3). Ceftazidime RSS remained close to 1 throughout, indicating no trend for ceftazidime accumulation. Avibactam geometric mean Cmax and AUClast were lower on Days 1 and 5 in the ceftazidime-avibactam dosing group, and the geometric mean CL was higher, compared with avibactam 500 mg administered alone. However, inter-individual variability of Vss was markedly higher on Days 1 and 5 in the group who received avibactam 500 mg plus ceftazidime 2000 mg (Table 3). On Day 10, the geometric mean RSS of avibactam co-administered with ceftazidime was 0.74 (Table 3) corresponding with a 26 % reduction in overall avibactam exposure when compared with Day 1. Cmax and AUC0–? dose-proportionality were assessed on Day 5 following multiple doses of avibactam 500–1000 mg; however, no formal statistical conclusion
H. Merdjan et al. Table 2 Avibactam and ceftazidime pharmacokinetic parameters following single intravenous infusions (SAD study; n = 8 per group) Avibactam dose (mg)
Ceftazidime dose (mg)
Cmax (mg/L)
tmaxa (h)
AUC0–? (hmg/L)
AUClast (hmg/L)
tb (h)
Vss (L)
CL (L/h)
CLR (L/h)
12.28 (14)
Avibactam data 50
0
2.65 (14)
0.50 (0.50–0.50)
3.66 (11)
3.70 (11)
1.48 (24)
20.96 (16)
13.52 (13)
100
0
4.89 (33)
0.50 (0.50–0.67)
8.15 (20)
8.21 (20)
1.80 (20)
23.58 (26)
12.18 (20)
11.12 (22)
250
0
11.88 (20)
0.50 (0.50–0.67)
19.44 (11)
19.54 (11)
1.70 (11)
22.81 (12)
12.80 (11)
15.68 (16)
250
1000
12.93 (29)
0.50 (0.50–0.67)
20.66 (15)
20.78 (15)
1.79 (10)
21.08 (32)
12.03 (18)
11.90 (31)
500
0
26.15 (58)
0.50 (0.50–0.67)
37.13 (27)
37.34 (27)
1.83 (13)
22.72 (37)
13.39 (25)
12.68 (27)
500 1000
2000 0
23.33 (26) 48.48 (22)
0.50 (0.50–0.67) 0.50 (0.50–1.00)
37.15 (22) 85.75 (16)
37.41 (22) 85.96 (16)
2.16 (53) 2.18 (28)
25.43 (26) 21.99 (12)
13.36 (19) 11.63 (17)
12.71 (22) 11.22 (18)
1500
0
99.06 (21)
0.50 (0.50–0.67)
145.10 (10)
145.18 (10)
2.65 (6)
19.39 (14)
10.33 (10)
8.53 (21)
2000
0
120.30 (23)
0.50 (0.50–1.00)
183.47 (15)
183.59 (15)
2.71 (5)
20.82 (20)
10.89 (14)
10.57 (21)
250
1000
57.35 (24)
0.50 (0.50–0.67)
128.26 (15)
129.28 (15)
1.82 (26)
18.88 (23)
7.74 (18)
6.63 (20)
500
2000
93.17 (31)
0.50 (0.50–1.00)
195.94 (25)
198.59 (26)
3.07 (66)
28.23 (33)
10.07 (23)
9.70 (26)
Ceftazidime data
Unless otherwise stated values are geometric mean (CV%) AUC area under the plasma concentration-time curve, AUClast AUC from time zero to time of last measurable plasma concentration, AUC0–? AUC on Day 1 from time zero to infinity, CL plasma clearance, CLR renal clearance, Cmax maximum observed plasma concentration, CV% coefficient of variation (%), SAD single ascending dose, SD standard deviation, t terminal half-life, tmax time to maximum plasma concentration, Vss apparent volume of distribution at steady state a
Median (range)
b
Arithmetic mean (SD)
could be drawn. CLR estimates shown in Table 3 should be interpreted with caution due to individual inconsistencies in avibactam excretion results including the amount excreted greater than 100 % or close to 0, very low clearance, and a quantifiable amount of avibactam recorded for a subject who received placebo. 3.3.3 Study 2: Part 2: Assessment of Oral Bioavailability Mean (CV%) avibactam Cmax after oral dosing [0.63 mg/L (33 %)] was 2.18 % of the value reported after intravenous infusion [28.86 mg/L (27 %)], and the avibactam AUClast after oral dosing was 6.20 % of the value reported after intravenous infusion. Absolute bioavailability after oral dosing [arithmetic mean (range)] was 6.85 % (4.48–11.65 %), and avibactam Cmax after oral dosing was observed between 30 min and 4 h post-dose with MAT estimated as 4.53 h, compared with a Cmax at 30 min postintravenous infusion. Inter-individual variability was comparable between intravenous and oral dosing in the region of 30 % (Fig. 4).
4 Discussion Avibactam administered alone or in combination with ceftazidime was generally well tolerated at doses ranging from 50 to 2000 mg administered as a single intravenous
infusion or as multiple intravenous infusions over 5–10 days. No serious or severe AEs were reported in either study. Six AEs were reported in four subjects in the 250 mg to 2000 mg dose groups in the SAD study (n = 70), of which five (abdominal pain, sense of oppression, somnolence, anxiety and postural dizziness) were considered by the investigator to be related to the study drug. These TEAEs were considered mild or moderate in intensity and recovered without corrective treatment and are not TEAEs that were observed during the MAD study reported here, or in subsequent phase I studies of avibactam [22–24]. In larger cohorts of patients in phase II trials, abdominal pain, anxiety and dizziness have been observed in [5 % of patients receiving avibactam in combination with ceftazidime, although these TEAEs were also observed in patients receiving the comparator agents in both these studies [25, 26]. In both parts of the second study (n = 49), no AEs considered related to the study drug were reported. ECG and vital sign parameters remained within the normal ranges in both studies across all tested doses, and no clinically significant changes in biochemistry, hematology and urinalysis parameters were observed. In both the SAD and MAD assessments, avibactam exposure generally increased proportionally to dose, and mean avibactam t was similar across all doses. The peak concentration after a single intravenous dose of either ceftazidime or avibactam in the SAD study was followed by a rapid, multi-exponential decline, indicative of tissue
Safety and Pharmacokinetics of Avibactam
Fig. 1 Plasma concentration-time profile of avibactam during (a) the single ascending dose study, (b) Day 1 of the multiple ascending dose (MAD) part of the second study and (c) Day 5 of the MAD part of the
second study. Arrows denote time of injection. Inset graphs show semi-log scale. tid, three times daily
binding and distribution in more than one compartment. In the MAD part of the second study the ratios for accumulation of avibactam (RSS) on Day 5 versus Day 1 were close to 1 across all dosing groups, indicating that there was no trend for accumulation and that steady-state had been achieved. In the present study, when administered as multipledoses of avibactam 500 mg plus ceftazidime 2000 mg, there was a decrease in avibactam exposure on Day 10 compared with Day 1. The reasons for this cannot be determined based on the design of the current study; however, in a later study where 500 mg avibactam was dosed in combination with 2000 mg ceftazidime three times daily
for 10 days, no such reduction in avibactam exposure at Day 10 was observed [22]. Based on the results of this study, it is not thought that avibactam pharmacokinetics are affected by concomitant use of ceftazidime as seen by the similarity of pharmacokinetic parameters when avibactam is administered alone (500 mg) or concomitant with ceftazidime (2000 mg) as a single dose. Ceftazidime data were also comparable to those observed previously in the literature, indicating that avibactam does not affect the pharmacokinetic or safety profile of ceftazidime [27, 28]. These data are in agreement with previous studies regarding the low propensity for ceftazidime to interact with other drugs [28] and are
H. Merdjan et al.
Fig. 2 Dose-proportionality of avibactam during the single ascending dose study (a) maximum plasma concentration (Cmax) (R2 = 0.8911) and (b) area under the plasma concentration versus time curve from
time zero to infinity (AUC0–?) (R2 = 0.9607) within the avibactam dose-range 500–2000 mg
Fig. 3 Mean cumulated amount of avibactam excreted in urine during the SAD study, as percentage of the dose
consistent with other reports showing that after 10 days of multiple dosing with avibactam 500 mg alone or ceftazidime-avibactam 2000–500 mg, there is no drug–drug interaction between ceftazidime and avibactam [22, 23]. Due to aberrant data in the MAD part of the second study, no conclusion could be drawn on urine excretion. However, in the SAD study, avibactam was largely excreted in the urine, with 80–90 % of the dose recovered as unchanged avibactam in the first 6 h. These results indicate that almost the entire avibactam dose is eliminated via the kidneys as the parent drug and is in agreement with subsequent studies that have been completed [29, 30]. Furthermore, it is known that avibactam clearance is reduced in patients with renal impairment, to a similar extent to that seen with ceftazidime [31, 32]. Population modeling has been completed using data from ceftazidime-avibactam phase I and II clinical trials, including the two trials reported here [33, 34]. Creatinine clearance was identified as the primary covariate that impacted on the clearance of both avibactam and ceftazidime, whereby drug clearance decreased with decreasing creatinine clearance [33]. The findings suggest that the magnitude of the avibactam dose
and the frequency of dosing in patients with renal impairment can follow the approved dosing regimen for ceftazidime [35]. The preliminary assessment of oral administration of 500 mg avibactam demonstrated a 93.8 % decrease in avibactam exposure (AUClast) after oral dosing compared with after intravenous dosing with absolute bioavailability being measured at approximately 7 %. Thus, there are no plans for avibactam to be administered orally in clinical practice at present. The pharmacokinetic and safety findings following intravenous infusion of avibactam in these preliminary studies have led to its investigation in phase II studies evaluating the efficacy and safety of ceftazidime-avibactam in patients with complicated urinary tract infections (NCT00690378) [26] and, concomitantly with metronidazole, in patients with complicated intra-abdominal infections (NCT00752219) [25]. Phase III trials evaluating ceftazidime 2000 mg in combination with avibactam 500 mg are now completed or in progress (NCT01499290, NCT01500239, NCT01595438, NCT01599806, NCT017 26023 and NCT01808092).
0
1000
500
500
2000
2000 114.53 (28)
22.11 (15)
124.07 (26)
50.90 (41)
44.45 (26)
26.48 (32)
36.33 (111)
127.98 (44)
57.48 (20)
40.78 (36)
29.74 (42)
37.29 (70)
Cmax (mg/L)
0.50 (0.25–0.75)
0.50 (0.25–0.75)
0.50 (0.50–0.75)
0.50 (0.50–0.75)
0.50 (0.50–4.00)
0.50 (0.50–0.75)
0.50 (0.50–0.75)
0.50 (0.25–0.50)
0.50 (0.50–0.50)
0.50 (0.50–0.75)
0.50 (0.50–1.50)
0.50 (0.50–0.50)
tmaxa (h)
245.57 (23)
35.89 (14)
251.47 (31)
82.08 (21)
68.13 (23)
43.12 (24)
50.63 (32)
252.62 (34)
81.22 (23)
60.48 (18)
47.32 (29)
52.18 (28)
AUClast (hmg/L)
–
–
–
–
–
–
–
265.67 (32)
82.76 (23)
61.48 (18)
48.49 (29)
53.12 (28)
AUC0–? (hmg/L)
1.91 (0.37)
1.50 (0.31)
1.98 (0.51)
1.47 (0.09)
1.38 (0.31)
1.59 (0.54)
1.67 (0.18)
1.76 (0.57)
1.38 (0.20)
1.37 (0.11)
1.49 (0.25)
1.44 (0.13)
tb (h)
19.98 (25)
24.22 (19)
20.40 (57)
20.90 (32)
19.16 (19)
20.53 (73)
16.61 (28)
17.98 (78)
20.11 (38)
19.99 (23)
17.99 (97)
15.24 (24)
Vss (L)
8.14 (27)
13.93 (16)
7.95 (40)
12.18 (19)
11.01 (21)
11.60 (37)
9.88 (21)
7.53 (45)
12.08 (23)
12.20 (18)
10.31 (57)
9.41 (19)
CL (L/h)
3.21 (82)
4.69 (83)
7.84 (101)
5.91 (33)
1.91 (85)
9.09 (91)
4.49 (52)
13.62 (111)
6.46 (23)
4.26 (51)
7.71 (62)
6.07 (29)
CLR (L/h)
4527 (35)
252.3 (31)
4206 (33)
801.9 (26)
598.4 (39)
390.54 (20)
513.8 (56)
–
–
–
–
–
Ctrough (ng/mL)
0.92 (65)
0.74 (64)
0.95 (17)
0.99 (13)
1.11 (23)
0.89 (15)
0.95 (6)
–
–
–
–
–
RSS
b
a
Arithmetic mean (SD)
Median (range)
AUC area under the plasma concentration-time curve, AUClast AUC from time zero to time of last measurable plasma concentration, AUC0–? AUC on Day 1 from time zero to infinity, CL plasma clearance, CLR renal clearance, Cmax maximum observed plasma concentration, Ctrough observed pre-dose plasma concentration, CV% coefficient of variation (%), MAD multiple ascending dose, RSS, accumulation ratio, SD, standard deviation, t terminal half-life, tmax time to maximum plasma concentration, Vss apparent volume of distribution at steady state
Unless otherwise stated values are geometric mean (CV%)
500
Ceftazidime data
500
Avibactam data
Day 10
2000
0
1000
Ceftazidime data
0
750
0
2000
500
Avibactam data 500
Day 5
2000
0
750
Ceftazidime data
0
2000
500
Ceftazidime dose (mg)
500
Avibactam data
Day 1
Avibactam dose (mg)
Table 3 Avibactam and ceftazidime pharmacokinetic parameters following multiple (three times daily) intravenous infusions on Days 1, 5 and 10 (MAD study; n = 8 per group)
Safety and Pharmacokinetics of Avibactam
H. Merdjan et al. Conflict of interest Antoine Tarral, Henri Merdjan and Manickam Rangaraju were employees of Novexel SA at the time of conduct of the studies.
References
Fig. 4 Plasma concentration-time profiles of avibactam 500 mg after single intravenous or oral administration during the absolute oral bioavailability part of the second study. Semi-log scale inset
5 Conclusion The studies presented here have shown that, in healthy subjects, avibactam 500 mg administered in the presence or absence of ceftazidime 2000 mg was generally well tolerated when given either as a single intravenous infusion, as multiple intravenous infusions, or when given orally. Ceftazidime and avibactam did not affect one another’s pharmacokinetics and there was no observed drug– drug interaction between the two agents. Avibactam concentration peaked at the end of intravenous infusion and avibactam pharmacokinetics were approximately dose proportional. There was no trend for accumulation when subjects were administered multiple doses. Oral dosing of avibactam resulted in absolute bioavailability of approximately 7 % demonstrating that it is not an effective dosing method for avibactam in its current formulation. These results contribute to a growing body of evidence supporting the intravenous dosing regimen currently being evaluated in phase III clinical trials of ceftazidimeavibactam. Acknowledgments The authors wish to thank Peter J Laud contracted to AstraZeneca from the Statistical Services Unit, Sheffield, for his expert review of the manuscript. These studies have been presented in part at the Interscience Conference on Antimicrobial Agents and Chemotherapy in 2007, and were funded by Novexel. Ceftazidime-avibactam is now being developed by AstraZeneca and Forest Laboratories Inc. a subsidiary of Actavis plc. Medical writing support was provided by Catherine Savage and Rob Campbell of Prime Medica Ltd, Knutsford, Cheshire, UK, funded by AstraZeneca. The design and conduct of the study, as well as analysis of the study data and opinions, conclusions, and interpretation of the data, are the responsibility of the authors.
1. Ho J, Tambyah P, Paterson D. Multiresistant Gram-negative infections: a global perspective. Curr Opin Infect Dis. 2010;23:546–53. 2. Kanj S, Kanafani Z. Current concepts in antimicrobial therapy against resistant gram-negative organisms: extended-spectrum beta-lactamase-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and multidrug-resistant Pseudomonas aeruginosa. Mayo Clin Proc. 2011;86:250–9. 3. Livermore DM. Current epidemiology and growing resistance of gram-negative pathogens. Korean J Intern Med. 2012;27:128–42. 4. Peleg A, Hooper D. Hospital-acquired infections due to gramnegative bacteria. N Engl J Med. 2010;362:1804–13. 5. Paterson D. Resistance in gram-negative bacteria: Enterobacteriaceae. Am J Infect Control. 2006;34:S20–8. 6. Magiorakos A, Suetens C, Monnet D, et al. The rise of carbapenem resistance in Europe: just the tip of the iceberg? Antimicrob Resist Infect Control. 2013;2:6. 7. Nordmann P, Naas T, Poirel L. Global spread of carbapenemaseproducing Enterobacteriaceae. Emerg Infect Dis. 2011;17:1791–8. 8. Tzouvelekis L, Markogiannakis A, Psichogiou M, et al. Carbapenemases in Klebsiella pneumoniae and other Enterobacteriaceae: an evolving crisis of global dimensions. Clin Microbiol Rev. 2012;25:682–707. 9. Stachyra T, Pechereau M, Bruneau J, et al. Mechanistic studies of the inactivation of TEM-1 and P99 by NXL104, a novel nonbeta-lactam beta-lactamase inhibitor. Antimicrob Agents Chemother. 2010;54:5132–8. 10. Aktas Z, Kayacan C, Oncul O. In vitro activity of avibactam (NXL104) in combination with beta-lactams against Gramnegative bacteria, including OXA-48 beta-lactamase-producing Klebsiella pneumoniae. Int J Antimicrob Agents. 2012;39:86–9. 11. Lagace-Wiens P, Tailor F, Simner P, et al. Activity of NXL104 in combination with beta-lactams against genetically characterized Escherichia coli and Klebsiella pneumoniae isolates producing class A extended-spectrum beta-lactamases and class C betalactamases. Antimicrob Agents Chemother. 2011;55:2434–7. 12. Livermore D, Mushtaq S, Warner M, et al. NXL104 combinations versus Enterobacteriaceae with CTX-M extended-spectrum beta-lactamases and carbapenemases. J Antimicrob Chemother. 2008;62:1053–6. 13. Stachyra T, Levasseur P, Pechereau M, et al. In vitro activity of the beta-lactamase inhibitor NXL104 against KPC-2 carbapenemase and Enterobacteriaceae expressing KPC carbapenemases. J Antimicrob Chemother. 2009;64:326–9. 14. Castanheira M, Sader H, Farrell D, et al. Activity of ceftarolineavibactam tested against Gram-negative organism populations, including strains expressing one or more beta-lactamases and methicillin-resistant Staphylococcus aureus carrying various staphylococcal cassette chromosome mec types. Antimicrob Agents Chemother. 2012;56:4779–85. 15. Mushtaq S, Warner M, Williams G, et al. Activity of chequerboard combinations of ceftaroline and NXL104 versus beta-lactamase-producing Enterobacteriaceae. J Antimicrob Chemother. 2010;65:1428–32. 16. Livermore DM, Mushtaq S, Warner M, et al. Activities of NXL104 combinations with ceftazidime and aztreonam against
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26. Vazquez J, Gonzalez Patzan L, Stricklin D, et al. Efficacy and safety of ceftazidime-avibactam versus imipenem-cilastatin in the treatment of complicated urinary tract infections, including acute pyelonephritis, in hospitalized adults: results of a prospective, investigator-blinded, randomized study. Curr Med Res Opin. 2012;28:1921–31. 27. Rains C, Bryson H, Peters D. Ceftazidime. An update of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy. Drugs. 1995;49:577–617. 28. Richards D, Brogden R. Ceftazidime. A review of its antibacterial activity, pharmacokinetic properties and therapeutic use. Drugs. 1985;29:105–61. 29. Merdjan H, Tarral A, Haazen W, Evene E, Robertson M, Sable C. Pharmacokinetics and tolerability of NXL104 in normal subjects and patients with varying degrees of renal insufficiency. Clin Microbiol Infect. 2010;16(Suppl 2):S465. 30. Vishwanathan K, Mair S, Gupta A, et al. Assessment of the mass balance recovery and metabolite profile of avibactam in humans and in vitro drug-drug interaction potential. Drug Metab Dispos. 2014;42:932–42. 31. Leroy A, Leguy F, Borsa F, et al. Pharmacokinetics of ceftazidime in normal and uremic subjects. Antimicrob Agents Chemother. 1984;25:638–42. 32. Welage L, Schultz R, Schentag J. Pharmacokinetics of ceftazidime in patients with renal insufficiency. Antimicrob Agents Chemother. 1984;25:201–4. 33. Li J, Zhou D, Nichols W, Das S. Evaluation of ceftazidimeavibactam (CAZ-AVI) dose regimens for Phase III study in patients with different renal function. In: 52nd Interscience conference on antimicrobial agents and chemotherapy. San Francisco; 2012 (Abstract A-635). 34. Li J, Knebel W, Riggs M, et al. Population pharmacokinetic modeling of ceftazidime (CAZ) and avibactam (AVI) in healthy volunteers and patients with complicated intra-abdominal infection (cIAI). In: 52nd Interscience conference of antimicrobial agents and chemotherapy. San Francisco; 2012 (Abstract A-634). 35. Wockhardt UK Ltd. Summary of product characteristics: ceftazidime. 2014. http://www.medicines.org.uk/emc/medicine/ 21129. Accessed 11 Mar 2015.
ORIGINAL RESEARCH ARTICLE
Safety and Pharmacokinetics of Single and Multiple Ascending Doses of Avibactam Alone and in Combination with Ceftazidime in Healthy Male Volunteers: Results of Two Randomized, Placebo-Controlled Studies Henri Merdjan1 • Manickam Rangaraju2 • Antoine Tarral3
Ó Springer International Publishing Switzerland 2015
Abstract Background and Objective Avibactam is a novel non-blactam b-lactamase inhibitor effective against Ambler class A, C and some class D b-lactamases that is currently in clinical development in combination with ceftazidime for the treatment of serious Gram-negative infections. It restores the in vitro activity of a range of b-lactams, including ceftazidime, against extended-spectrum blactamase-producing pathogens. Two phase I studies assessed the safety and pharmacokinetics of avibactam in healthy subjects when administered alone or with ceftazidime. Methods The first study (NXL104-1001) was a placebocontrolled, single-ascending dose study assessing avibactam 50, 100, 250, 500, 1000, 1500 or 2000 mg given as a 30-min intravenous infusion. After a 7-day washout, subjects in the 250 and 500 mg dosing groups received a second avibactam dose with concomitant ceftazidime 1000 or 2000 mg, respectively. The second study (NXL104-
1002) was performed in two parts. Part 1 assessed multipleascending doses of avibactam. Subjects were randomized to receive avibactam 500, 750 or 1000 mg every 8 h (q8 h) over 5 days, or ceftazidime-avibactam 2000–500 mg q8 h over 10 days. Part 2 assessed bioavailability of avibactam after a single oral dose (500 mg) relative to a single 30-min intravenous infusion (500 mg). Results No serious or severe adverse events were reported in either study. Avibactam exposure generally increased proportionally to dose and there was no trend for accumulation after multiple doses. Almost all avibactam was excreted largely unchanged in the urine within the first 6 h. Concomitant ceftazidime did not affect avibactam’s safety and pharmacokinetic profile. Avibactam exposure after oral dosing was very low at 6.2 % of that observed after intravenous infusion. Conclusion Avibactam was generally well tolerated across all dosing regimens, when given alone or with ceftazidime. Avibactam exposure was dose related in both studies, and avibactam pharmacokinetics were linear and not affected by ceftazidime.
The authors were formerly employees of Novexel SA.
Electronic supplementary material The online version of this article (doi:10.1007/s40261-015-0283-9) contains supplementary material, which is available to authorized users. & Henri Merdjan [email protected] 1
Present Address: Pharsight Consulting Services Europe, Regus Business Centre, 37-39 Avenue Ledru Rollin, CS11237, 75570 Paris Cedex 12, France
2
Present Address: Polyphor Ltd, Allschwil, Switzerland
3
Present Address: DNDi Drugs for Neglected Diseases Initiative, Geneva, Switzerland
Key Points Avibactam is generally well tolerated in healthy subjects when administered alone or in combination with ceftazidime as single or multiple intravenous infusions, or when given orally. Avibactam pharmacokinetics are approximately dose proportional. Avibactam pharmacokinetics are not affected by the presence of ceftazidime.
H. Merdjan et al.
1 Introduction Infections caused by Gram-negative organisms are a major concern due to the increasing prevalence of multidrug-resistant pathogens, with limited treatment options available [1–4]. The proliferation of plasmids encoding extendedspectrum b-lactamases (ESBLs) has been responsible for the spread of resistance to extended-spectrum cephalosporins in organisms such as Klebsiella pneumoniae and Escherichia coli [3, 5]. Moreover, resistance to carbapenems, the current treatment of choice for ESBL-producing pathogens, is increasing due to the spread of carbapenemases, including K. pneumoniae carbapenemase (KPC) [6–8]. Avibactam is a novel non-b-lactam b-lactamase inhibitor, which binds covalently to Ambler class A b-lactamases, including KPCs, Ambler class C and some class D b-lactamases [9]. Avibactam has limited intrinsic antimicrobial activity but restores the in vitro activity of b-lactams including ceftazidime [10–13], ceftaroline, the active metabolite of ceftaroline fosamil [14, 15], and aztreonam [16] against ESBL-producing pathogens. Furthermore, in murine models of ceftazidime-resistant infection, avibactam restores the in vivo activity of ceftazidime resulting in effective bacterial clearance [17–19]. This report presents the results from the first phase I trials to assess avibactam in humans. The two studies evaluated the safety, tolerability and pharmacokinetics of avibactam alone and in combination with ceftazidime given as either single or multiple ascending doses in healthy male subjects.
2 Methods The first study (sponsor protocol number NXL104-1001) was a randomized, double-blind, placebo-controlled, single ascending dose (SAD) study in which avibactam was given as a single dose either alone or in combination with ceftazidime. The second study (sponsor protocol number NXL104-1002) was conducted in two parts. The first part was a multiple ascending dose (MAD) study in which multiple doses of avibactam were administered alone or with ceftazidime every 8 h (q8 h), over 5 days. The second part, conducted in a separate cohort of subjects, was a preliminary evaluation of the bioavailability of avibactam after a single oral dose. The study protocols were approved by an independent ethics committee (CPP Ile de France VIII) and were performed in accordance with the ethical principles of the Declaration of Helsinki and in compliance with Good Clinical Practice. All subjects provided written,
informed consent. The Investigator and Sponsor were blinded to treatment allocation throughout the trial. 2.1 Subjects In both studies, healthy adult male subjects aged 18–45 years were eligible for inclusion if they had a body mass index (BMI) of 18–27 kg/m2, negative serology for HIV antibody, hepatitis B surface antigen and hepatitis C antibody, and had a negative urine drug screen. In addition, subjects were required to have no history of hypersensitivity to any medications. No concomitant medications were permitted 14 days prior to first dose and for the duration of the study with the exception of 1–2 tablets (total dose B1000 mg) per day of paracetamol (acetaminophen) for headache. Exclusion criteria included electrocardiogram (ECG) abnormalities which may confound QT interval (QTc) analysis; clinically significant illness (mutually agreed by the Sponsor and the Investigator on a case-by-case basis) in the 3 months before the study; presence or sequelae of gastrointestinal, liver or kidney disease, or other conditions known to interfere with the absorption, distribution, metabolism or excretion of any drug; clinically significant abnormal vital signs including diastolic blood pressure [90 mmHg and/or systolic blood pressure [150 mmHg and pulse rate (as detailed in the supplemental material); smoker of [5 cigarettes/day in previous 3 months; history of drug abuse within 1 year of randomization; blood or plasma donation [500 mL during the 3 months prior to commencement of study; and consumption of grapefruit-containing products within 7 days of the first study dose. In addition, both the MAD and the oral bioavailability part of the second study excluded subjects with QTc C420 ms, pronounced sinus bradycardia (\40 beats per min) or hypokalemia (\3.5 mEq/L); or with a family history of long QT syndrome, unexplained sudden death, sick sinus syndrome or any clinically relevant cardiovascular disease. 2.2 Study Design 2.2.1 Study 1: Single Ascending Dose Study Subjects were assigned sequentially to one of seven dosing groups (n = 10 per group): avibactam 50, 100, 250, 500, 1000, 1500 or 2000 mg in 250 mL 5 % glucose solution. Once assigned to a dose group, subjects were randomized to receive a single 30-min intravenous infusion on Day 1 of placebo (n = 2 per group) or avibactam (n = 8 per group). After a 7-day wash-out, subjects in the 250 and 500 mg
Safety and Pharmacokinetics of Avibactam
dosing groups were given a second avibactam dose plus ceftazidime 1000 or 2000 mg, respectively (n = 8 per group) or a second placebo dose (n = 2 per group) (Supplemental Figure 1). Dosing started with the lowest dosing group and the decision to proceed to the next dose was based on safety and tolerability results and, where available, pharmacokinetic data. For pharmacokinetic analysis, two 5 mL blood samples were collected pre-dose, 10, 30, and 40 min after the start of infusion, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h after the start of infusion. Two 10 mL urine samples were collected for pharmacokinetic analysis pre-dose, and 0–6, 6–12, 12–24 and 24–48 h post-dose. 2.2.2 Study 2: Part 1: Assessment of Multiple Ascending Doses Subjects were assigned sequentially to one of four dosing groups (n = 10 per group): avibactam 500, 750 or 1000 mg alone in 250 mL 5 % glucose solution, or avibactam 500 mg in combination with ceftazidime 2000 mg in 250 mL 5 % glucose solution. Subjects were then randomized to receive a 30-min intravenous infusion of either placebo (n = 2 per group) or avibactam (n = 8 per group), q8 h over 5 days or, for subjects assigned to the avibactam plus ceftazidime group, over 10 days (Supplemental Figure 2). Testing started with the lowest dosing group and the decision to proceed to the next dose level was based on safety and tolerability results. Where possible, the decision to proceed to the next dose level was also based upon proportional increase in systemic exposure and, where available, pharmacokinetic data falling within the no-observed-adverse-effect level of exposure determined in animal studies [20]. For pharmacokinetic analysis, two 2 mL blood samples were collected pre-dose, 15, 30 and 45 min, and 1, 1.5, 2, 4, 6, 8, 8.5, 9 and 16 h after the start of the morning infusion on Days 1 and 5. On Day 3, two 2 mL blood samples were collected pre-dose, 30 min, 1, 8, 8.5 and 9 h after start of the morning infusion; and on Day 10 in the ceftazidime-avibactam dosing groups’ samples were collected 8 h post-last infusion. Two 10 mL urine samples were collected for pharmacokinetic analysis pre-dose and 0–8, 8–16 and 16–24 h after the first dose on Days 1 and 5; and for the avibactam 500 mg plus ceftazidime 2000 mg group on Day 10. 2.2.3 Study 2: Part 2: Assessment of Oral Bioavailability The absolute oral bioavailability part of the second study had an open, cross-over design in which eight subjects received a 30-min intravenous infusion of avibactam 500 mg in 250 mL 5 % glucose solution, or oral
administration of avibactam 500 mg in 5 % glucose solution. Treatment was administered in a randomized order, separated by a 7-day wash-out period. Two 2 mL blood samples were taken pre-dose, 15, 30 and 45 min, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h after start of infusion or oral dosing. Two 10 mL urine samples were obtained pre-dose, 0–6, 6–12 and 12–24 h post-dose. 2.3 Safety and Tolerability In both studies, safety and tolerability were assessed by adverse event (AE) monitoring coded using the Medical Dictionary for Regulatory Activities [version 7.1 (MedDRA MSSO, Chantilly, VA, USA)], local tolerability at injection site, 12-lead ECG, vital signs (blood pressure and heart rate), and clinical laboratory data (hematology, biochemistry and urinalysis). AEs were reported by the Investigator as mild, moderate or severe according to the classifications outlined in the supplemental material. Serious AEs were classified as such based on the outcome or action criteria usually associated with events that pose a threat to life or functioning. An AE was considered as a treatment-emergent AE (TEAE) if it started between the beginning of administration of the first dose of the study drug (intravenous or oral) and 48 h after the end of administration; or if it started before the start of administration of the first dose of the study drug and worsened in intensity after treatment administration. 2.4 Pharmacokinetic Analysis Blood and urine samples were collected in duplicate in both studies: one sample for analysis and the second for backup purposes. Concentrations of avibactam (sourced from MP5, Riom, France) and ceftazidime (sourced from Sandoz GmbH, Kundl, Austria) were determined separately using liquid chromatography-tandem mass spectrometry utilizing validated bioanalytical assays. The lower limit of quantification was 10 ng/mL in plasma, and 100 ng/mL in urine for avibactam, and 50 ng/mL in plasma and 100 ng/mL in urine for ceftazidime. Measurement of ceftazidime and avibactam plasma concentrations is described in the supplementary materials. Pharmacokinetic parameters determined in each study included: maximum observed plasma concentration (Cmax); time to maximum plasma concentration (tmax); terminal half-life (t); apparent volume of distribution at steady state (Vss); plasma clearance (CL); area under the plasma concentration–time curve (AUC) from time zero to time of last measurable plasma concentration (AUClast); on Day 1, AUC from time zero to infinity (AUC0–?); and on Day 5 and 10, AUC during the dosing interval (AUC0–s). Renal clearance (CLR), and urinary excretion and recovery were
H. Merdjan et al.
also determined. Additionally, in the MAD part of the second study, geometric mean accumulation ratio (RSS) and observed pre-dose plasma concentration (Ctrough) were calculated on Days 3 or 8, and 5 or 10; and in the oral bioavailability part of the second study absolute bioavailability, intravenous mean residence time, oral mean residence time and oral mean absorption time (MAT) were calculated. 2.5 Statistics These were the first studies to evaluate the safety and tolerability of avibactam in humans, therefore sample size was based on accepted industry standards for this type of investigation [21]. The safety population comprised all randomized subjects who received at least part of a dose of study drug. The pharmacokinetic-analysis population comprised only subjects receiving avibactam or ceftazidime-avibactam who had avibactam plasma concentrations considered interpretable by the investigator. Pharmacokinetic parameters were derived using WinNonlin software version 5.01 (Pharsight Corporation, Mountain View, CA, USA). Descriptive statistics comparing the pharmacokinetic parameters and safety analyses
were performed using SAS software version 8.2 (SAS Institute, Cary, NC, USA).
3 Results 3.1 Subjects In the SAD study, 56 subjects received a dose of avibactam (alone or in combination with ceftazidime) and 14 subjects received placebo. All subjects completed the study. The mean [standard deviation (SD)] age was 29.6 (6.9) years; body weight 73.03 (7.96) kg; BMI 23.32 (2.35) kg/m2. The majority of subjects (49; 70.0 %) were Caucasian; 13 (18.6 %) were Black, one (1.4 %) was Asian and seven (10.0 %) were of other ethnic origin. In the MAD part of the second study, 33 subjects received avibactam (alone or in combination with ceftazidime) and eight received placebo. One subject, randomized to avibactam 750 mg, discontinued on Day 1 due to personal reasons and is included in the safety but not the pharmacokinetic-analysis population. All other subjects completed the study. The mean (SD) age was 30.2 (6.7) years; body weight 74.95 (9.45) kg; BMI 23.51 (1.96) kg/m2.
Table 1 Summary of TEAEs by preferred terms after single ascending doses in the SAD study or multiple (three times daily) doses in the MAD part of the second study (safety population) SAD study
Total (n = 70)
Placebo (n = 14)
Avibactam 250 mg (n = 8)a
Avibactam 500 mg (n = 8)
Avibactam 2000 mg (n = 8)
Total number of TEAEs
6b
0
3
2
1
Number (%) of subjects reporting a TEAE
4 (5.7)
0
2 (25.0)
1 (12.5)
1 (12.5)
Abdominal pain
1 (1.4)
0
1 (12.5)
0
0
Sense of oppression
1 (1.4)
0
0
1 (12.5)
0
Somnolence
1 (1.4)
0
0
1 (12.5)
0
Anxiety
1 (1.4)
0
1 (12.5)
0
0
Postural dizziness
1 (1.4)
0
1 (12.5)
0
0
Orthostatic hypotension
1 (1.4)
0
0
0
1 (12.5)
Total (n = 41)
Placebo (n = 8)
Avibactam 500 mg (n = 8)
Avibactam 750 mg (n = 9)
Avibactam 1000 mg (n = 8)
Avibactam 500 mg ? ceftazidime 2000 mg (n = 8) 3 (37.5)
MAD study
c
Number (%) of subjects reporting a TEAE
5 (12.2)
1 (12.5)
0
1 (11.1)
0
Infusion site erythema
1 (2.4)
1 (12.5)
0
0
0
0
Injections site hematoma
2 (4.9)
0
0
0
0
2 (25.0)
Injections site inflammation
1 (2.4)
0
0
1 (11.1)
0
0
Arthralgia
1 (2.4)
0
0
0
0
1 (12.5)
AE adverse event, MAD multiple ascending dose, SAD single ascending dose, TEAE treatment-emergent adverse event a
Only avibactam dosing groups in which a TEAE was reported are displayed for the SAD study
b
Six AEs were reported in four subjects. One event of anxiety in one subject in the 250 mg group; one event of abdominal pain and one event of postural dizziness in one subject in the 250 mg group; and one event of a sense of oppression and one event of somnolence in one subject in the 500 mg group
c
No TEAEs were reported in the absolute oral bioavailability part of the second study (n = 8)
Safety and Pharmacokinetics of Avibactam
The majority of subjects (22; 53.7 %) were Caucasian, 11 (26.8 %) were Black, two (4.9 %) were Asian and six (14.6 %) were of other ethnic origin. In the absolute oral bioavailability part of the second study, eight subjects received avibactam and all completed the study. All were male with a mean (SD) age of 28.9 (8) years, two subjects were Caucasian (25 %), three were Black (37.5 %) and three were of other ethnic origin. 3.2 Safety There were no serious or severe AEs reported in either study and no subjects discontinued due to AEs. In the SAD study, six TEAEs were reported in four subjects (Table 1), of which five (anxiety in one subject in the 250 mg group; abdominal pain and postural dizziness in one subject in the 250 mg group; and sense of oppression and somnolence in one subject in the 500 mg group) were considered by the investigator to be related to the study treatment. The TEAE of orthostatic hypertension (one subject in the 2000 mg group) was considered to be probably unrelated. Five of the six TEAEs were of mild intensity and one was moderate and all resolved without corrective treatment. In the MAD part of the second study, five TEAEs (one during administration of placebo, one during administration of avibactam alone, and three during administration of ceftazidime-avibactam) were reported in five subjects (Table 1) all of which were considered probably not related to the study drug. All AEs resolved spontaneously with the exception of one event of moderate hematoma at the injection site, which was ongoing at the last observation 8 h after the end of the last infusion. There were no TEAEs in the oral bioavailability part of the second study. There were no clinically significant abnormal values reported for any of the ECG, vital signs, hematology, biochemistry and urinalysis parameters in either study. Serum creatinine and hepatic function laboratory values are reported in supplemental Tables 1–3. 3.3 Pharmacokinetics of Avibactam Following Single and Multiple Doses 3.3.1 Study 1: Single Ascending Dose Study After a single-intravenous dose, peak avibactam and ceftazidime concentrations were generally observed at the end of the infusion (at 30 min) (Table 2) followed by a rapid multi-exponential decline (bi- or triphasic) (avibactam, Fig. 1a; ceftazidime, data not shown). Avibactam geometric mean Cmax and AUC increased with increasing avibactam dose (Table 2). Avibactam exposure was approximately dose-proportional (Fig. 2), although this was not formally assessed. The arithmetic mean t was similar
across all doses (Table 2; Fig. 1a). Cmax and AUC of avibactam 250 or 500 mg alone were comparable with those of avibactam 250 or 500 mg co-administered with ceftazidime 1000 or 2000 mg, respectively (Table 2). Avibactam was excreted largely unchanged in the urine. Overall, 80–90 % of the dose was excreted in the first 6 h, with 85–100 % of the parent drug excreted over 48 h in all dose groups (Fig. 3). Ceftazidime was excreted extensively unchanged in the urine (96–108 % after 1000–2000 mg, respectively). 3.3.2 Study 2: Part 1: Assessment of Multiple Ascending Doses Peak avibactam and ceftazidime concentrations were generally observed at the end of the infusion (at 30 min) on Day 1, Day 5 and, in the case of ceftazidime-avibactam, Day 10, followed by a rapid decline at the end of each infusion (Table 3) (Avibactam, Fig. 1b, c; ceftazidime, data not shown). Avibactam plasma concentrations were still measurable in all subjects at the end of the 8 h dosing interval (Fig. 1b, c). Avibactam geometric mean Cmax increased with increasing dose (Table 3). The arithmetic mean t calculated over the dosing interval was comparable between Day 1 and Day 5 (Table 3). In addition, RSS was close to 1 for each dose, indicating that there was no trend for accumulation of avibactam over the 5 days of treatment (Table 3). Inter-individual variability [coefficient of variation (CV) %] of avibactam pharmacokinetic parameters was comparable across all dosing groups on Day 1, with the exception of Cmax in the 500 mg group where inter-individual variability reached 70 % (Table 3). This result could be ascribed to one subject whose individual Cmax value was approximately fourfold greater than the other subjects. When avibactam 500 mg was administered concomitantly with ceftazidime 2000 mg, all ceftazidime pharmacokinetic parameters remained comparable across Days 1, 5 and 10, with the exception of CLR (Table 3). Ceftazidime RSS remained close to 1 throughout, indicating no trend for ceftazidime accumulation. Avibactam geometric mean Cmax and AUClast were lower on Days 1 and 5 in the ceftazidime-avibactam dosing group, and the geometric mean CL was higher, compared with avibactam 500 mg administered alone. However, inter-individual variability of Vss was markedly higher on Days 1 and 5 in the group who received avibactam 500 mg plus ceftazidime 2000 mg (Table 3). On Day 10, the geometric mean RSS of avibactam co-administered with ceftazidime was 0.74 (Table 3) corresponding with a 26 % reduction in overall avibactam exposure when compared with Day 1. Cmax and AUC0–? dose-proportionality were assessed on Day 5 following multiple doses of avibactam 500–1000 mg; however, no formal statistical conclusion
H. Merdjan et al. Table 2 Avibactam and ceftazidime pharmacokinetic parameters following single intravenous infusions (SAD study; n = 8 per group) Avibactam dose (mg)
Ceftazidime dose (mg)
Cmax (mg/L)
tmaxa (h)
AUC0–? (hmg/L)
AUClast (hmg/L)
tb (h)
Vss (L)
CL (L/h)
CLR (L/h)
12.28 (14)
Avibactam data 50
0
2.65 (14)
0.50 (0.50–0.50)
3.66 (11)
3.70 (11)
1.48 (24)
20.96 (16)
13.52 (13)
100
0
4.89 (33)
0.50 (0.50–0.67)
8.15 (20)
8.21 (20)
1.80 (20)
23.58 (26)
12.18 (20)
11.12 (22)
250
0
11.88 (20)
0.50 (0.50–0.67)
19.44 (11)
19.54 (11)
1.70 (11)
22.81 (12)
12.80 (11)
15.68 (16)
250
1000
12.93 (29)
0.50 (0.50–0.67)
20.66 (15)
20.78 (15)
1.79 (10)
21.08 (32)
12.03 (18)
11.90 (31)
500
0
26.15 (58)
0.50 (0.50–0.67)
37.13 (27)
37.34 (27)
1.83 (13)
22.72 (37)
13.39 (25)
12.68 (27)
500 1000
2000 0
23.33 (26) 48.48 (22)
0.50 (0.50–0.67) 0.50 (0.50–1.00)
37.15 (22) 85.75 (16)
37.41 (22) 85.96 (16)
2.16 (53) 2.18 (28)
25.43 (26) 21.99 (12)
13.36 (19) 11.63 (17)
12.71 (22) 11.22 (18)
1500
0
99.06 (21)
0.50 (0.50–0.67)
145.10 (10)
145.18 (10)
2.65 (6)
19.39 (14)
10.33 (10)
8.53 (21)
2000
0
120.30 (23)
0.50 (0.50–1.00)
183.47 (15)
183.59 (15)
2.71 (5)
20.82 (20)
10.89 (14)
10.57 (21)
250
1000
57.35 (24)
0.50 (0.50–0.67)
128.26 (15)
129.28 (15)
1.82 (26)
18.88 (23)
7.74 (18)
6.63 (20)
500
2000
93.17 (31)
0.50 (0.50–1.00)
195.94 (25)
198.59 (26)
3.07 (66)
28.23 (33)
10.07 (23)
9.70 (26)
Ceftazidime data
Unless otherwise stated values are geometric mean (CV%) AUC area under the plasma concentration-time curve, AUClast AUC from time zero to time of last measurable plasma concentration, AUC0–? AUC on Day 1 from time zero to infinity, CL plasma clearance, CLR renal clearance, Cmax maximum observed plasma concentration, CV% coefficient of variation (%), SAD single ascending dose, SD standard deviation, t terminal half-life, tmax time to maximum plasma concentration, Vss apparent volume of distribution at steady state a
Median (range)
b
Arithmetic mean (SD)
could be drawn. CLR estimates shown in Table 3 should be interpreted with caution due to individual inconsistencies in avibactam excretion results including the amount excreted greater than 100 % or close to 0, very low clearance, and a quantifiable amount of avibactam recorded for a subject who received placebo. 3.3.3 Study 2: Part 2: Assessment of Oral Bioavailability Mean (CV%) avibactam Cmax after oral dosing [0.63 mg/L (33 %)] was 2.18 % of the value reported after intravenous infusion [28.86 mg/L (27 %)], and the avibactam AUClast after oral dosing was 6.20 % of the value reported after intravenous infusion. Absolute bioavailability after oral dosing [arithmetic mean (range)] was 6.85 % (4.48–11.65 %), and avibactam Cmax after oral dosing was observed between 30 min and 4 h post-dose with MAT estimated as 4.53 h, compared with a Cmax at 30 min postintravenous infusion. Inter-individual variability was comparable between intravenous and oral dosing in the region of 30 % (Fig. 4).
4 Discussion Avibactam administered alone or in combination with ceftazidime was generally well tolerated at doses ranging from 50 to 2000 mg administered as a single intravenous
infusion or as multiple intravenous infusions over 5–10 days. No serious or severe AEs were reported in either study. Six AEs were reported in four subjects in the 250 mg to 2000 mg dose groups in the SAD study (n = 70), of which five (abdominal pain, sense of oppression, somnolence, anxiety and postural dizziness) were considered by the investigator to be related to the study drug. These TEAEs were considered mild or moderate in intensity and recovered without corrective treatment and are not TEAEs that were observed during the MAD study reported here, or in subsequent phase I studies of avibactam [22–24]. In larger cohorts of patients in phase II trials, abdominal pain, anxiety and dizziness have been observed in [5 % of patients receiving avibactam in combination with ceftazidime, although these TEAEs were also observed in patients receiving the comparator agents in both these studies [25, 26]. In both parts of the second study (n = 49), no AEs considered related to the study drug were reported. ECG and vital sign parameters remained within the normal ranges in both studies across all tested doses, and no clinically significant changes in biochemistry, hematology and urinalysis parameters were observed. In both the SAD and MAD assessments, avibactam exposure generally increased proportionally to dose, and mean avibactam t was similar across all doses. The peak concentration after a single intravenous dose of either ceftazidime or avibactam in the SAD study was followed by a rapid, multi-exponential decline, indicative of tissue
Safety and Pharmacokinetics of Avibactam
Fig. 1 Plasma concentration-time profile of avibactam during (a) the single ascending dose study, (b) Day 1 of the multiple ascending dose (MAD) part of the second study and (c) Day 5 of the MAD part of the
second study. Arrows denote time of injection. Inset graphs show semi-log scale. tid, three times daily
binding and distribution in more than one compartment. In the MAD part of the second study the ratios for accumulation of avibactam (RSS) on Day 5 versus Day 1 were close to 1 across all dosing groups, indicating that there was no trend for accumulation and that steady-state had been achieved. In the present study, when administered as multipledoses of avibactam 500 mg plus ceftazidime 2000 mg, there was a decrease in avibactam exposure on Day 10 compared with Day 1. The reasons for this cannot be determined based on the design of the current study; however, in a later study where 500 mg avibactam was dosed in combination with 2000 mg ceftazidime three times daily
for 10 days, no such reduction in avibactam exposure at Day 10 was observed [22]. Based on the results of this study, it is not thought that avibactam pharmacokinetics are affected by concomitant use of ceftazidime as seen by the similarity of pharmacokinetic parameters when avibactam is administered alone (500 mg) or concomitant with ceftazidime (2000 mg) as a single dose. Ceftazidime data were also comparable to those observed previously in the literature, indicating that avibactam does not affect the pharmacokinetic or safety profile of ceftazidime [27, 28]. These data are in agreement with previous studies regarding the low propensity for ceftazidime to interact with other drugs [28] and are
H. Merdjan et al.
Fig. 2 Dose-proportionality of avibactam during the single ascending dose study (a) maximum plasma concentration (Cmax) (R2 = 0.8911) and (b) area under the plasma concentration versus time curve from
time zero to infinity (AUC0–?) (R2 = 0.9607) within the avibactam dose-range 500–2000 mg
Fig. 3 Mean cumulated amount of avibactam excreted in urine during the SAD study, as percentage of the dose
consistent with other reports showing that after 10 days of multiple dosing with avibactam 500 mg alone or ceftazidime-avibactam 2000–500 mg, there is no drug–drug interaction between ceftazidime and avibactam [22, 23]. Due to aberrant data in the MAD part of the second study, no conclusion could be drawn on urine excretion. However, in the SAD study, avibactam was largely excreted in the urine, with 80–90 % of the dose recovered as unchanged avibactam in the first 6 h. These results indicate that almost the entire avibactam dose is eliminated via the kidneys as the parent drug and is in agreement with subsequent studies that have been completed [29, 30]. Furthermore, it is known that avibactam clearance is reduced in patients with renal impairment, to a similar extent to that seen with ceftazidime [31, 32]. Population modeling has been completed using data from ceftazidime-avibactam phase I and II clinical trials, including the two trials reported here [33, 34]. Creatinine clearance was identified as the primary covariate that impacted on the clearance of both avibactam and ceftazidime, whereby drug clearance decreased with decreasing creatinine clearance [33]. The findings suggest that the magnitude of the avibactam dose
and the frequency of dosing in patients with renal impairment can follow the approved dosing regimen for ceftazidime [35]. The preliminary assessment of oral administration of 500 mg avibactam demonstrated a 93.8 % decrease in avibactam exposure (AUClast) after oral dosing compared with after intravenous dosing with absolute bioavailability being measured at approximately 7 %. Thus, there are no plans for avibactam to be administered orally in clinical practice at present. The pharmacokinetic and safety findings following intravenous infusion of avibactam in these preliminary studies have led to its investigation in phase II studies evaluating the efficacy and safety of ceftazidime-avibactam in patients with complicated urinary tract infections (NCT00690378) [26] and, concomitantly with metronidazole, in patients with complicated intra-abdominal infections (NCT00752219) [25]. Phase III trials evaluating ceftazidime 2000 mg in combination with avibactam 500 mg are now completed or in progress (NCT01499290, NCT01500239, NCT01595438, NCT01599806, NCT017 26023 and NCT01808092).
0
1000
500
500
2000
2000 114.53 (28)
22.11 (15)
124.07 (26)
50.90 (41)
44.45 (26)
26.48 (32)
36.33 (111)
127.98 (44)
57.48 (20)
40.78 (36)
29.74 (42)
37.29 (70)
Cmax (mg/L)
0.50 (0.25–0.75)
0.50 (0.25–0.75)
0.50 (0.50–0.75)
0.50 (0.50–0.75)
0.50 (0.50–4.00)
0.50 (0.50–0.75)
0.50 (0.50–0.75)
0.50 (0.25–0.50)
0.50 (0.50–0.50)
0.50 (0.50–0.75)
0.50 (0.50–1.50)
0.50 (0.50–0.50)
tmaxa (h)
245.57 (23)
35.89 (14)
251.47 (31)
82.08 (21)
68.13 (23)
43.12 (24)
50.63 (32)
252.62 (34)
81.22 (23)
60.48 (18)
47.32 (29)
52.18 (28)
AUClast (hmg/L)
–
–
–
–
–
–
–
265.67 (32)
82.76 (23)
61.48 (18)
48.49 (29)
53.12 (28)
AUC0–? (hmg/L)
1.91 (0.37)
1.50 (0.31)
1.98 (0.51)
1.47 (0.09)
1.38 (0.31)
1.59 (0.54)
1.67 (0.18)
1.76 (0.57)
1.38 (0.20)
1.37 (0.11)
1.49 (0.25)
1.44 (0.13)
tb (h)
19.98 (25)
24.22 (19)
20.40 (57)
20.90 (32)
19.16 (19)
20.53 (73)
16.61 (28)
17.98 (78)
20.11 (38)
19.99 (23)
17.99 (97)
15.24 (24)
Vss (L)
8.14 (27)
13.93 (16)
7.95 (40)
12.18 (19)
11.01 (21)
11.60 (37)
9.88 (21)
7.53 (45)
12.08 (23)
12.20 (18)
10.31 (57)
9.41 (19)
CL (L/h)
3.21 (82)
4.69 (83)
7.84 (101)
5.91 (33)
1.91 (85)
9.09 (91)
4.49 (52)
13.62 (111)
6.46 (23)
4.26 (51)
7.71 (62)
6.07 (29)
CLR (L/h)
4527 (35)
252.3 (31)
4206 (33)
801.9 (26)
598.4 (39)
390.54 (20)
513.8 (56)
–
–
–
–
–
Ctrough (ng/mL)
0.92 (65)
0.74 (64)
0.95 (17)
0.99 (13)
1.11 (23)
0.89 (15)
0.95 (6)
–
–
–
–
–
RSS
b
a
Arithmetic mean (SD)
Median (range)
AUC area under the plasma concentration-time curve, AUClast AUC from time zero to time of last measurable plasma concentration, AUC0–? AUC on Day 1 from time zero to infinity, CL plasma clearance, CLR renal clearance, Cmax maximum observed plasma concentration, Ctrough observed pre-dose plasma concentration, CV% coefficient of variation (%), MAD multiple ascending dose, RSS, accumulation ratio, SD, standard deviation, t terminal half-life, tmax time to maximum plasma concentration, Vss apparent volume of distribution at steady state
Unless otherwise stated values are geometric mean (CV%)
500
Ceftazidime data
500
Avibactam data
Day 10
2000
0
1000
Ceftazidime data
0
750
0
2000
500
Avibactam data 500
Day 5
2000
0
750
Ceftazidime data
0
2000
500
Ceftazidime dose (mg)
500
Avibactam data
Day 1
Avibactam dose (mg)
Table 3 Avibactam and ceftazidime pharmacokinetic parameters following multiple (three times daily) intravenous infusions on Days 1, 5 and 10 (MAD study; n = 8 per group)
Safety and Pharmacokinetics of Avibactam
H. Merdjan et al. Conflict of interest Antoine Tarral, Henri Merdjan and Manickam Rangaraju were employees of Novexel SA at the time of conduct of the studies.
References
Fig. 4 Plasma concentration-time profiles of avibactam 500 mg after single intravenous or oral administration during the absolute oral bioavailability part of the second study. Semi-log scale inset
5 Conclusion The studies presented here have shown that, in healthy subjects, avibactam 500 mg administered in the presence or absence of ceftazidime 2000 mg was generally well tolerated when given either as a single intravenous infusion, as multiple intravenous infusions, or when given orally. Ceftazidime and avibactam did not affect one another’s pharmacokinetics and there was no observed drug– drug interaction between the two agents. Avibactam concentration peaked at the end of intravenous infusion and avibactam pharmacokinetics were approximately dose proportional. There was no trend for accumulation when subjects were administered multiple doses. Oral dosing of avibactam resulted in absolute bioavailability of approximately 7 % demonstrating that it is not an effective dosing method for avibactam in its current formulation. These results contribute to a growing body of evidence supporting the intravenous dosing regimen currently being evaluated in phase III clinical trials of ceftazidimeavibactam. Acknowledgments The authors wish to thank Peter J Laud contracted to AstraZeneca from the Statistical Services Unit, Sheffield, for his expert review of the manuscript. These studies have been presented in part at the Interscience Conference on Antimicrobial Agents and Chemotherapy in 2007, and were funded by Novexel. Ceftazidime-avibactam is now being developed by AstraZeneca and Forest Laboratories Inc. a subsidiary of Actavis plc. Medical writing support was provided by Catherine Savage and Rob Campbell of Prime Medica Ltd, Knutsford, Cheshire, UK, funded by AstraZeneca. The design and conduct of the study, as well as analysis of the study data and opinions, conclusions, and interpretation of the data, are the responsibility of the authors.
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Safety and Pharmacokinetics of Avibactam
17.
18.
19.
20.
21.
22.
23.
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