Pharmacology Chemotherapy 1991;37:389-397
© 1991 S. Kargor AG. Basel 0009-3157/91/0376-0389 S 2.75/0
Pharmacokinetics of Rufloxacin in Healthy Volunteers after Repeated Oral Doses R. Mattinaa, G. Bonfiglioa, C.E. Cocuzzcv', G. Gulisanob, M. Cesanac, B.P. Imbimboc 0 Institute of Medical Microbiology. University of Milan; h Institute of Subtropical Diseases. University of Catania; c Medical Department. Mediolanum Farmaccutici, Milan, Italy
Abstract. Rufloxacin is a new broad-spectrum fluoroquinolone antibacterial agent. The pharmacokinetics and safety of rufloxacin were evaluated after repeated oral ad ministration to healthy volunteers. The drug was administered once a day for 6 consec utive days following two different dose schedules. The first group of 11 subjects was giv en a loading dose of 300 mg on the first day and 150 mg on the subsequent 5 days. The second group of 12 subjects was given a loading dose of 400 mg and 200 mg for 5 days. Serum levels and urine concentrations of rufloxacin were determined by microbiological assay. A simultaneous fit of all data points for each subject was done according to a onecompartmcnt open model. The drug was rapidly absorbed (absorption half-life 17±6 min in the 300+150 mg and 11 ±5 min in the 400 + 200 mg dose regimen group) and reached maximal serum concentrations (2.77±0.24 and 3.62±0.35 ug/ml) 4.2 + 0.4 and 4.0±0.9 h after the first administration. Steady-state serum concentrations (3.19±0.31 and 4.06 + 0.33 pg/ml) were reached in 3.7 + 0.7 and 4.5 ±0.4 days. Elimination half-lives were 29.5 + 2.4 and 36.0 + 2.8 h. Apparent volumes of distribution were 111 + 8 and 136 + 16 liters and apparent plasma clearances were 46 + 5 and 44 + 4 ml/min. Renal clearances were 18 + 3 and 17 + 2 ml/min. The percentage of the total dose excreted in urine throughout the study was 36.1+4.0% in the 300 + 150 mg and 43.7 + 2.5% in the 400 + 200 mg dose schedule group. Mean extents of accumulation were 2.4 ±0.2 and 2.5 ±0.1. Treatments were well tolerated, with only minor side effects (nausea, insomnia and postprandial vomiting) in 3 subjects and with no abnormalities being noted in rou tine laboratory examinations. Two and 3 days after the last administration, measurable antimicrobial activity was still observed in plasma and urine, indicating that the long half-life of rufloxacin assures valuable antibacterial coverage even after discontinuation of treatment.
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Key Words. Rufloxacin • Pharmacokinetics • Once-a-day administration • Repeated doses
Mattina/Bonfiglio/Cocuzza/Gulisano/Cesana/Imbimbo
Introduction
Rufloxacin, a new quinolone carboxylic acid derivative [1] (fig. 1), is highly active in vitro and in vivo against a broad spec trum of gram-negative and gram-positive organisms, including those resistant to [(-lactam antibiotics [2, 3]. In animals (rats, dogs and monkeys), the drug is well ab sorbed after oral administration, with an absolute bioavailability of about 60%, is distributed extensively in tissues, with high tissue-plasma ratios, has a long half-life of 12-24 h and about 30-40% is excreted in urine [4], Previous studies have shown that single oral doses up to 400 mg are well tol erated in healthy volunteers [5]. A single dose pharmacokinetic study in normal vol unteers showed that an oral dose of 400 mg rufloxacin was eliminated slowly, with a plasma half-life of 31-39 h [61. The study described here was designed to evaluate the pharmacokinetics and safety of multiple oral doses of rufloxacin. The results of this study should lead to the formulation of appropriate dosage re gimens for the treatment of infectious dis eases caused by rufloxacin-susceptible or ganisms.
Materials and Methods Study Design Twenty-three male subjects were randomly di vided into two groups. In the first group, 11 subjects were given a single loading dose of 300 mg (two cap sules of 150 mg) on the first day and single doses of 150 mg (one capsule) on the subsequent 5 days (300 + 150 mg dose schedule). In the second group. 12 subjects were given a single loading dose of 400 mg (two capsules of 200 mg) on the first day and sin gle doses of 200 mg (one capsule) on the subsequent 5 days (400 + 200 mg dose schedule). Each dose was
taken in the morning, after an overnight fast, with about 1«) ml of tap water. Fasting was continued for 4 It after administration of the drug. During the study, all the subjects were evaluated on an outpa tient basis either at the Department of Subtropical Diseases of the University of Catania or at the 2nd Division of Infectious Diseases of the Garibaldi Hospital in Catania. Italy. Subjects The II male subjects of the 300+150 mg dose schedule group were between 21 and 52 years of age (mean 35.0 years) and weighed between 62 and 77 kg (mean 68.9 kg); their heights ranged from 164 to 174 cm (mean 168 cm). The 12 male subjects of the 400 + 200 mg dose schedule group were between 22 and 60 years of age (mean 34.8 years) and weighed between 53 and 82 kg (mean 68.5 kg); their heights ranged from 162 to 184 cm (mean 172 cm). All sub jects were judged to be in good health as deter mined by physical examination, electrocardiogram, full blood count, coagulation tests, serum chemistry profiles (fasting blood glucose, urea nitrogen, sodi um. potassium, chloride, serum creatinine, uric acid, calcium, inorganic phosphorus, cholesterol, total protein, albumin, total bilirubin, serum aspartate aminotransferase, scrum alanine aminotransferase) and urinalysis. None of the subjects had a history of serious systemic illness, drug or alcohol abuse, or hypersensitivity to any food or drug. All subjects gave written informed consent before entering the study. The study was conducted according to the principles of the Declaration of Helsinki and was approved by the Hospital's Ethical Committee. SafeI)’ Evaluation Blood pressure and heart rate were measured at regular intervals. Tests of hematology, blood chem istry and urinalysis were conducted before the study and on days I. 3 and 6. The subjects were closely checked every day for any reactions. Sampling o f Mood and Urine Blood samples (6 ml) used for rufloxacin assay were collected via an indwelling venous catheter from a forearm vein just prior to the morning dose and 2, 4. 8. 12 and 24 h after the dose on day 1 and just before and 4 h after the morning dose on days 2-5. On day 6. blood samples for rufloxacin concen tration were obtained immediately before the last
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39«
391
Pharmacokinetics of Rufloxacin
o
morning dose and 2, 4, 8, 12, 24, 48 and 72 hours af ter. Serum was prepared from each sample for sub sequent assay. Urine was collected at intervals of 0-4, 4-8. 8-12 and 12-24 It on days 1-6. Additional urine fractions were collected 24-48, 48-72. 72-96 and 96-120 h after the last dose. Each sample was shaken, and after measurement of the volume, a 10ml aliquot was removed and frozen for later analy sis.
Pharmacokinetic Analysis Since analysis of individual serum concentration versus time courses revealed no significant differ ences between single and repeated doses, pharma cokinetic parameters were estimated with simulta neous fitting of all data points for each subject ac cording to a one-compartment open model with first-order input [8]. The one-compartment model was selected using Akaike's information criterion [9|, the Schwartz test [10] and the Ip index [11]. Nonlinear-regression analysis was performed with the program TOPF1T. The lag time (tlag) was calculated from the computer fitting. The area under the sc rum concentration versus time curve from zero to infinity (AUC,,^) was calculated as C „ A “ C(o,/k.,, in which C(m is the coefficient and k,, and kc are the exponents of the fitted biexponential equation. The absorption half-life (t,„:l) was calculated as ln(2)/ka and the elimination half-life (t,„) as ln(2)/kc. The mean residence time (MRT) was calculated as (C(ll)/k; - C(l,/k*/(C(l))/kc - C(1))/k;l). The apparent
•HCI
Fig. 1. Chemical structure of rufloxacin. volume of distribution (V/F) was calculated as dose/ kc'A U C (^ , and the apparent total body clearcnce (CL/F) as dosc/AUC,^. The maximum drug con centration after the first administration (Cmax) and the time to reach it (tmax) were obtained from the in dividual data. The steady-state drug concentration (Cmaxss) and the corresponding time to reach it (tmaxss) were obtained from derivatives of the fitted equation. The areas under the serum concentrationtime curve from 0 to 24 h after the first (AUC„_24lsl) and the last administration (AUCm246lh) were calcu lated by the linear trapezoidal rule. The renal clear ance (CLk) was calculated by dividing the amount of drug excreted in urine in the 0-24 h after the first administration by the AUC„_241s,. The renal clear ance at the steady state (CLRss) was calculated by dividing the amount of the drug excreted in urine in the 0-24 h after the last dose by the AUC((_24(llh. The percent of the drug excreted in urine (fc) was calcu lated by dividing the total amount excreted in urine up to 72 h after the last administration by the total amount of drug administered during treatment. The extent of accumulation ratio (R) was calculated by dividing AUCl(_24(lth by AUC„_,4I„ after correction for the dose [12]. Standard pharmacokinetic symbols were adopted [13]. Results are expressed as mean ± SEM.
Results
One subject in the 400 + 200 mg dose schedule (No. 19) dropped out after 3 days of treatment for personal reasons not re lated to the drug. Since serum concentra tion data were available for up to the third day of treatment and urinary excretion da-
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Assays Concentrations of rufloxacin in scrum and urine were determined by microbiological assay with Escherichia coli Kp 05124 as the test organism [7]. The medium used was antibiotic medium No. 1 at pH 7.0 (Difco Laboratories, Detroit, Mich., USA). Standards were prepared with pooled normal hu man serum for scrum sample and with phosphate buffer (pH 7.2) for urine samples. The plates were incubated overnight at 37°C. The standards, con trols and samples were run in quadruplicate. The linear-regression analysis of the standard calibra tion lines obtained by plotting the log antibiotic con centrations versus the zone diameters of inhibition indicated excellent linearity of the assay between 1.56 and 12.5 gg/ml. The sensitivity limit of the assay was 0.78 ng/ml. The coefficients of variation of the assay were 6% at 3.12 pg/ml and 9% at 0.78 ug/ml.
COOH
392
Mattina/Bonfiglio/Cocuzza/Gulisano/Ccsana/lmhimbo
5-1
ta for 2 days for this subject, he was in cluded in the pharmacokinetic analysis, and when possible, pharmacokinetic pa rameters were calculated. The urines of subject No. 23 in the 400 + 200 mg dose schedule group went missing, and hence the pharmacokinetic parameters for renal excretion of rufloxacin were not available for this subject. Concentrations o f Rufloxacin in Scrum The mean serum concentrations of ru floxacin during and after the 300 + 150 mg and the 400 + 200 mg dose schedules are shown in figure 2. After the first admin
istration, Cmax (2.77 ±0.24 pg/ml in the 300 + 150 mg group and 3.62 ± 0.35 pg/ml in the 400 + 200 mg group) was reached gen erally after 2-4 h (tmax 4.2 ±0.4 and 4.0 ±0.9 h). After repeated administration, Cmaxss increased to 3.19 ±0.31 and 4.06±0.33 pg/ml in the two groups and were reached in 3.7 ±0.7 days in the 300 +150 mg group and 4.1 ± 0.3 days in the 400 + 200 mg group. AU(V 24 increased with time after the first (46.3 ±4.0 and 58.5 ±4.4 ug-h/ml) and the last adminis tration (56.4 ±7.0 and 71.4 ±5.3 pg’h/ml). The extent of accumulation was 2.4 ±0.2 for the 300 + 150 mg dose schedule and
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Fig. 2. Mean (±SEM ) serum concentrations of rufloxacin during two different repeated oral schedules, the first with a single oral loading dose of 300 mg followed by single oral daily doses of 150 mg for 5 days ( • ) and the second with a single oral loading dose of 400 mg followed by single oral daily doses of 200 mg for 5 days (O). Arrows indicate drug administrations.
Pharmacokinetics of Rufloxacin
393
Subject No.
tlag, min tl/ja. min tmax» h Cmax, pg/ml ‘max.»- dayS Cmax.xx- dg/ml V, h MRT, h V/F. liters CL/F, ml/min CLr , ml/min CL r ,,, ml/min AUC(WJ. |sl, ug-h/ml AUC(|_,4 61h, ug-h/ml A U C,^, ug-h/ml R fc,%
Mean
SLM
1
2
3
4
5
6
7
8
9
10
11
2 38 4 1.82 3.1 1.85 26.8 39.5 162 70 33 54
58 30 8 4.27 5.1 5.51 39.7 57.9 73 21 7 7
0 65 4 3.18 0.2 3.25 18.6 28.5 77 48 10 16
105 5 4 2.83 5.1 3.25 29.2 42.2 104 41 21 10
105 7 4 2.11 5.1 2.79 27.6 40.0 116 49 36 37
103 5 4 2.90 4.1 2.77 24.3 35.1 107 51 29 15
108 7 2 2.19 0.1 2.39 23.5 34.1 122 60 13 11
104 6 4 1.85 5.1 2.92 41.3 59.8 146 41 14 17
89 6 4 3.95 5.1 4.42 32.9 47.6 83 29 13 7
77 23 4 2.86 5.1 3.51 39.5 57.5 116 34 7 II
107 3 4 2.54 0.1 2.47 21.5 31.1 119 64 14 20
78 17 4.2 2.77 3.7 3.19 29.5 43.0 111 46 18 19
13 6 0.4 0.24 0.7 0.31 2.4 3.4 8 5 3 4
30.2
63.8
63.0
38.2
40.9
42.3
37.1
34.1
68.5
52.0
38.8
46.3
4.0
32.0
108.4 44.3
60.2
45.8
42.7
39.5
54.1
86.4
68.7
38.6
56.4
7.0
71.5 2.1 57.3
234.6 104.2 121.5 102.8 97.8 3.4 1.4 3.2 2.2 2.0 28.8 32.6 30.0 66.9 30.7
83.2 2.1 25.9
122.2 172.0 147.9 77.9 3.2 2.5 2.6 2.0 34.2 35.6 30.6 24.6
121.4 2.4 36.1
14.5 0.2 4.0
2.5 ±0.1 for the 400 + 200 mg dose schedule. The pharmacokinetic parameters de rived from a one-compartmcnt model fit ting of scrum rufloxacin concentrations are shown in tables 1 and 2. The pharma cokinetic analysis shows that the drug, after a delay (t!ag) of 78 ±13 min in the 300 + 150 mg and 45 ±16 min in the 400 + 200 mg dose schedule group, was rapidly absorbed, with ty,a of 17 ±6 and
min for the two groups. This initial delay is probably due to dissolution and gastric emptying of the pharmaceutical formula tion. After absorption, the drug was exten sively distributed in the tissues, with V/F of 1U±8 and 136±16 liters for the 300 + 150 mg and the 400 + 200 mg dose schedules, respectively. The drug re mained in the body for a long time (MRT of 43 ±3 and 52 ±4 h) and was cleared slowly from the plasma (CL/F of 46 ±5
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Table 1. Individual pharmacokinetic parameters of rufloxac in for subjects on the 300 + 150 mg dose schedule
394
Mattina/Bonfiglio/Cocuzza/Gulisano/Ccsana/Imhimbo
Tabic 2. Individual pharmacokinetic parameters of rufloxacin for subjects on the 400 + 200 mg dose schedule Subject No.
hag- min t,„a, min *max> h Cma,. Hg/ml tmax,». days ^max. ss’ 1 t./,, h MRT. h V/F, liters CL/F. ml/min CLr , ml/min CLr jj, ml/min
12
13
14
15
16
17
18
19
2 3 2 3.64 5.0 4.80 54.5 78.6 141 30 10 8
0 47 4 2.86 5.1 3.29 29.4 43.5 129 51 14 18
118 5 12 1.91 5.1 2.27 49.2 71.0 280 66 29 25
1 3 2 5.40 1.0 5.40 23.8 34.3 73 36 18 14
0 4 2 5.39 5.0 5.74 24.8 35.9 70 33 12 26
0 4 2 3.15 5.0 3.57 28.8 41.6 126 50 15 25
115 5 4 2.70 5.1 3.62 39.5 57.2 153 45 18 25
61.0
55.9
31.9
84.8
85.7
55.8
54.4
93.0
64.0
48.6
83.3
94.7
60.8
66.0
20
Mean
SEM
21
22
23
0 89 4 47 2 8 3.95 5.43 2.0 5.2 5.28 4.57 44.6 34.7 64.4 51.2 99 105 26 35 8 17 25
0 4 2 3.07 5.0 2.98 35.6 51.4 173 56 17 31
108 6 4 2.42 5.1 2.64 28.5 41.3 167 68 28 23
104 5 4 3.48 5.1 4.56 38.4 55.5 119 36
45 11 4.0 3.62 4.5 4.06 36.0 52.2 136 44 17 20
16 5 0.9 0.35 0.4 0.33 2.8 4.0 16 4 2 3
69.8
61.6
48.6
42.2
59.7
58.5
4.4
82.8
51.5
50.4
89.3
71.4
5.3
A U C ()_24 ]st,
pg-h/ml A U C (1_24, 6ih>
pg-h/ml A U C W
222.4 131.2 101.3 188.0 203.3 132.3 149.3 259.4 190.3 173.4 98.1 3.0 3.0 2.4 2.7 2.4 2.3 2.0 2.2 2.2 2.1 33.9 47.8 35.7 45.4 48.2 29.0 47.1 51.2 53.6 45.0
185.9 169.6 3.0 2.5 43.7 -
14.1 0 .1
2.5
and 44 ±4 ml/min). Plasma half-life was istration. Four days after the last adminis 39.5 ± 2.4 h for the 300 +150 mg group and tration, rufloxacin was still clearly detect 36.0 ±2.8 h for the 400 + 200 mg group. able in urine (10.7 ±2.9 pg/ml in the 300 + 150 mg dose schedule group and 32.7 Concentrations o f Rufloxacin in Urine pg/ml in the 400 + 200 mg dose schedule Mean concentrations of rufloxacin in group). CLr were 18 ±3 ml/min for the urine collected 0-4 h after the last dose 300 + 150 mg group and 17 ±2 ml/min for were 46.3 ±4.6 pg/ml in the 300 + 150 mg the 400 + 200 mg group, these values being dose group and 85.4 ±8.3 pg/ml in the 39.1 and 38.6% of the CL/F. CLR calculat 400 + 200 mg dose group (tables 3, 4); the ed at the steady state (CLRss) remained corresponding concentrations at 12-24 h unchanged for both groups (19 ±4 and were 34.3 ±3.8 and 72.7 ±10.7 pg/ml and 20±3 ml/min). fe was 36.1 ±4.0% for the remained at 25.6 ±3.8 and 48.9 ±9.4 ,ug/ml 300 + 150 mg dose group and 43.7 ±2.5% values in the 48-72 h after the last admin for the 400 + 200 mg group.
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pg-h/ml R fc, %
Pharmacokinetics of Rufloxacin
395 Table 4. Mean (±SEM ) urinary rufloxacin excre tions (mg) on the two different dose schedules
300+150 mg
400 + 2(H) mg
Hour interval
400 + 200 mg
Hour interval
Day of treatment
300+150 mg
Day of treatment 1
0-4 4-8 8-12 12-24
38.6 ±7.2 43.2 ±4.2 45.0 ±6.0 36.4 ±6.5
40.9 ±7.9 54.8 ±7.7 44.8 ±4.1 45.5 ±7.4
1 2 3 4 5 6
2
0-4 4-8 8-12 12-24
47.7 ±10.6 48.8 ±4.8 43.1 ±5.4 41.3 ±6.0
73.0 ±22.1 89.5 ±13.7 79.7 ±12.0 81.0 ± 14.8
0-24 0-24 0-24 0-24 0-24 0-24 24-48 48-72 72-96 96-120
45.6 ± 6.5 42.8 ±4.7 55.9 ±6.8 47.3 ±5.0 43.2 ±4.4 52.8 ±7.8 30.8 ±5.0 31.9 ±7.7 18.8 ±3.6 10.1 ±2.8
56.1 ±4.8 80.1 ±7.6 87.2 ±15.8 21.7 ±25.0 87.4 ±9.3 88.8 ±9.6 67.8 ±11.5 53.2 ±6.4 38.4 ±6.2 37.0 ±5.1
3
0-4 4-8 8-12 12-24
48.7 ±4.7 46.6 ±5.1 44.3 ±4.5 41.2 ±3.9
84.8 ±13.9 75.1 ±14.2 81.6 ±19.2 69.0 ±9.4
4
0-4 4-8 8-12 12-24
43.6 ±4.2 40.8 ±4.7 38.2 ±3.0 32.3 ±4.2
113.8 ±16.3 86.4 ±17.7 83.6 ±18.1 62.2 ±8.9
5
0-4 4-8 8-12 12-24
30.6 ±5.0 46.1 ±4.1 41.9 ±4.6 34.9 ±4.3
74.7 ±9.5 95.0 ±13.5 82.7 ± 11.6 86.7 ±10.6
6
0-4 4-8 8-12 12-24 24-48 48-72 72-96 96-120
46.3 ±4.6 48.8 ±5.4 39.5 ±5.2 34.3 ±3.8 24.9 ±4.0 25.6 ±3.8 19.0 ±3.8 10.7 ±2.9
85.4 ±8.3 69.9 ±8.6 75.0 ±12.7 72.7 ±10.7 60.9 ±12.7 48.9 ±9.4 34.1 ±4.6 32.7 ±5.9
Side Effects Rufloxacin was well tolerated at both dose schedules. No clinically significant changes were observed in any of the phys ical or laboratory tests. One subject
(No. 5) in the 300 + 150 mg group had mild nausea on the third day of treatment that disappeared 4 h after the administration of the drug. In the 400 + 200 mg dose schedule group, 1 subject (No. 13) com plained of mild insomnia during the sec ond day of treatment which had disap peared by the third night. Another subject in the same group (No. 18) had nausea on the third day and postprandial vomiting on the fourth day of treatment.
Discussion
This is the first report on the safety and pharmacokinetics of rufloxacin after mul tiple oral doses, and it has shown that the drug is well tolerated at loading doses of 300 or 400 mg once daily followed by sin gle daily doses of 150 or 200 mg, respec tively, for 5 days. In order to overcome bias from sepa rate estimations of pharmacokinetic pa rameters, a simultaneous fit of all data
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Tabic 3. Mean (±SEM ) urinary rufloxacin con centrations (ug/ml) for the two different dose sched ules
points for each subject was done based on a one-compartment open model with firstorder input. The simultaneous fit used 20 data points and yielded a robust (16 de grees of freedom) estimate of the pharma cokinetic parameters. The disposition of rufloxacin was described by a onc-compartment model also after single oral ad ministration [6]. In this study microbiological assays were used instead of high-performance liquid chromatography determinations to efficiently compare the concentrations reached by the drug in serum and urine with the in vitro minimum inhibitory con centrations (MICs) of the drug against the susceptible microorganisms. The dosage regimens adopted in this study are relatively close and were select ed in an attempt to attain a scrum concen tration higher than 2 pg/ml, a value equal to the MIC for most of the susceptible bacteria [2, 3], However, doses higher than 400 mg were not used because it was found that they were not well tolerated after sin gle administration [5]. The loading dose in the two schedules was double the mainte nance dose and was chosen in order to reach the steady state more rapidly. The steady state was in fact reached in a rela tively short period of time (about 4 days) in spite of the long half-life of the drug. Calculated steady state peak concentra tions in serum after the 400 + 200 mg dose schedule were 4.06 ±0.33 pg/ml, approxi mately twice the MICs for most suscep tible organisms. Concentrations greater than 2 pg/ml were detected in serum at least 24 h after the last administration by this dose schedule. The most important aspect of the pharmacokinetic profile of rufloxacin af
Mattina/Bonfiglio/Cocuzza/Gulisano/Cesana/Imbimbo
ter repeated oral doses is its long serum half-life (30-35 h). The long t/; could be linked to the low free fraction of the drug in tissue [14], The large V/F of rufloxacin (about 120 liters) may be due to the extensive distri bution of the drug in tissue and/or to the high protein binding of the drug in plasma [about 80%, Segre, pers. commun.]. Rufloxacin concentrations in urine 0-4 h after the last dose were 46.3 ±4.6 pg/ ml for the 300 + 150 mg and 85.4 ±9.3 pg/ ml for the 400 + 200 mg dose schedule group, a much higher level than the MICs for most organisms responsible for urinary tract infections. At 12-24 h after the last administration, levels in urine were 34.3 ±3.8 and 72.7 ±10.7 ug/ml in the two groups. Even 3 days after the last dose, the concentrations of rufloxacin in urine re mained much higher than the MICs (25.6±3.8 ug/ml in the 300± 150 mg and 48.9 ±9.4 pg/ml in the 400 + 200 mg dose schedule group). The CLr of about 18 ml/min is lower than the glomerular filtration rate report ed for humans and indicates that some of the drug undergoes renal tubular reab sorption. The CLU represents about 39% of the CL/F of rufloxacin in both groups, indicating that a consistent amount of the drug is cleared by the first pass effect. Few side effects were observed in this study of healthy male volunteers. Howev er, further monitoring for other adverse reactions will be important in future stud ies of patients with infectious diseases, and particularly in the elderly and in those with concomitant diseases. The long half-life of rufloxacin and its pharmacokinetic profile allow for the once daily oral treatment of bacterial infec
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396
Pharmacokinetics of Rufloxacin
Acknowledgements The drug was supplied and the study was sup ported by a grant from Mediolanum Farmaceutici. Milan, Italy. The authors wish to thank Yvonne Pomposo who provided editorial assistance with the preparation of the manuscript.
References 1 Cccchctti V, Fravolini A, Fringuclli R. ct al: Quinolone carboxylic acids. 2. Synthesis and anti bacterial evaluation of 7-oxo-2,3-dihydro-7Hpyrido[l,2,3-dc][1.4] bcnzothiazinc-6-carboxylic acids. J Med Chem 1987;30:465-473. 2 Ravizzola G, Pinsi G, Pirali F, et al: Rufloxacin (MF934): In vitro and in vivo antibacterial activ ity. Drugs Exp Clin Res 1989;15:11-15. 3 Ravizzola G, Pinsi G, Pirali F, et al: Rufloxacin (MF 934): Pharmacokinetic properties and ‘in vi vo’ activity (abstract 932). 7th Mediterranean Congr Chemother, Barcelona. May 1990, p 200. 4 Segre G, Cerretani D, Cerri D, et al: A new tricy clic fluoroquinolone, rufloxacin (MF-934), with interesting antibacterial and pharmacokinetic characteristics. Drugs Exp Clin Res 1988;14: 747-754.
5 Segre G, Cerretani D. Moltoni L, et al: Plasma and urine pharmacokinetics of rufloxacin in healthy volunteers after single and multiple oral doses. Eur J Clin Pharmacol I989;36(suppl): A333. 6 Imbimbo BP. Broccali GP, Cesana M, et al: In ter- and intrasubjcct variabilities in the pharma cokinetics of rufloxacin after single oral adminis tration to healthy volunteers. Antimicrob Agents Chemother 1991;32:390-393. 7 Bennett JV. Brodic JL, Benner EJ, et al: Simpli fied. accurate method for antibiotic assay of clin ical specimens. Appl Microbiol 1966;14:170-177. 8 Wagner JG: Fundamentals of Clinical Pharma cokinetics. Hamilton, Drug Intelligence Publica tions. 1975. pp 102-106. 9 Akaike H: An information criterion (AIC). Math Sci 1976;14:5-9. 10 Schwarz G: Estimating the dimension of a mod el. Ann Stat 1979;6:461^464. 11 Imbimbo BP. Imbimbo E, Daniotti S, et al: A new criterion for selection of pharmacokinetic multicxponential equations. J Pharm Sci 1988;77: 784-789. 12 Colburn WA: Estimating the accumulation of drugs. J Pharm Sci 1983;73:883-834. 13 Aronson JK. Dcngler HJ, Dettli L, ct al: Stan dardization of symbols in clinical pharmacology. Eur J Clin Pharmacol 1988;35:1-7. 14 Gibaldi M. Levy G. McNamara PJ: Effect of plasma protein and tissue binding on the biolog ic half-life of drugs. Clin Pharmacol Thcr 1978; 24:1-4.
Bruno P. Imbimbo Medical Department Mediolanum Farmaceutici Via C. Colombo 49 1-20090 Trezzano S/N, Milan (Italy)
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tions. The once-a-day dose regimen should improve patients’ compliance. The long ty, should decrease the risks of rein fection due to doses missed during treat ment and maintain a persistent antibacte rial activity for 2-3 days after the termina tion of treatment. In addition, the smooth serum drug level profiles obtained after oral administration of rufloxacin should prevent those adverse effects associated with excessive peak plasma concentra tions.
397
© 1991 S. Kargor AG. Basel 0009-3157/91/0376-0389 S 2.75/0
Pharmacokinetics of Rufloxacin in Healthy Volunteers after Repeated Oral Doses R. Mattinaa, G. Bonfiglioa, C.E. Cocuzzcv', G. Gulisanob, M. Cesanac, B.P. Imbimboc 0 Institute of Medical Microbiology. University of Milan; h Institute of Subtropical Diseases. University of Catania; c Medical Department. Mediolanum Farmaccutici, Milan, Italy
Abstract. Rufloxacin is a new broad-spectrum fluoroquinolone antibacterial agent. The pharmacokinetics and safety of rufloxacin were evaluated after repeated oral ad ministration to healthy volunteers. The drug was administered once a day for 6 consec utive days following two different dose schedules. The first group of 11 subjects was giv en a loading dose of 300 mg on the first day and 150 mg on the subsequent 5 days. The second group of 12 subjects was given a loading dose of 400 mg and 200 mg for 5 days. Serum levels and urine concentrations of rufloxacin were determined by microbiological assay. A simultaneous fit of all data points for each subject was done according to a onecompartmcnt open model. The drug was rapidly absorbed (absorption half-life 17±6 min in the 300+150 mg and 11 ±5 min in the 400 + 200 mg dose regimen group) and reached maximal serum concentrations (2.77±0.24 and 3.62±0.35 ug/ml) 4.2 + 0.4 and 4.0±0.9 h after the first administration. Steady-state serum concentrations (3.19±0.31 and 4.06 + 0.33 pg/ml) were reached in 3.7 + 0.7 and 4.5 ±0.4 days. Elimination half-lives were 29.5 + 2.4 and 36.0 + 2.8 h. Apparent volumes of distribution were 111 + 8 and 136 + 16 liters and apparent plasma clearances were 46 + 5 and 44 + 4 ml/min. Renal clearances were 18 + 3 and 17 + 2 ml/min. The percentage of the total dose excreted in urine throughout the study was 36.1+4.0% in the 300 + 150 mg and 43.7 + 2.5% in the 400 + 200 mg dose schedule group. Mean extents of accumulation were 2.4 ±0.2 and 2.5 ±0.1. Treatments were well tolerated, with only minor side effects (nausea, insomnia and postprandial vomiting) in 3 subjects and with no abnormalities being noted in rou tine laboratory examinations. Two and 3 days after the last administration, measurable antimicrobial activity was still observed in plasma and urine, indicating that the long half-life of rufloxacin assures valuable antibacterial coverage even after discontinuation of treatment.
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Key Words. Rufloxacin • Pharmacokinetics • Once-a-day administration • Repeated doses
Mattina/Bonfiglio/Cocuzza/Gulisano/Cesana/Imbimbo
Introduction
Rufloxacin, a new quinolone carboxylic acid derivative [1] (fig. 1), is highly active in vitro and in vivo against a broad spec trum of gram-negative and gram-positive organisms, including those resistant to [(-lactam antibiotics [2, 3]. In animals (rats, dogs and monkeys), the drug is well ab sorbed after oral administration, with an absolute bioavailability of about 60%, is distributed extensively in tissues, with high tissue-plasma ratios, has a long half-life of 12-24 h and about 30-40% is excreted in urine [4], Previous studies have shown that single oral doses up to 400 mg are well tol erated in healthy volunteers [5]. A single dose pharmacokinetic study in normal vol unteers showed that an oral dose of 400 mg rufloxacin was eliminated slowly, with a plasma half-life of 31-39 h [61. The study described here was designed to evaluate the pharmacokinetics and safety of multiple oral doses of rufloxacin. The results of this study should lead to the formulation of appropriate dosage re gimens for the treatment of infectious dis eases caused by rufloxacin-susceptible or ganisms.
Materials and Methods Study Design Twenty-three male subjects were randomly di vided into two groups. In the first group, 11 subjects were given a single loading dose of 300 mg (two cap sules of 150 mg) on the first day and single doses of 150 mg (one capsule) on the subsequent 5 days (300 + 150 mg dose schedule). In the second group. 12 subjects were given a single loading dose of 400 mg (two capsules of 200 mg) on the first day and sin gle doses of 200 mg (one capsule) on the subsequent 5 days (400 + 200 mg dose schedule). Each dose was
taken in the morning, after an overnight fast, with about 1«) ml of tap water. Fasting was continued for 4 It after administration of the drug. During the study, all the subjects were evaluated on an outpa tient basis either at the Department of Subtropical Diseases of the University of Catania or at the 2nd Division of Infectious Diseases of the Garibaldi Hospital in Catania. Italy. Subjects The II male subjects of the 300+150 mg dose schedule group were between 21 and 52 years of age (mean 35.0 years) and weighed between 62 and 77 kg (mean 68.9 kg); their heights ranged from 164 to 174 cm (mean 168 cm). The 12 male subjects of the 400 + 200 mg dose schedule group were between 22 and 60 years of age (mean 34.8 years) and weighed between 53 and 82 kg (mean 68.5 kg); their heights ranged from 162 to 184 cm (mean 172 cm). All sub jects were judged to be in good health as deter mined by physical examination, electrocardiogram, full blood count, coagulation tests, serum chemistry profiles (fasting blood glucose, urea nitrogen, sodi um. potassium, chloride, serum creatinine, uric acid, calcium, inorganic phosphorus, cholesterol, total protein, albumin, total bilirubin, serum aspartate aminotransferase, scrum alanine aminotransferase) and urinalysis. None of the subjects had a history of serious systemic illness, drug or alcohol abuse, or hypersensitivity to any food or drug. All subjects gave written informed consent before entering the study. The study was conducted according to the principles of the Declaration of Helsinki and was approved by the Hospital's Ethical Committee. SafeI)’ Evaluation Blood pressure and heart rate were measured at regular intervals. Tests of hematology, blood chem istry and urinalysis were conducted before the study and on days I. 3 and 6. The subjects were closely checked every day for any reactions. Sampling o f Mood and Urine Blood samples (6 ml) used for rufloxacin assay were collected via an indwelling venous catheter from a forearm vein just prior to the morning dose and 2, 4. 8. 12 and 24 h after the dose on day 1 and just before and 4 h after the morning dose on days 2-5. On day 6. blood samples for rufloxacin concen tration were obtained immediately before the last
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39«
391
Pharmacokinetics of Rufloxacin
o
morning dose and 2, 4, 8, 12, 24, 48 and 72 hours af ter. Serum was prepared from each sample for sub sequent assay. Urine was collected at intervals of 0-4, 4-8. 8-12 and 12-24 It on days 1-6. Additional urine fractions were collected 24-48, 48-72. 72-96 and 96-120 h after the last dose. Each sample was shaken, and after measurement of the volume, a 10ml aliquot was removed and frozen for later analy sis.
Pharmacokinetic Analysis Since analysis of individual serum concentration versus time courses revealed no significant differ ences between single and repeated doses, pharma cokinetic parameters were estimated with simulta neous fitting of all data points for each subject ac cording to a one-compartment open model with first-order input [8]. The one-compartment model was selected using Akaike's information criterion [9|, the Schwartz test [10] and the Ip index [11]. Nonlinear-regression analysis was performed with the program TOPF1T. The lag time (tlag) was calculated from the computer fitting. The area under the sc rum concentration versus time curve from zero to infinity (AUC,,^) was calculated as C „ A “ C(o,/k.,, in which C(m is the coefficient and k,, and kc are the exponents of the fitted biexponential equation. The absorption half-life (t,„:l) was calculated as ln(2)/ka and the elimination half-life (t,„) as ln(2)/kc. The mean residence time (MRT) was calculated as (C(ll)/k; - C(l,/k*/(C(l))/kc - C(1))/k;l). The apparent
•HCI
Fig. 1. Chemical structure of rufloxacin. volume of distribution (V/F) was calculated as dose/ kc'A U C (^ , and the apparent total body clearcnce (CL/F) as dosc/AUC,^. The maximum drug con centration after the first administration (Cmax) and the time to reach it (tmax) were obtained from the in dividual data. The steady-state drug concentration (Cmaxss) and the corresponding time to reach it (tmaxss) were obtained from derivatives of the fitted equation. The areas under the serum concentrationtime curve from 0 to 24 h after the first (AUC„_24lsl) and the last administration (AUCm246lh) were calcu lated by the linear trapezoidal rule. The renal clear ance (CLk) was calculated by dividing the amount of drug excreted in urine in the 0-24 h after the first administration by the AUC„_241s,. The renal clear ance at the steady state (CLRss) was calculated by dividing the amount of the drug excreted in urine in the 0-24 h after the last dose by the AUC((_24(llh. The percent of the drug excreted in urine (fc) was calcu lated by dividing the total amount excreted in urine up to 72 h after the last administration by the total amount of drug administered during treatment. The extent of accumulation ratio (R) was calculated by dividing AUCl(_24(lth by AUC„_,4I„ after correction for the dose [12]. Standard pharmacokinetic symbols were adopted [13]. Results are expressed as mean ± SEM.
Results
One subject in the 400 + 200 mg dose schedule (No. 19) dropped out after 3 days of treatment for personal reasons not re lated to the drug. Since serum concentra tion data were available for up to the third day of treatment and urinary excretion da-
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Assays Concentrations of rufloxacin in scrum and urine were determined by microbiological assay with Escherichia coli Kp 05124 as the test organism [7]. The medium used was antibiotic medium No. 1 at pH 7.0 (Difco Laboratories, Detroit, Mich., USA). Standards were prepared with pooled normal hu man serum for scrum sample and with phosphate buffer (pH 7.2) for urine samples. The plates were incubated overnight at 37°C. The standards, con trols and samples were run in quadruplicate. The linear-regression analysis of the standard calibra tion lines obtained by plotting the log antibiotic con centrations versus the zone diameters of inhibition indicated excellent linearity of the assay between 1.56 and 12.5 gg/ml. The sensitivity limit of the assay was 0.78 ng/ml. The coefficients of variation of the assay were 6% at 3.12 pg/ml and 9% at 0.78 ug/ml.
COOH
392
Mattina/Bonfiglio/Cocuzza/Gulisano/Ccsana/lmhimbo
5-1
ta for 2 days for this subject, he was in cluded in the pharmacokinetic analysis, and when possible, pharmacokinetic pa rameters were calculated. The urines of subject No. 23 in the 400 + 200 mg dose schedule group went missing, and hence the pharmacokinetic parameters for renal excretion of rufloxacin were not available for this subject. Concentrations o f Rufloxacin in Scrum The mean serum concentrations of ru floxacin during and after the 300 + 150 mg and the 400 + 200 mg dose schedules are shown in figure 2. After the first admin
istration, Cmax (2.77 ±0.24 pg/ml in the 300 + 150 mg group and 3.62 ± 0.35 pg/ml in the 400 + 200 mg group) was reached gen erally after 2-4 h (tmax 4.2 ±0.4 and 4.0 ±0.9 h). After repeated administration, Cmaxss increased to 3.19 ±0.31 and 4.06±0.33 pg/ml in the two groups and were reached in 3.7 ±0.7 days in the 300 +150 mg group and 4.1 ± 0.3 days in the 400 + 200 mg group. AU(V 24 increased with time after the first (46.3 ±4.0 and 58.5 ±4.4 ug-h/ml) and the last adminis tration (56.4 ±7.0 and 71.4 ±5.3 pg’h/ml). The extent of accumulation was 2.4 ±0.2 for the 300 + 150 mg dose schedule and
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Fig. 2. Mean (±SEM ) serum concentrations of rufloxacin during two different repeated oral schedules, the first with a single oral loading dose of 300 mg followed by single oral daily doses of 150 mg for 5 days ( • ) and the second with a single oral loading dose of 400 mg followed by single oral daily doses of 200 mg for 5 days (O). Arrows indicate drug administrations.
Pharmacokinetics of Rufloxacin
393
Subject No.
tlag, min tl/ja. min tmax» h Cmax, pg/ml ‘max.»- dayS Cmax.xx- dg/ml V, h MRT, h V/F. liters CL/F, ml/min CLr , ml/min CL r ,,, ml/min AUC(WJ. |sl, ug-h/ml AUC(|_,4 61h, ug-h/ml A U C,^, ug-h/ml R fc,%
Mean
SLM
1
2
3
4
5
6
7
8
9
10
11
2 38 4 1.82 3.1 1.85 26.8 39.5 162 70 33 54
58 30 8 4.27 5.1 5.51 39.7 57.9 73 21 7 7
0 65 4 3.18 0.2 3.25 18.6 28.5 77 48 10 16
105 5 4 2.83 5.1 3.25 29.2 42.2 104 41 21 10
105 7 4 2.11 5.1 2.79 27.6 40.0 116 49 36 37
103 5 4 2.90 4.1 2.77 24.3 35.1 107 51 29 15
108 7 2 2.19 0.1 2.39 23.5 34.1 122 60 13 11
104 6 4 1.85 5.1 2.92 41.3 59.8 146 41 14 17
89 6 4 3.95 5.1 4.42 32.9 47.6 83 29 13 7
77 23 4 2.86 5.1 3.51 39.5 57.5 116 34 7 II
107 3 4 2.54 0.1 2.47 21.5 31.1 119 64 14 20
78 17 4.2 2.77 3.7 3.19 29.5 43.0 111 46 18 19
13 6 0.4 0.24 0.7 0.31 2.4 3.4 8 5 3 4
30.2
63.8
63.0
38.2
40.9
42.3
37.1
34.1
68.5
52.0
38.8
46.3
4.0
32.0
108.4 44.3
60.2
45.8
42.7
39.5
54.1
86.4
68.7
38.6
56.4
7.0
71.5 2.1 57.3
234.6 104.2 121.5 102.8 97.8 3.4 1.4 3.2 2.2 2.0 28.8 32.6 30.0 66.9 30.7
83.2 2.1 25.9
122.2 172.0 147.9 77.9 3.2 2.5 2.6 2.0 34.2 35.6 30.6 24.6
121.4 2.4 36.1
14.5 0.2 4.0
2.5 ±0.1 for the 400 + 200 mg dose schedule. The pharmacokinetic parameters de rived from a one-compartmcnt model fit ting of scrum rufloxacin concentrations are shown in tables 1 and 2. The pharma cokinetic analysis shows that the drug, after a delay (t!ag) of 78 ±13 min in the 300 + 150 mg and 45 ±16 min in the 400 + 200 mg dose schedule group, was rapidly absorbed, with ty,a of 17 ±6 and
min for the two groups. This initial delay is probably due to dissolution and gastric emptying of the pharmaceutical formula tion. After absorption, the drug was exten sively distributed in the tissues, with V/F of 1U±8 and 136±16 liters for the 300 + 150 mg and the 400 + 200 mg dose schedules, respectively. The drug re mained in the body for a long time (MRT of 43 ±3 and 52 ±4 h) and was cleared slowly from the plasma (CL/F of 46 ±5
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Table 1. Individual pharmacokinetic parameters of rufloxac in for subjects on the 300 + 150 mg dose schedule
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Mattina/Bonfiglio/Cocuzza/Gulisano/Ccsana/Imhimbo
Tabic 2. Individual pharmacokinetic parameters of rufloxacin for subjects on the 400 + 200 mg dose schedule Subject No.
hag- min t,„a, min *max> h Cma,. Hg/ml tmax,». days ^max. ss’ 1 t./,, h MRT. h V/F, liters CL/F. ml/min CLr , ml/min CLr jj, ml/min
12
13
14
15
16
17
18
19
2 3 2 3.64 5.0 4.80 54.5 78.6 141 30 10 8
0 47 4 2.86 5.1 3.29 29.4 43.5 129 51 14 18
118 5 12 1.91 5.1 2.27 49.2 71.0 280 66 29 25
1 3 2 5.40 1.0 5.40 23.8 34.3 73 36 18 14
0 4 2 5.39 5.0 5.74 24.8 35.9 70 33 12 26
0 4 2 3.15 5.0 3.57 28.8 41.6 126 50 15 25
115 5 4 2.70 5.1 3.62 39.5 57.2 153 45 18 25
61.0
55.9
31.9
84.8
85.7
55.8
54.4
93.0
64.0
48.6
83.3
94.7
60.8
66.0
20
Mean
SEM
21
22
23
0 89 4 47 2 8 3.95 5.43 2.0 5.2 5.28 4.57 44.6 34.7 64.4 51.2 99 105 26 35 8 17 25
0 4 2 3.07 5.0 2.98 35.6 51.4 173 56 17 31
108 6 4 2.42 5.1 2.64 28.5 41.3 167 68 28 23
104 5 4 3.48 5.1 4.56 38.4 55.5 119 36
45 11 4.0 3.62 4.5 4.06 36.0 52.2 136 44 17 20
16 5 0.9 0.35 0.4 0.33 2.8 4.0 16 4 2 3
69.8
61.6
48.6
42.2
59.7
58.5
4.4
82.8
51.5
50.4
89.3
71.4
5.3
A U C ()_24 ]st,
pg-h/ml A U C (1_24, 6ih>
pg-h/ml A U C W
222.4 131.2 101.3 188.0 203.3 132.3 149.3 259.4 190.3 173.4 98.1 3.0 3.0 2.4 2.7 2.4 2.3 2.0 2.2 2.2 2.1 33.9 47.8 35.7 45.4 48.2 29.0 47.1 51.2 53.6 45.0
185.9 169.6 3.0 2.5 43.7 -
14.1 0 .1
2.5
and 44 ±4 ml/min). Plasma half-life was istration. Four days after the last adminis 39.5 ± 2.4 h for the 300 +150 mg group and tration, rufloxacin was still clearly detect 36.0 ±2.8 h for the 400 + 200 mg group. able in urine (10.7 ±2.9 pg/ml in the 300 + 150 mg dose schedule group and 32.7 Concentrations o f Rufloxacin in Urine pg/ml in the 400 + 200 mg dose schedule Mean concentrations of rufloxacin in group). CLr were 18 ±3 ml/min for the urine collected 0-4 h after the last dose 300 + 150 mg group and 17 ±2 ml/min for were 46.3 ±4.6 pg/ml in the 300 + 150 mg the 400 + 200 mg group, these values being dose group and 85.4 ±8.3 pg/ml in the 39.1 and 38.6% of the CL/F. CLR calculat 400 + 200 mg dose group (tables 3, 4); the ed at the steady state (CLRss) remained corresponding concentrations at 12-24 h unchanged for both groups (19 ±4 and were 34.3 ±3.8 and 72.7 ±10.7 pg/ml and 20±3 ml/min). fe was 36.1 ±4.0% for the remained at 25.6 ±3.8 and 48.9 ±9.4 ,ug/ml 300 + 150 mg dose group and 43.7 ±2.5% values in the 48-72 h after the last admin for the 400 + 200 mg group.
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pg-h/ml R fc, %
Pharmacokinetics of Rufloxacin
395 Table 4. Mean (±SEM ) urinary rufloxacin excre tions (mg) on the two different dose schedules
300+150 mg
400 + 2(H) mg
Hour interval
400 + 200 mg
Hour interval
Day of treatment
300+150 mg
Day of treatment 1
0-4 4-8 8-12 12-24
38.6 ±7.2 43.2 ±4.2 45.0 ±6.0 36.4 ±6.5
40.9 ±7.9 54.8 ±7.7 44.8 ±4.1 45.5 ±7.4
1 2 3 4 5 6
2
0-4 4-8 8-12 12-24
47.7 ±10.6 48.8 ±4.8 43.1 ±5.4 41.3 ±6.0
73.0 ±22.1 89.5 ±13.7 79.7 ±12.0 81.0 ± 14.8
0-24 0-24 0-24 0-24 0-24 0-24 24-48 48-72 72-96 96-120
45.6 ± 6.5 42.8 ±4.7 55.9 ±6.8 47.3 ±5.0 43.2 ±4.4 52.8 ±7.8 30.8 ±5.0 31.9 ±7.7 18.8 ±3.6 10.1 ±2.8
56.1 ±4.8 80.1 ±7.6 87.2 ±15.8 21.7 ±25.0 87.4 ±9.3 88.8 ±9.6 67.8 ±11.5 53.2 ±6.4 38.4 ±6.2 37.0 ±5.1
3
0-4 4-8 8-12 12-24
48.7 ±4.7 46.6 ±5.1 44.3 ±4.5 41.2 ±3.9
84.8 ±13.9 75.1 ±14.2 81.6 ±19.2 69.0 ±9.4
4
0-4 4-8 8-12 12-24
43.6 ±4.2 40.8 ±4.7 38.2 ±3.0 32.3 ±4.2
113.8 ±16.3 86.4 ±17.7 83.6 ±18.1 62.2 ±8.9
5
0-4 4-8 8-12 12-24
30.6 ±5.0 46.1 ±4.1 41.9 ±4.6 34.9 ±4.3
74.7 ±9.5 95.0 ±13.5 82.7 ± 11.6 86.7 ±10.6
6
0-4 4-8 8-12 12-24 24-48 48-72 72-96 96-120
46.3 ±4.6 48.8 ±5.4 39.5 ±5.2 34.3 ±3.8 24.9 ±4.0 25.6 ±3.8 19.0 ±3.8 10.7 ±2.9
85.4 ±8.3 69.9 ±8.6 75.0 ±12.7 72.7 ±10.7 60.9 ±12.7 48.9 ±9.4 34.1 ±4.6 32.7 ±5.9
Side Effects Rufloxacin was well tolerated at both dose schedules. No clinically significant changes were observed in any of the phys ical or laboratory tests. One subject
(No. 5) in the 300 + 150 mg group had mild nausea on the third day of treatment that disappeared 4 h after the administration of the drug. In the 400 + 200 mg dose schedule group, 1 subject (No. 13) com plained of mild insomnia during the sec ond day of treatment which had disap peared by the third night. Another subject in the same group (No. 18) had nausea on the third day and postprandial vomiting on the fourth day of treatment.
Discussion
This is the first report on the safety and pharmacokinetics of rufloxacin after mul tiple oral doses, and it has shown that the drug is well tolerated at loading doses of 300 or 400 mg once daily followed by sin gle daily doses of 150 or 200 mg, respec tively, for 5 days. In order to overcome bias from sepa rate estimations of pharmacokinetic pa rameters, a simultaneous fit of all data
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Tabic 3. Mean (±SEM ) urinary rufloxacin con centrations (ug/ml) for the two different dose sched ules
points for each subject was done based on a one-compartment open model with firstorder input. The simultaneous fit used 20 data points and yielded a robust (16 de grees of freedom) estimate of the pharma cokinetic parameters. The disposition of rufloxacin was described by a onc-compartment model also after single oral ad ministration [6]. In this study microbiological assays were used instead of high-performance liquid chromatography determinations to efficiently compare the concentrations reached by the drug in serum and urine with the in vitro minimum inhibitory con centrations (MICs) of the drug against the susceptible microorganisms. The dosage regimens adopted in this study are relatively close and were select ed in an attempt to attain a scrum concen tration higher than 2 pg/ml, a value equal to the MIC for most of the susceptible bacteria [2, 3], However, doses higher than 400 mg were not used because it was found that they were not well tolerated after sin gle administration [5]. The loading dose in the two schedules was double the mainte nance dose and was chosen in order to reach the steady state more rapidly. The steady state was in fact reached in a rela tively short period of time (about 4 days) in spite of the long half-life of the drug. Calculated steady state peak concentra tions in serum after the 400 + 200 mg dose schedule were 4.06 ±0.33 pg/ml, approxi mately twice the MICs for most suscep tible organisms. Concentrations greater than 2 pg/ml were detected in serum at least 24 h after the last administration by this dose schedule. The most important aspect of the pharmacokinetic profile of rufloxacin af
Mattina/Bonfiglio/Cocuzza/Gulisano/Cesana/Imbimbo
ter repeated oral doses is its long serum half-life (30-35 h). The long t/; could be linked to the low free fraction of the drug in tissue [14], The large V/F of rufloxacin (about 120 liters) may be due to the extensive distri bution of the drug in tissue and/or to the high protein binding of the drug in plasma [about 80%, Segre, pers. commun.]. Rufloxacin concentrations in urine 0-4 h after the last dose were 46.3 ±4.6 pg/ ml for the 300 + 150 mg and 85.4 ±9.3 pg/ ml for the 400 + 200 mg dose schedule group, a much higher level than the MICs for most organisms responsible for urinary tract infections. At 12-24 h after the last administration, levels in urine were 34.3 ±3.8 and 72.7 ±10.7 ug/ml in the two groups. Even 3 days after the last dose, the concentrations of rufloxacin in urine re mained much higher than the MICs (25.6±3.8 ug/ml in the 300± 150 mg and 48.9 ±9.4 pg/ml in the 400 + 200 mg dose schedule group). The CLr of about 18 ml/min is lower than the glomerular filtration rate report ed for humans and indicates that some of the drug undergoes renal tubular reab sorption. The CLU represents about 39% of the CL/F of rufloxacin in both groups, indicating that a consistent amount of the drug is cleared by the first pass effect. Few side effects were observed in this study of healthy male volunteers. Howev er, further monitoring for other adverse reactions will be important in future stud ies of patients with infectious diseases, and particularly in the elderly and in those with concomitant diseases. The long half-life of rufloxacin and its pharmacokinetic profile allow for the once daily oral treatment of bacterial infec
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396
Pharmacokinetics of Rufloxacin
Acknowledgements The drug was supplied and the study was sup ported by a grant from Mediolanum Farmaceutici. Milan, Italy. The authors wish to thank Yvonne Pomposo who provided editorial assistance with the preparation of the manuscript.
References 1 Cccchctti V, Fravolini A, Fringuclli R. ct al: Quinolone carboxylic acids. 2. Synthesis and anti bacterial evaluation of 7-oxo-2,3-dihydro-7Hpyrido[l,2,3-dc][1.4] bcnzothiazinc-6-carboxylic acids. J Med Chem 1987;30:465-473. 2 Ravizzola G, Pinsi G, Pirali F, et al: Rufloxacin (MF934): In vitro and in vivo antibacterial activ ity. Drugs Exp Clin Res 1989;15:11-15. 3 Ravizzola G, Pinsi G, Pirali F, et al: Rufloxacin (MF 934): Pharmacokinetic properties and ‘in vi vo’ activity (abstract 932). 7th Mediterranean Congr Chemother, Barcelona. May 1990, p 200. 4 Segre G, Cerretani D, Cerri D, et al: A new tricy clic fluoroquinolone, rufloxacin (MF-934), with interesting antibacterial and pharmacokinetic characteristics. Drugs Exp Clin Res 1988;14: 747-754.
5 Segre G, Cerretani D. Moltoni L, et al: Plasma and urine pharmacokinetics of rufloxacin in healthy volunteers after single and multiple oral doses. Eur J Clin Pharmacol I989;36(suppl): A333. 6 Imbimbo BP. Broccali GP, Cesana M, et al: In ter- and intrasubjcct variabilities in the pharma cokinetics of rufloxacin after single oral adminis tration to healthy volunteers. Antimicrob Agents Chemother 1991;32:390-393. 7 Bennett JV. Brodic JL, Benner EJ, et al: Simpli fied. accurate method for antibiotic assay of clin ical specimens. Appl Microbiol 1966;14:170-177. 8 Wagner JG: Fundamentals of Clinical Pharma cokinetics. Hamilton, Drug Intelligence Publica tions. 1975. pp 102-106. 9 Akaike H: An information criterion (AIC). Math Sci 1976;14:5-9. 10 Schwarz G: Estimating the dimension of a mod el. Ann Stat 1979;6:461^464. 11 Imbimbo BP. Imbimbo E, Daniotti S, et al: A new criterion for selection of pharmacokinetic multicxponential equations. J Pharm Sci 1988;77: 784-789. 12 Colburn WA: Estimating the accumulation of drugs. J Pharm Sci 1983;73:883-834. 13 Aronson JK. Dcngler HJ, Dettli L, ct al: Stan dardization of symbols in clinical pharmacology. Eur J Clin Pharmacol 1988;35:1-7. 14 Gibaldi M. Levy G. McNamara PJ: Effect of plasma protein and tissue binding on the biolog ic half-life of drugs. Clin Pharmacol Thcr 1978; 24:1-4.
Bruno P. Imbimbo Medical Department Mediolanum Farmaceutici Via C. Colombo 49 1-20090 Trezzano S/N, Milan (Italy)
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tions. The once-a-day dose regimen should improve patients’ compliance. The long ty, should decrease the risks of rein fection due to doses missed during treat ment and maintain a persistent antibacte rial activity for 2-3 days after the termina tion of treatment. In addition, the smooth serum drug level profiles obtained after oral administration of rufloxacin should prevent those adverse effects associated with excessive peak plasma concentra tions.
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