Journal of Antimicrobial Chemotherapy (1978) 4 (Suppl. B), 69-78
Unavailability and pharmacokinetics of cefoxitin sodium
J. J. Schrogie, R. O. Davies, K. C. Yeb, D. Rogers, G. I. Holmes, H. Skeggs and C. M. Martin
This review paper establishes four major conclusions about cefoxitin sodium: 1. After i.v. administration, cefoxitin is distributed rapidly into the plasma and tissue fluids, and has a serum half-life of 40 to 60 min. It is not metabolized appreciably ( < 1 %) in animals or man. The volumes of distribution ( Vu V^, and V^) of the drug are similar to those found with cephalothin. 2. After i.m. administration, peak serum levels of cefoxitin are achieved in 20 to 30 min, and virtually the entire dose is available to the systemic circulation. The bioavailability of i.m. cefoxitin sodium is not affected by the use of lidocaine (0-5 % or 10%) as a diluent. 3. Cefoxitin is rapidly excreted intact into the urine by glomerular filtration and by renal tubular secretion. Renal clearance is greater than 250 ml/min/1-73 m1; about 75 % of each dose is recovered within the first 3 h after dosing. Probenecid administered concurrently decreases the excretion rate and increases the serum haJflife of cefoxitin. 4. The pharmacokinetics of i.v. cefoxitin are adequately described by use of a two-compartment, open model. Chemistry and microbiology Cefoxitin sodium (MK-306) is a new semi-synthetic cephamycin antibiotic, a derivative of cephamycin C. Its empirical formula is C18H1(SN3Na0i,Sg (MW 449-44). The sodium salt, rather than cefoxitin free acid, is used pharmaceutically because of the extreme insolubility of the free acid in aqueous vehicles and the high solubility (> 100 mg/ml) of the salt. The structural formula of cefoxitin sodium is shown in Figure 1. The structural significance of cefoxitin lies in the methoxy group at the 7a-position; this substituent
CHj0C0NH 2 COO"No + Figure 1. The structural formula of cefoxitin sodium (sodium 3-(hydroxymethyl)-7cr-methoxy-8-oxo-7[2-{2-thienyl)acetamido}-5-thia-l-azabicyclo[4.2.0]oct-2-erje-2-carboxylate carbamate (ester)). 69 03O5-7453/78/0701-BO69 501.00/0 © (1978) The British Society for Antimicrobial Chemotherapy
Downloaded from http://jac.oxfordjournals.org/ at Florida Atlantic University on May 21, 2015
Merck Sharp and Dohme Research Laboratories, West Point, Pennsylvania, U.S.A.
70
J. J. Schrogle et al.
Absorption In preclinical studies, cefoxitin sodium had been administered orally to mice, rats, and monkeys from whom blood and urine samples were collected periodically for bioassay.* Only about 2 % of the dose given to rats and mice and about 10% of the dose given to monkeys was excreted in the urine. Cefoxitin was not detectable in the blood of animals dosed orally with the drug. As a result, subsequent laboratory studies in vivo and clinical studies utilized parenteral administration of the drug. Binding and distribution In vitro The binding of cefoxitin to human plasma protein was studied by means of an ultrafiltration technique. At serum concentrations of 10 and 100/xg/ml, 73% of the drug was bound to plasma protein. In vivo (human) The distribution of cefoxitin into cerebrospinal fluid (CSF) had been studied by Liut (unpublished data) in 50 volunteers and patients undergoing diagnostic or therapeutic examination by lumbar, cisternal, or ventricular tap. Cefoxitin sodium, 2 g, was infused i.v. over 30 min in single or multiple doses, and specimens of serum and CSF were obtained 30 min after completion of the infusion. Both in normal subjects and in patients with increased CSF protein, levels of cefoxitin in the CSF were highest after the administration of multiple doses, especially when probenecid was given concurrently. In the presence of meningeal irritation, the concentration of cefoxitin in the CSF was somewhat greater. In patients with elevated CSF protein given single doses of cefoxitin, the mean concentration of cefoxitin was 52 and >0-63/xg/ml in serum and CSF, respectively. In • These unpublished data are onfileat the Merck Sharp & Dohme Research Laboratories, t C. Liu, Kansas City, Kansas.
Downloaded from http://jac.oxfordjournals.org/ at Florida Atlantic University on May 21, 2015
confers upon cefoxitin a high degree of resistance to inactivation by cephalosporinases (/Mactamases) produced by Gram-negative bacteria. Hence, cefoxitin has a very broad antibacterial spectrum in vivo and in vitro that includes all strains of cephalosporinsensitive bacteria and, more importantly, the majority of cephalosporin-resistant (i.e., cephalosporinase-producing) bacteria. These include Serratia marcescens, indolepositive Proteus, Providencia, anaerobic Gram-negative rods such as Bacteroides fragilis, as well as common pathogenic species of Gram-negative rods (Escherichia coli, Klebsiella, indole-negative Proteus, Salmonella, and Shigella). However, the spectrum does not include Pseudomonas aeruginosa and enterococci. This review summarizes information from eight clinical studies that specifically evaluated the pharmacokinetics and bioavailability of cefoxitin and the relevant results of preclinical studies; also cited are other supportive clinical studies that report the penetration of cefoxitin into cerebrospinal fluid and other body fluids during clinical use of the drug. The antimicrobial activity of cefoxitin in serum and urine was assayed by the cupplate diffusion technique (Grove & Randall, 1955), using test strains of Staphylococcus aureus or Bacillus subtilis. Chemical assays for cefoxitin and its metabolites utilized highpressure liquid chromatography (HPLQ. The minimum inhibitory concentration (MIC) of cefoxitin in serum for more than 90 % of organisms susceptible to the drug is 16^g/ml.
Bloavallablllty and phannacoldaedcs
71
Metabolism In several human studies, urine specimens were examined for cefoxitin and its metabolites by bioassay, an improved HPLC procedure, and thin-layer chromatography (unpublished data). More than 90% of the cefoxitin administered i.v. or i.m. was recovered from the urine as intact drug. Less than 1 % of the dose was present as the decarbamoyl metabolite, most of which was found 2 to 4 h after dosing (Sonneville, Kartodirdjo, Skeggs, Till & Martin, 1976). In some individuals, the metabolite was not detected. These results demonstrate that cefoxitin is not metabolized appreciably in man. Disposition Humans with normal renal function Studies of the disposition of cefoxitin sodium given i.v. to 9 volunteers were performed by Sonneville (1976). Single i.v. doses of 0-5, 1, and 2 g were infused over 3 min, according to a randomized crossover design. Serum level curves that were obtained are shown in Figure 2. The harmonic mean of the terminal serum half-life was 42, 59, and 56 min for
— • 0-5g
\
A
100 •=
50
i
20
|
10 r
o-— o I-Og t-
—x
2-0g
t
-\\
\ \
to
5 \
2 I
-
x
' \
> \
i
0
i
:
i
60
\ i
i
1
1
X 1
120 180 Time (mm)
I
1
1
240
Figure 2. Mean serum levels of cefoxitin after i.v. administration of single 0-5-, 1-, and 2-g doses over 3 min to apparently healthy volunteers (Sonneville et al, 1976).
Downloaded from http://jac.oxfordjournals.org/ at Florida Atlantic University on May 21, 2015
patients given 3 to 5 doses of cefoxitin every 6 h, plus probenecid, levels were 67 and 2 1 /xg/ml in serum and CSF, respectively. The failure of Geddes et al. (1977) to find cefoxitin in the CSF of 2 patients 1 h after the administration of a single 2-g i.v. dose infused over 5 min was, therefore, not unexpected, and was consistent with the results obtained by Liu. In a study by Geddes et al. (1977), biliary excretion of cefoxitin had been measured in 2 patients with post-cholecystectomy T-tubes in place. The concentrations of drug in the bile greatly exceeded the MIC for most Gram-negative bowel flora. In a lactating woman treated with cefoxitin for a urinary tract infection, the concentration of cefoxitin in breast milk 2 h after a 1-g i.v. dose was 5-6 mg/1.
72
J. J. Schrogie et al. Table I. Mean terminal serum half-life, renal clearance, and per cent urinary recovery in apparently healthy volunteers given cefoxitin i.v. 0-12 h i.v. dose (g)
Infusion time (min)
3
2 0 30 mg/kg
3 30 3 30
subjects*
4 9 8 2 9 6 6 6 9 9 18 3
5
half-life (min)
Renal clearance (ml/min/1 -73 m1)
urinary recovery (%dose)
38 42 43 38
2500 331-9 332-2 387-5 290-3 281-1 268-4 285-0 3220 247-7 205-9 4451 3290
78-0 86-7 98-5 770 741 800 760 99-0 77-6 78 0 104-0 1110
Terminal
59 41 49 47 47 56 59 50 47
89-9t
* Not all subjects included in all calculations, t 0 to 6 h recovery.
the 0-5-g, 1-g, and 2-g doses, respectively. Renal clearance of cefoxitin during the 2-h period after the infusion was 331-9, 290-3, and 247-7 ml/min/1 -73 m s for the 0-5-g, 1-g, and 2-g doses, respectively; about 77% of each dose was recovered within the first 12 h. Other studies (Goodwin, Raftery, Goldberg, Skeggs, Till & Martin, 1974; Kosmidis, Hamilton-Miller, Gilchrist, Kerry & Bmmfitt, 1973), in which single 0-25-g, 1-g, and 2-g doses were administered i.v. over periods ranging from 1 to 120 min, also demonstrated a terminal serum half-life between 40 and 60 min, renal clearance usually greater than 250 ml/min/1-73 m 2 , and 0-12 h urinary recoveries of cefoxitin of 70 to nearly 100% of Table II. Mean terminal serum half-life, renal clearance, and per cent urinary recovery in apparently healthy volunteers given cefoxitin i.m. 0-12 h
Dose (8) 0-25 0-5 10
2 0
Diluent
No. of
(W or L)* subjects! W W W W L L L L L L L
4 9 9 8 8 6 6 8 6 18 18
Terminal half-life Renal clearance (min) (ml/min/1 -73 m1) 440 460 45 0 64-8 69-4 89-8 69-6 47-9 75-6 53-9 52-8
• W = water; L = 0 5 or 1-0% lidocaine. t Not all subjects included in all calculations. } 0 to 6 h recovery.
320-0 358-9 405-8 197-2 245-7 347-7 356-4 280-3 330-4 280-3 288-9
urinary recovery (%dosc) 88-7| 870 900 74-8 821 95 0 90-4 77-4 86-3 83 0 78 0
Downloaded from http://jac.oxfordjournals.org/ at Florida Atlantic University on May 21, 2015
1 3 3 3 3 3 30 120
0-25 0-5 1-0
No. of
Bloavailability and phannacoklnetics
73
• • I g Lv.over 3 min o — o Ig Lm. with water x x Ig Lm.wlthO-5% lidocaine
180
240
Time (min)
Figure 3. Mean serum levels of ccfoxitin after administration of single 1 -0-g doses to apparently healthy volunteers (Sonneville et aJ., 1976).
the dose (Table I). Results of studies (Kosmidis et ai, 1973; also unpublished data) of the disposition of cefoxitin sodium administered i.m. in single doses of 0-25, 0-5, 10, and 2 0 g are summarized in Table II. Serum level curves after i.m. doses of 10 and 2 0 g, with and without lidocaine, are shown in Figures 3 and 4, respectively. The mean terminal half-life ranged from 44 to 90 min, renal clearance usually exceeded 250 ml/min/1 -73 m 2 , and 0 to 12 h urinary recoveries of cefoxitin ranged from 77 to 95 % of the dose. These results demonstrate that cefoxitin is cleared rapidly from the serum and is excreted rapidly and extensively into the urine in humans with normal renal function. The longer half-life after i.m. dosing has been attributed to continued absorption of the
• — « 2 g i v. over 3 0 min o—o 2g |jn. with 0 5% lidocaine x x 2g i.m.wlth 1 0 % lidocaine
\J\J
50
20
• r
•
^
\ N
10
2 I
•
_ 11
1 1
60
1
1 1
1
1
120 180 Time (min)
I
I
I 240
Figure 4. Mean serum levels of cefoxitin after administration of single 2 0-g doses to apparently healthy volunteers (unpublished study no. 46).
Downloaded from http://jac.oxfordjournals.org/ at Florida Atlantic University on May 21, 2015
120
60
74
J . J. Scbrogle et al. Table III. Effect of probenecid (1 0 g i.v.) on elimination of cefoxitin ( 1 0 g i.v.) in 6 apparently healthy volunteers Cp.0*
Cefoxitin Cefoxitin + probenecid
(ug/ml)
(min)
(0-1 h)
(0-12 h)
121 40-4
41 83
54-6 30-5
741 68-4
drug. The elimination of cefoxitin was not aifected by the use of lidocaine as a diluent for i.m. injection. Urinary recovery as a percent of dose was comparable after both i.v. and i.m. administration of cefoxitin. Effect of probenecid Since cefoxitin is eliminated by renal tubular secretion, as well as by glomerular filtration, the effect of probenecid on the elimination of cefoxitin was evaluated in man. Six apparently healthy volunteers received 1 g of cefoxitin i.v. after having received 1 g of probenecid i.v. as an infusion begun 1 h earlier (Goodwin et al., 1974) (Table III). The mean terminal serum half-life of cefoxitin under control conditions was 41 min; after probenecid, it increased to 83 min. The mean serum level of cefoxitin 60 min after a 3-min infusion was 121 /xg/ml during the control period and 40-4/ig/ml after probenecid had been given. Mean urinary recovery of cefoxitin during the first hour after dosing was 54-6% of the dose during the control period, but 30-5% of the dose after probenecid; however, after 12 h, recoveries during the control period and the probenecid-treatment period were comparable (74-1 and 68-4%, respectively.) Pharmacokinetics Antimicrobial activity in serum and urine after the administration of cefoxitin represents unchanged drug. The kinetics of the distribution and elimination of cefoxitin after its i.v administration are best represented by a two-compartment, open model, as shown in Figure 5. Note that klt, kn, and k10 represent first-order rate constants for intercompartmental drug movement; Vx is the apparent volume of distribution of the central compartment; Ar0 is the zero-order infusion rate; and T is the infusion time. The adequacy of this two-compartment, open model has been verified in various ways (Till, Benet & Kwan, 1974), e.g., the mean urinary excretion of cefoxitin (Table IV and Figure 6) predicted
*o Dose • * o r
"
Central compartment
*I2 ~
*2I
..
Peripheral compartment
J*'° Metabolism and excretion
Figure 5. Two-compartment open model showing distribution and elimination of cefoxitin following i.v. administration.
Downloaded from http://jac.oxfordjournals.org/ at Florida Atlantic University on May 21, 2015
* Cp« = Plasma concentration 60 min after a 3-min infusion, t £/(%) = Per cent of dose excreted in urine.
Bioavailablllty and pharmacoklnetics
75
I7OO 1500 1300
O
—
i 1100o
o
900
I
• Observed
700
2
I 5OO
-
1
0
1
1
I 24
2 Tlme(h)
Figure 6. Predicted and observed mean cumulative urinary recovery after 2 g i.v. cefoxitin infused over 30 min in apparently normal volunteers (unpublished study no. 46).
from individual kinetic parameters derived from a typical study (Table V) agrees closely with the results obtained. The model parameters obtained from the various studies in apparently healthy volunteers are listed in Table V; these estimated model parameters are comparable in the various studies and for all dose levels tested. They describe the distribution of drug between the peripheral and central compartments and show the rapid elimination of drug from the central compartment; the volume of distribution (KJ of the central compartment is about 8 1, reflecting the presence of drug in body fluids as well as in plasma. The 25-3 ±4-7 1 value for Vdff and of 16-1 ±2-5 1 for K ^ , determined by use of a twocompartment, open model, are in close agreement with the values so determined for cephalothin and ccphalexin (Nightingale, Greene & Quintiliani, 1975). The study by Sonneville et al. (1976) had suggested that the kinetics of cefoxitin might be dose dependent. When 0-5-g, 1-g, and 2-g i.v. doses were compared, kl0 and klt for the 2-g dose were significantly smaller (/»
Unavailability and pharmacokinetics of cefoxitin sodium
J. J. Schrogie, R. O. Davies, K. C. Yeb, D. Rogers, G. I. Holmes, H. Skeggs and C. M. Martin
This review paper establishes four major conclusions about cefoxitin sodium: 1. After i.v. administration, cefoxitin is distributed rapidly into the plasma and tissue fluids, and has a serum half-life of 40 to 60 min. It is not metabolized appreciably ( < 1 %) in animals or man. The volumes of distribution ( Vu V^, and V^) of the drug are similar to those found with cephalothin. 2. After i.m. administration, peak serum levels of cefoxitin are achieved in 20 to 30 min, and virtually the entire dose is available to the systemic circulation. The bioavailability of i.m. cefoxitin sodium is not affected by the use of lidocaine (0-5 % or 10%) as a diluent. 3. Cefoxitin is rapidly excreted intact into the urine by glomerular filtration and by renal tubular secretion. Renal clearance is greater than 250 ml/min/1-73 m1; about 75 % of each dose is recovered within the first 3 h after dosing. Probenecid administered concurrently decreases the excretion rate and increases the serum haJflife of cefoxitin. 4. The pharmacokinetics of i.v. cefoxitin are adequately described by use of a two-compartment, open model. Chemistry and microbiology Cefoxitin sodium (MK-306) is a new semi-synthetic cephamycin antibiotic, a derivative of cephamycin C. Its empirical formula is C18H1(SN3Na0i,Sg (MW 449-44). The sodium salt, rather than cefoxitin free acid, is used pharmaceutically because of the extreme insolubility of the free acid in aqueous vehicles and the high solubility (> 100 mg/ml) of the salt. The structural formula of cefoxitin sodium is shown in Figure 1. The structural significance of cefoxitin lies in the methoxy group at the 7a-position; this substituent
CHj0C0NH 2 COO"No + Figure 1. The structural formula of cefoxitin sodium (sodium 3-(hydroxymethyl)-7cr-methoxy-8-oxo-7[2-{2-thienyl)acetamido}-5-thia-l-azabicyclo[4.2.0]oct-2-erje-2-carboxylate carbamate (ester)). 69 03O5-7453/78/0701-BO69 501.00/0 © (1978) The British Society for Antimicrobial Chemotherapy
Downloaded from http://jac.oxfordjournals.org/ at Florida Atlantic University on May 21, 2015
Merck Sharp and Dohme Research Laboratories, West Point, Pennsylvania, U.S.A.
70
J. J. Schrogle et al.
Absorption In preclinical studies, cefoxitin sodium had been administered orally to mice, rats, and monkeys from whom blood and urine samples were collected periodically for bioassay.* Only about 2 % of the dose given to rats and mice and about 10% of the dose given to monkeys was excreted in the urine. Cefoxitin was not detectable in the blood of animals dosed orally with the drug. As a result, subsequent laboratory studies in vivo and clinical studies utilized parenteral administration of the drug. Binding and distribution In vitro The binding of cefoxitin to human plasma protein was studied by means of an ultrafiltration technique. At serum concentrations of 10 and 100/xg/ml, 73% of the drug was bound to plasma protein. In vivo (human) The distribution of cefoxitin into cerebrospinal fluid (CSF) had been studied by Liut (unpublished data) in 50 volunteers and patients undergoing diagnostic or therapeutic examination by lumbar, cisternal, or ventricular tap. Cefoxitin sodium, 2 g, was infused i.v. over 30 min in single or multiple doses, and specimens of serum and CSF were obtained 30 min after completion of the infusion. Both in normal subjects and in patients with increased CSF protein, levels of cefoxitin in the CSF were highest after the administration of multiple doses, especially when probenecid was given concurrently. In the presence of meningeal irritation, the concentration of cefoxitin in the CSF was somewhat greater. In patients with elevated CSF protein given single doses of cefoxitin, the mean concentration of cefoxitin was 52 and >0-63/xg/ml in serum and CSF, respectively. In • These unpublished data are onfileat the Merck Sharp & Dohme Research Laboratories, t C. Liu, Kansas City, Kansas.
Downloaded from http://jac.oxfordjournals.org/ at Florida Atlantic University on May 21, 2015
confers upon cefoxitin a high degree of resistance to inactivation by cephalosporinases (/Mactamases) produced by Gram-negative bacteria. Hence, cefoxitin has a very broad antibacterial spectrum in vivo and in vitro that includes all strains of cephalosporinsensitive bacteria and, more importantly, the majority of cephalosporin-resistant (i.e., cephalosporinase-producing) bacteria. These include Serratia marcescens, indolepositive Proteus, Providencia, anaerobic Gram-negative rods such as Bacteroides fragilis, as well as common pathogenic species of Gram-negative rods (Escherichia coli, Klebsiella, indole-negative Proteus, Salmonella, and Shigella). However, the spectrum does not include Pseudomonas aeruginosa and enterococci. This review summarizes information from eight clinical studies that specifically evaluated the pharmacokinetics and bioavailability of cefoxitin and the relevant results of preclinical studies; also cited are other supportive clinical studies that report the penetration of cefoxitin into cerebrospinal fluid and other body fluids during clinical use of the drug. The antimicrobial activity of cefoxitin in serum and urine was assayed by the cupplate diffusion technique (Grove & Randall, 1955), using test strains of Staphylococcus aureus or Bacillus subtilis. Chemical assays for cefoxitin and its metabolites utilized highpressure liquid chromatography (HPLQ. The minimum inhibitory concentration (MIC) of cefoxitin in serum for more than 90 % of organisms susceptible to the drug is 16^g/ml.
Bloavallablllty and phannacoldaedcs
71
Metabolism In several human studies, urine specimens were examined for cefoxitin and its metabolites by bioassay, an improved HPLC procedure, and thin-layer chromatography (unpublished data). More than 90% of the cefoxitin administered i.v. or i.m. was recovered from the urine as intact drug. Less than 1 % of the dose was present as the decarbamoyl metabolite, most of which was found 2 to 4 h after dosing (Sonneville, Kartodirdjo, Skeggs, Till & Martin, 1976). In some individuals, the metabolite was not detected. These results demonstrate that cefoxitin is not metabolized appreciably in man. Disposition Humans with normal renal function Studies of the disposition of cefoxitin sodium given i.v. to 9 volunteers were performed by Sonneville (1976). Single i.v. doses of 0-5, 1, and 2 g were infused over 3 min, according to a randomized crossover design. Serum level curves that were obtained are shown in Figure 2. The harmonic mean of the terminal serum half-life was 42, 59, and 56 min for
— • 0-5g
\
A
100 •=
50
i
20
|
10 r
o-— o I-Og t-
—x
2-0g
t
-\\
\ \
to
5 \
2 I
-
x
' \
> \
i
0
i
:
i
60
\ i
i
1
1
X 1
120 180 Time (mm)
I
1
1
240
Figure 2. Mean serum levels of cefoxitin after i.v. administration of single 0-5-, 1-, and 2-g doses over 3 min to apparently healthy volunteers (Sonneville et al, 1976).
Downloaded from http://jac.oxfordjournals.org/ at Florida Atlantic University on May 21, 2015
patients given 3 to 5 doses of cefoxitin every 6 h, plus probenecid, levels were 67 and 2 1 /xg/ml in serum and CSF, respectively. The failure of Geddes et al. (1977) to find cefoxitin in the CSF of 2 patients 1 h after the administration of a single 2-g i.v. dose infused over 5 min was, therefore, not unexpected, and was consistent with the results obtained by Liu. In a study by Geddes et al. (1977), biliary excretion of cefoxitin had been measured in 2 patients with post-cholecystectomy T-tubes in place. The concentrations of drug in the bile greatly exceeded the MIC for most Gram-negative bowel flora. In a lactating woman treated with cefoxitin for a urinary tract infection, the concentration of cefoxitin in breast milk 2 h after a 1-g i.v. dose was 5-6 mg/1.
72
J. J. Schrogie et al. Table I. Mean terminal serum half-life, renal clearance, and per cent urinary recovery in apparently healthy volunteers given cefoxitin i.v. 0-12 h i.v. dose (g)
Infusion time (min)
3
2 0 30 mg/kg
3 30 3 30
subjects*
4 9 8 2 9 6 6 6 9 9 18 3
5
half-life (min)
Renal clearance (ml/min/1 -73 m1)
urinary recovery (%dose)
38 42 43 38
2500 331-9 332-2 387-5 290-3 281-1 268-4 285-0 3220 247-7 205-9 4451 3290
78-0 86-7 98-5 770 741 800 760 99-0 77-6 78 0 104-0 1110
Terminal
59 41 49 47 47 56 59 50 47
89-9t
* Not all subjects included in all calculations, t 0 to 6 h recovery.
the 0-5-g, 1-g, and 2-g doses, respectively. Renal clearance of cefoxitin during the 2-h period after the infusion was 331-9, 290-3, and 247-7 ml/min/1 -73 m s for the 0-5-g, 1-g, and 2-g doses, respectively; about 77% of each dose was recovered within the first 12 h. Other studies (Goodwin, Raftery, Goldberg, Skeggs, Till & Martin, 1974; Kosmidis, Hamilton-Miller, Gilchrist, Kerry & Bmmfitt, 1973), in which single 0-25-g, 1-g, and 2-g doses were administered i.v. over periods ranging from 1 to 120 min, also demonstrated a terminal serum half-life between 40 and 60 min, renal clearance usually greater than 250 ml/min/1-73 m 2 , and 0-12 h urinary recoveries of cefoxitin of 70 to nearly 100% of Table II. Mean terminal serum half-life, renal clearance, and per cent urinary recovery in apparently healthy volunteers given cefoxitin i.m. 0-12 h
Dose (8) 0-25 0-5 10
2 0
Diluent
No. of
(W or L)* subjects! W W W W L L L L L L L
4 9 9 8 8 6 6 8 6 18 18
Terminal half-life Renal clearance (min) (ml/min/1 -73 m1) 440 460 45 0 64-8 69-4 89-8 69-6 47-9 75-6 53-9 52-8
• W = water; L = 0 5 or 1-0% lidocaine. t Not all subjects included in all calculations. } 0 to 6 h recovery.
320-0 358-9 405-8 197-2 245-7 347-7 356-4 280-3 330-4 280-3 288-9
urinary recovery (%dosc) 88-7| 870 900 74-8 821 95 0 90-4 77-4 86-3 83 0 78 0
Downloaded from http://jac.oxfordjournals.org/ at Florida Atlantic University on May 21, 2015
1 3 3 3 3 3 30 120
0-25 0-5 1-0
No. of
Bloavailability and phannacoklnetics
73
• • I g Lv.over 3 min o — o Ig Lm. with water x x Ig Lm.wlthO-5% lidocaine
180
240
Time (min)
Figure 3. Mean serum levels of ccfoxitin after administration of single 1 -0-g doses to apparently healthy volunteers (Sonneville et aJ., 1976).
the dose (Table I). Results of studies (Kosmidis et ai, 1973; also unpublished data) of the disposition of cefoxitin sodium administered i.m. in single doses of 0-25, 0-5, 10, and 2 0 g are summarized in Table II. Serum level curves after i.m. doses of 10 and 2 0 g, with and without lidocaine, are shown in Figures 3 and 4, respectively. The mean terminal half-life ranged from 44 to 90 min, renal clearance usually exceeded 250 ml/min/1 -73 m 2 , and 0 to 12 h urinary recoveries of cefoxitin ranged from 77 to 95 % of the dose. These results demonstrate that cefoxitin is cleared rapidly from the serum and is excreted rapidly and extensively into the urine in humans with normal renal function. The longer half-life after i.m. dosing has been attributed to continued absorption of the
• — « 2 g i v. over 3 0 min o—o 2g |jn. with 0 5% lidocaine x x 2g i.m.wlth 1 0 % lidocaine
\J\J
50
20
• r
•
^
\ N
10
2 I
•
_ 11
1 1
60
1
1 1
1
1
120 180 Time (min)
I
I
I 240
Figure 4. Mean serum levels of cefoxitin after administration of single 2 0-g doses to apparently healthy volunteers (unpublished study no. 46).
Downloaded from http://jac.oxfordjournals.org/ at Florida Atlantic University on May 21, 2015
120
60
74
J . J. Scbrogle et al. Table III. Effect of probenecid (1 0 g i.v.) on elimination of cefoxitin ( 1 0 g i.v.) in 6 apparently healthy volunteers Cp.0*
Cefoxitin Cefoxitin + probenecid
(ug/ml)
(min)
(0-1 h)
(0-12 h)
121 40-4
41 83
54-6 30-5
741 68-4
drug. The elimination of cefoxitin was not aifected by the use of lidocaine as a diluent for i.m. injection. Urinary recovery as a percent of dose was comparable after both i.v. and i.m. administration of cefoxitin. Effect of probenecid Since cefoxitin is eliminated by renal tubular secretion, as well as by glomerular filtration, the effect of probenecid on the elimination of cefoxitin was evaluated in man. Six apparently healthy volunteers received 1 g of cefoxitin i.v. after having received 1 g of probenecid i.v. as an infusion begun 1 h earlier (Goodwin et al., 1974) (Table III). The mean terminal serum half-life of cefoxitin under control conditions was 41 min; after probenecid, it increased to 83 min. The mean serum level of cefoxitin 60 min after a 3-min infusion was 121 /xg/ml during the control period and 40-4/ig/ml after probenecid had been given. Mean urinary recovery of cefoxitin during the first hour after dosing was 54-6% of the dose during the control period, but 30-5% of the dose after probenecid; however, after 12 h, recoveries during the control period and the probenecid-treatment period were comparable (74-1 and 68-4%, respectively.) Pharmacokinetics Antimicrobial activity in serum and urine after the administration of cefoxitin represents unchanged drug. The kinetics of the distribution and elimination of cefoxitin after its i.v administration are best represented by a two-compartment, open model, as shown in Figure 5. Note that klt, kn, and k10 represent first-order rate constants for intercompartmental drug movement; Vx is the apparent volume of distribution of the central compartment; Ar0 is the zero-order infusion rate; and T is the infusion time. The adequacy of this two-compartment, open model has been verified in various ways (Till, Benet & Kwan, 1974), e.g., the mean urinary excretion of cefoxitin (Table IV and Figure 6) predicted
*o Dose • * o r
"
Central compartment
*I2 ~
*2I
..
Peripheral compartment
J*'° Metabolism and excretion
Figure 5. Two-compartment open model showing distribution and elimination of cefoxitin following i.v. administration.
Downloaded from http://jac.oxfordjournals.org/ at Florida Atlantic University on May 21, 2015
* Cp« = Plasma concentration 60 min after a 3-min infusion, t £/(%) = Per cent of dose excreted in urine.
Bioavailablllty and pharmacoklnetics
75
I7OO 1500 1300
O
—
i 1100o
o
900
I
• Observed
700
2
I 5OO
-
1
0
1
1
I 24
2 Tlme(h)
Figure 6. Predicted and observed mean cumulative urinary recovery after 2 g i.v. cefoxitin infused over 30 min in apparently normal volunteers (unpublished study no. 46).
from individual kinetic parameters derived from a typical study (Table V) agrees closely with the results obtained. The model parameters obtained from the various studies in apparently healthy volunteers are listed in Table V; these estimated model parameters are comparable in the various studies and for all dose levels tested. They describe the distribution of drug between the peripheral and central compartments and show the rapid elimination of drug from the central compartment; the volume of distribution (KJ of the central compartment is about 8 1, reflecting the presence of drug in body fluids as well as in plasma. The 25-3 ±4-7 1 value for Vdff and of 16-1 ±2-5 1 for K ^ , determined by use of a twocompartment, open model, are in close agreement with the values so determined for cephalothin and ccphalexin (Nightingale, Greene & Quintiliani, 1975). The study by Sonneville et al. (1976) had suggested that the kinetics of cefoxitin might be dose dependent. When 0-5-g, 1-g, and 2-g i.v. doses were compared, kl0 and klt for the 2-g dose were significantly smaller (/»
