Drugs 42 (Suppl. 3): 13-21, 1991 0012-6667/91/0300-0013/$4.50/0 © Adis International Limited. All rights reserved. DRSUP320Sa
A Review of the Pharmacokinetics of Cefpodoxime Proxetil Marie T. Borin Clinical Pharmacokinetics Unit, Upjohn Laboratories, The Upjohn Company, Kalamazoo, Michigan, USA
Summary
Cefpodoxime proxetil is an orally absorbed broad spectrum third generation cephalosporin antibacterial. It is a prod rug that is de-esterified in vivo to its active metabolite, cefpodoxime. After single- and multiple-dose (l2-hourly) administration of cefpodoxime proxetil in the therapeutic dose range of 100 to 400mg of cefpodoxime equivalents, average peak plasma concentrations of cefpodoxime range from 1.0 to 4.5 mg/L and occur between 1.9 and 3.1 hours after administration. The half-life of cefpodoxime ranges from 1.9 to 2.8 hours. The absolute bioavailability of cefpodoxime proxetil tablets is 50%, and absorption is enhanced by concomitant administration of food. Raising gastric pH by pretreatment with antacids or H2-receptor antagonists results in reduced absorption. Binding of cefpodoxime to human plasma or serum protein is low (18 to 23%), suggesting that cefpodoxime should readily transfer across the capillary lining into tissues. Cefpodoxime undergoes minimal metabolism in humans. Drug not absorbed is degraded in the gastrointestinal tract and excreted in the faeces. As expected for a drug eliminated primarily by renal excretion, the disposition of cefpodoxime is altered in patients with impaired renal function; the half-life increases, while apparent plasma clearance and renal clearance decrease. The pharmacokinetics of cefpodoxime after oral administration of cefpodoxime proxetil are not affected by age.
Cefpodoxime proxetil is an orally absorbed broad spectrum third generation cephalosporin antibacterial. It is a prodrug that is de-esterified in vivo to its active metabolite, cefpodoxime. Cefpodoxime acts by binding to penicillin-binding proteins, thereby causing abnormal bacterial cell wall synthesis and lysis (Yokota et al. 1988). It is active in vitro and in vivo against a wide range of Grampositive and Gram-negative organisms, including staphylococci, streptococci, Haemophilus influenzae, Neisseria gonorrhoeae, Escherichia coli, Klebsiella pneumoniae, Citrobacter spp., and Proteus spp. (Fass & Helsel 1988; Jones & Barry 1988; Jones et al. 1988; Utsui et al. 1987). Clinical studies have
demonstrated the safety and efficacy of cefpodoxime proxetil for the treatment of urinary tract infections (Fujii et al. 1988; Yamasaki et al. 1988), gonorrhoea (Takizawa et al. 1988), skin and skin structure infections (Hoshino et al. 1988; Matsumoto et al. 1988; Nakayama et al. 1988), and upper and lower respiratory tract infections (Hayashi & Ohnuma 1988; Ishibashi et al. 1988; Kobayashi et al. 1988; Safran 1990). Cefpodoxime proxetil, administered as a dry syrup formulation, has been shown to be effective and safe in the treatment of urinary tract infections, pharyngitis/tonsillitis, otitis media, and skin and skin structure infections in paediatric patients (Fujii et al. 1989; Iwai et al. 1989;
Drugs 42 (Suppl. 3) 1991
14
Niino et al. 1989). Gastrointestinal tract-related events are the most frequently reported adverse effects associated with cefpodoxime proxetil use. The pharmacokinetics of cefpodoxime proxetil have been studied not only in healthy adult volunteers, but also in patients of all ages and in individuals with impaired renal function. Concentrations of cefpodoxime in plasma, serum, urine, and other biological fluids and tissues have been determined by both microbiological (Hisoaka et al. 1988; Patel 1990) and high performance liquid chromatography (HPLC) methods (Bombardt et al. 1991; Molina et al. 1991; Sekine et al. 1988; Steenwyk et al. 1991). There has been good agreement between assay results; however, the HPLC assay in plasma is more sensitive than the microbiological method (Borin et al. 1991). In the following review, the stated dosage of cefpodoxime proxetil reflects only the cefpodoxime component of the prodrug (cefpodoxime equivalents).
1. Absorption and Plasma Concentrations 1.1 Single-Dose Studies Cefpodoxime pharmacokinetic parameters after single-dose administration of cefpodoxime proxetil tablets to healthy adults are provided in table I. After administration of single doses ranging from 100 to 800mg, the drug was fairly rapidly absorbed, with an absorption half-life of 0.52 to 1.0 hours and a lag time for absorption of 0.3 to 0.4 hours; the terminal elimination half-life ranged from 2.1 hours after the 100mg dose to 3.2 hours after the 800mg dose (Borin et al. 1991). The pharmacokinetics of cefpodoxime were linear and dose proportional over the therapeutic dose range of 100 to 400mg. At doses exceeding 400mg, there was evidence of dose dependency in cefpodoxime pharmacokinetic parameters; peak plasma cefpodoxime concentration (C max ) and area under the plasma concentration-time curve (AUC) increased less than proportionately with dose, urinary recovery was lower, and elimination half-life was longer (Borin et al. 1991; Tremblay et al. 1990). The slower rate of drug absorption and the decrease in the extent
of absorption observed with increasing dose may be due to limitations in drug dissolution at the higher doses. The absolute bioavailability of cefpodoxime proxetil administered as a 100mg tablet, relative to an intravenous infusion of cefpodoxime sodium, was about 50% (Tremblay et al. 1990). The lack of complete drug absorption is probably due to degradation of cefpodoxime proxetil in the gastrointestinal tract. 1.2 Multiple-Dose Studies Pharmacokinetic parameters after multiple-dose administration of cefpodoxime proxetil tablets to healthy volunteers are presented in table I. After twice-daily (12-hourly) administration of 100, 200, and 400mg doses for 15 days to healthy normal volunteers, steady-state was achieved after the first dose, and drug accumulation was negligible. Dose proportionality and linearity in cefpodoxime pharmacokinetic parameters were observed over this dose range after the initial dose and at steady-state. Average 12-hour (trough) plasma concentrations of cefpodoxime on the last day of administration were 0.089 mg/L after the 100mg dose, 0.15 mg/L after the 200mg dose, and 0.28 mg/L after the 400mg dose (Borin et al. 1991).
2. Distribution The volume of distribution of cefpodoxime after intravenous administration of cefpodoxime sodium is about 32L (Tremblay et al. 1990), which corresponds with the extensive drug distribution observed in human body fluids and tissues after oral administration of cefpodoxime proxetil (table II). Clinically relevant concentrations of cefpodoxime were present as early as I hour after administration (myometrium) and were sustained for up to 12 hours after administration (lung tissue and pleural fluid). Very low concentrations « 0.08 mg/ L) of cefpodoxime have been detected in breast milk (Yamamoto et al. 1988). Penetration of drug from plasma into skin blister fluid or inflammatory fluid was essentially 100%
O'Neill et al. (1990) Hughes et al. (1989)
8
8
7
100 q12h 200 q12h 400 q12h 200 q12h 400 q12h
100 200 400 600 800 200 400 100 200 400 800 100 100 200 200 200 200 200 100
Dosea (mg)
2.33 4.20
24.0
2.4
2.3
3.07/2.43
2.38/2,00
2.34/2.23 3.76/3.62
2.25/1.88
2.00 2.25 2.56 3.25 2.86 3.1 2.9 2.36 2.42 2.50 2.94 2.25 2.38 2.9 2.75 2.44 2.75 2.50 2.20
t max (h)
1.23/1.19
1.45 2.34 3.72 5.31 6.61 2.18 4.16 1.37 2.60 4.50 6.95 0.96 1.32 2.1 2.62 2.24 2.32 2.34 1.36
Cmax (mg/L)
11.8
22.5/20.5
12.8/11.8
6.57/6.56
7.38 13.1 22.7 35.8 44.3 11.8 25.0 7.03 14.5 26.5 46.4 4.75 7.27 12.4 13.5 13.4 12.8 14.8 6,82
AUC (mg/L· h)
306/339
2.24/2.27
2.7
296
309
279/304
2.29/2.32
2.6
271/275
238
278
249 268 305 288 309 275 264
CLp/f (ml/min)
2.28/2.28
2.09 2.45 2.84 2.75 3.15 2.7 2.6 2.11 2.31 2.42 2.88 2.42 2.67 2.2 2.08 2.17 2.24 2.55 1.87
Half-life (h)
28.7/29.2
29.5/30.3
78.7/87.9 85.2/95.8
29,5/35.3
40.2 39.2 23.8 27.9 42.8 38.4 32.2 41.0 32.4 39.4 32.2 35.9
39.5 32.3 32.3 30.0 26.8
UR (%of dose)
79.1/93.3
74.3 88,3
97.8 93.2 60.7 79.2 158 91.7 88.4
97.6 84.4 96.0 84.7 81.2
CLR (ml/min)
a Dose expressed as cefpodoxime equivalents. b Selected values presented as initial/steady-state. Abbreviations: AUC = area under the plasma or serum concentration-time curve; Cmax = peak plasma or serum concentration; t max = time to peak plasma or serum concentration; CLp/f = apparent systemic clearance; CLR = renal clearance; UR = urinary recovery; q = every.
Borin et al. (1990)
8
Multiple dose b Borin et al. (1991)
8
12 6 9
Hughes et al. (1990) St Peter et al. (1990) Uchida et al. (1988)
17
12 12 6 16
Borin et al. (1990)
Tremblay et al. (1990)
No. of subjects
8 8 8 8 7 8 8 12
Single dose Borin et al. (1991)
References
Table I. Cefpodoxime pharmacokinetic parameters in healthy adults after various oral doses of cefpodoxime proxetil
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A Review of the Pharmacokinetics of Cefpodoxime Proxetil Marie T. Borin Clinical Pharmacokinetics Unit, Upjohn Laboratories, The Upjohn Company, Kalamazoo, Michigan, USA
Summary
Cefpodoxime proxetil is an orally absorbed broad spectrum third generation cephalosporin antibacterial. It is a prod rug that is de-esterified in vivo to its active metabolite, cefpodoxime. After single- and multiple-dose (l2-hourly) administration of cefpodoxime proxetil in the therapeutic dose range of 100 to 400mg of cefpodoxime equivalents, average peak plasma concentrations of cefpodoxime range from 1.0 to 4.5 mg/L and occur between 1.9 and 3.1 hours after administration. The half-life of cefpodoxime ranges from 1.9 to 2.8 hours. The absolute bioavailability of cefpodoxime proxetil tablets is 50%, and absorption is enhanced by concomitant administration of food. Raising gastric pH by pretreatment with antacids or H2-receptor antagonists results in reduced absorption. Binding of cefpodoxime to human plasma or serum protein is low (18 to 23%), suggesting that cefpodoxime should readily transfer across the capillary lining into tissues. Cefpodoxime undergoes minimal metabolism in humans. Drug not absorbed is degraded in the gastrointestinal tract and excreted in the faeces. As expected for a drug eliminated primarily by renal excretion, the disposition of cefpodoxime is altered in patients with impaired renal function; the half-life increases, while apparent plasma clearance and renal clearance decrease. The pharmacokinetics of cefpodoxime after oral administration of cefpodoxime proxetil are not affected by age.
Cefpodoxime proxetil is an orally absorbed broad spectrum third generation cephalosporin antibacterial. It is a prodrug that is de-esterified in vivo to its active metabolite, cefpodoxime. Cefpodoxime acts by binding to penicillin-binding proteins, thereby causing abnormal bacterial cell wall synthesis and lysis (Yokota et al. 1988). It is active in vitro and in vivo against a wide range of Grampositive and Gram-negative organisms, including staphylococci, streptococci, Haemophilus influenzae, Neisseria gonorrhoeae, Escherichia coli, Klebsiella pneumoniae, Citrobacter spp., and Proteus spp. (Fass & Helsel 1988; Jones & Barry 1988; Jones et al. 1988; Utsui et al. 1987). Clinical studies have
demonstrated the safety and efficacy of cefpodoxime proxetil for the treatment of urinary tract infections (Fujii et al. 1988; Yamasaki et al. 1988), gonorrhoea (Takizawa et al. 1988), skin and skin structure infections (Hoshino et al. 1988; Matsumoto et al. 1988; Nakayama et al. 1988), and upper and lower respiratory tract infections (Hayashi & Ohnuma 1988; Ishibashi et al. 1988; Kobayashi et al. 1988; Safran 1990). Cefpodoxime proxetil, administered as a dry syrup formulation, has been shown to be effective and safe in the treatment of urinary tract infections, pharyngitis/tonsillitis, otitis media, and skin and skin structure infections in paediatric patients (Fujii et al. 1989; Iwai et al. 1989;
Drugs 42 (Suppl. 3) 1991
14
Niino et al. 1989). Gastrointestinal tract-related events are the most frequently reported adverse effects associated with cefpodoxime proxetil use. The pharmacokinetics of cefpodoxime proxetil have been studied not only in healthy adult volunteers, but also in patients of all ages and in individuals with impaired renal function. Concentrations of cefpodoxime in plasma, serum, urine, and other biological fluids and tissues have been determined by both microbiological (Hisoaka et al. 1988; Patel 1990) and high performance liquid chromatography (HPLC) methods (Bombardt et al. 1991; Molina et al. 1991; Sekine et al. 1988; Steenwyk et al. 1991). There has been good agreement between assay results; however, the HPLC assay in plasma is more sensitive than the microbiological method (Borin et al. 1991). In the following review, the stated dosage of cefpodoxime proxetil reflects only the cefpodoxime component of the prodrug (cefpodoxime equivalents).
1. Absorption and Plasma Concentrations 1.1 Single-Dose Studies Cefpodoxime pharmacokinetic parameters after single-dose administration of cefpodoxime proxetil tablets to healthy adults are provided in table I. After administration of single doses ranging from 100 to 800mg, the drug was fairly rapidly absorbed, with an absorption half-life of 0.52 to 1.0 hours and a lag time for absorption of 0.3 to 0.4 hours; the terminal elimination half-life ranged from 2.1 hours after the 100mg dose to 3.2 hours after the 800mg dose (Borin et al. 1991). The pharmacokinetics of cefpodoxime were linear and dose proportional over the therapeutic dose range of 100 to 400mg. At doses exceeding 400mg, there was evidence of dose dependency in cefpodoxime pharmacokinetic parameters; peak plasma cefpodoxime concentration (C max ) and area under the plasma concentration-time curve (AUC) increased less than proportionately with dose, urinary recovery was lower, and elimination half-life was longer (Borin et al. 1991; Tremblay et al. 1990). The slower rate of drug absorption and the decrease in the extent
of absorption observed with increasing dose may be due to limitations in drug dissolution at the higher doses. The absolute bioavailability of cefpodoxime proxetil administered as a 100mg tablet, relative to an intravenous infusion of cefpodoxime sodium, was about 50% (Tremblay et al. 1990). The lack of complete drug absorption is probably due to degradation of cefpodoxime proxetil in the gastrointestinal tract. 1.2 Multiple-Dose Studies Pharmacokinetic parameters after multiple-dose administration of cefpodoxime proxetil tablets to healthy volunteers are presented in table I. After twice-daily (12-hourly) administration of 100, 200, and 400mg doses for 15 days to healthy normal volunteers, steady-state was achieved after the first dose, and drug accumulation was negligible. Dose proportionality and linearity in cefpodoxime pharmacokinetic parameters were observed over this dose range after the initial dose and at steady-state. Average 12-hour (trough) plasma concentrations of cefpodoxime on the last day of administration were 0.089 mg/L after the 100mg dose, 0.15 mg/L after the 200mg dose, and 0.28 mg/L after the 400mg dose (Borin et al. 1991).
2. Distribution The volume of distribution of cefpodoxime after intravenous administration of cefpodoxime sodium is about 32L (Tremblay et al. 1990), which corresponds with the extensive drug distribution observed in human body fluids and tissues after oral administration of cefpodoxime proxetil (table II). Clinically relevant concentrations of cefpodoxime were present as early as I hour after administration (myometrium) and were sustained for up to 12 hours after administration (lung tissue and pleural fluid). Very low concentrations « 0.08 mg/ L) of cefpodoxime have been detected in breast milk (Yamamoto et al. 1988). Penetration of drug from plasma into skin blister fluid or inflammatory fluid was essentially 100%
O'Neill et al. (1990) Hughes et al. (1989)
8
8
7
100 q12h 200 q12h 400 q12h 200 q12h 400 q12h
100 200 400 600 800 200 400 100 200 400 800 100 100 200 200 200 200 200 100
Dosea (mg)
2.33 4.20
24.0
2.4
2.3
3.07/2.43
2.38/2,00
2.34/2.23 3.76/3.62
2.25/1.88
2.00 2.25 2.56 3.25 2.86 3.1 2.9 2.36 2.42 2.50 2.94 2.25 2.38 2.9 2.75 2.44 2.75 2.50 2.20
t max (h)
1.23/1.19
1.45 2.34 3.72 5.31 6.61 2.18 4.16 1.37 2.60 4.50 6.95 0.96 1.32 2.1 2.62 2.24 2.32 2.34 1.36
Cmax (mg/L)
11.8
22.5/20.5
12.8/11.8
6.57/6.56
7.38 13.1 22.7 35.8 44.3 11.8 25.0 7.03 14.5 26.5 46.4 4.75 7.27 12.4 13.5 13.4 12.8 14.8 6,82
AUC (mg/L· h)
306/339
2.24/2.27
2.7
296
309
279/304
2.29/2.32
2.6
271/275
238
278
249 268 305 288 309 275 264
CLp/f (ml/min)
2.28/2.28
2.09 2.45 2.84 2.75 3.15 2.7 2.6 2.11 2.31 2.42 2.88 2.42 2.67 2.2 2.08 2.17 2.24 2.55 1.87
Half-life (h)
28.7/29.2
29.5/30.3
78.7/87.9 85.2/95.8
29,5/35.3
40.2 39.2 23.8 27.9 42.8 38.4 32.2 41.0 32.4 39.4 32.2 35.9
39.5 32.3 32.3 30.0 26.8
UR (%of dose)
79.1/93.3
74.3 88,3
97.8 93.2 60.7 79.2 158 91.7 88.4
97.6 84.4 96.0 84.7 81.2
CLR (ml/min)
a Dose expressed as cefpodoxime equivalents. b Selected values presented as initial/steady-state. Abbreviations: AUC = area under the plasma or serum concentration-time curve; Cmax = peak plasma or serum concentration; t max = time to peak plasma or serum concentration; CLp/f = apparent systemic clearance; CLR = renal clearance; UR = urinary recovery; q = every.
Borin et al. (1990)
8
Multiple dose b Borin et al. (1991)
8
12 6 9
Hughes et al. (1990) St Peter et al. (1990) Uchida et al. (1988)
17
12 12 6 16
Borin et al. (1990)
Tremblay et al. (1990)
No. of subjects
8 8 8 8 7 8 8 12
Single dose Borin et al. (1991)
References
Table I. Cefpodoxime pharmacokinetic parameters in healthy adults after various oral doses of cefpodoxime proxetil
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