Marie T. Borin

A Review of the Pharmacokinetics of Cefpodoxime Proxetil

SummaryCefpodoxime 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. After single- and multiple-dose (12-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.

In vitro and in vivo evaluation of whole and half tablets of sustained-release adinazolam mesylate

The mechanism of release from sustained-release adinazolam mesylate tablets was assessed by the Higuchi equation and by analysis of drug release profiles through 60% released using the Peppas equation. Computed values of the diffusional exponent, n, ranged from 0.59 to 0.66. Values of n in this range are consistent with a mixed mechanism of release, with diffusion of drug through the hydrated polymer matrix and relaxation of this matrix being the principal processes controlling release. The rate of in vitro drug release was increased for half tablets relative to whole tablets and is attributed to an increase in the surface to volume ratio of half tablets of about 16%. This increase in surface-to-volume ratio of half tablets was reflected by an increase in the constant, k, from the Peppas equation of 20–23% and by an increase in the slope of Higuchi plots of 12–18% for four lots of tablets. In vivo/in vitro relationships from two bioavailability studies were thoroughly evaluated. Using either a linear or a quadratic relationship, an in vivo/in vitro correlation exists for sustained-release adinazolam mesylate tablets.

The effect of food on gastrointestinal (GI) transit of sustained-release ibuprofen tablets as evaluated by gamma scintigraphy

The GI transit of radiolabeled sustained-release ibuprofen 800-mg tablets in eight healthy, fed volunteers was monitored using external gamma scintigraphy. Ibuprofen serum concentrations were determined from blood samples drawn over 36 hr following dosing. Sustained-release ibuprofen tablets containing 0.18% of 170Er2O3 (>96% 170Er) in the bulk formulation were manufactured under pilot-scale conditions and were radiolabeled utilizing a neutron activation procedure which converted stable 170Er to radioactive 171Er (t1/2 = 7.5 hr). At the time of dosing, each tablet contained 50 µCi of 171Er. Dosage form position was reported at various time intervals. In five subjects the sustained-release tablet remained in the stomach and eroded slowly over 7–12 hr, resulting in gradual increases in small bowel radioactivity. In the remaining three subjects, the intact tablet was ejected from the stomach and a gastric residence time of approximately 4 hr was measured. This is in marked contrast to a previous study conducted in fasted volunteers in which gastric retention time ranged from 10 to 60 min. Differences in GI transit between fed and fasted volunteers had little effect on ibuprofen bioavailability. AUC and Tmax were unaltered and Cmax was increased by 24%, which is in agreement with results from a previous, crossover-design food effect study.

Single dose bioavailability of acetaminophen following oral administration

Saliva acetaminophen concentrations were determined in 15 subjects after administration of 5 different doses of commercial acetaminophen tablets (325 mg, 500 mg, 1000 mg, 1500 mg and 2000 mg acetaminophen). Drug concentration-time profiles were best described by either a one- or two-compartment pharmacokinetic model, depending on the treatment and subject. Statistically significant (P < 0.05) differences in elimination rate and dose-corrected area under the curve were found among treatments (doses) suggestive of dose-dependent pharmacokinetics.

Pharmacokinetic and Tolerance Studies of Cefpodoxime after Single‐ and Multiple‐Dose Oral Administration of Cefpodoxime Proxetil

Cefpodoxime proxetil, a third generation, broad‐spectrum, oral cephalosporin, was administered in single doses of 100, 200, 400, 600, and 800 mg (dose expressed as Cefpodoxime equivalents) and multiple doses of 100, 200, and 400 mg twice daily to healthy volunteers. The pharmacokinetics of the active metabolite, cefpodoxime, and tolerance of Cefpodoxime proxetil were determined. Results from the single‐dose study indicate that Cefpodoxime exhibits nonlinear pharmacokinetics over the dose range of 100 to 800 mg. This nonlinearity is primarily due to differences in dose‐normalized AUC and Cmax, urinary recovery, and half‐life between one or more of the higher‐dose treatment groups and the 100‐mg dosing group. After multiple‐dose (twice daily) administration for 15 days, steady state is achieved on the second day of dosing, and there is no drug accumulation. Cefpodoxime pharmacokinetics are linear with dose over the clinically relevant dosing range of 100 to 400 mg. Microbiologic and HPLC plasma assay results are highly correlated, with close agreement between HPLC‐ and microbioiogic‐determined pharmacokinetic parameter estimates. Cefpodoxime proxetil was well tolerated in both studies. The most frequent medical events were related to gastrointestinal problems and consisted of transient loose stools in three subjects in the single‐dose study and antibiotic‐associated diarrhea in one subject in the multiple‐dose study.

Effect of competing anions on binding of bile salts by cholestyramine

The binding of bile salts by cholestyramine may be influenced by other anions, as the Langmuir adsorption coefficients for three bile salts tested were similar to the model anion, citrate. However, the selectivity coefficient indicated preferential binding of cholate anion in comparison to citrate anion. Binding experiments confirmed cholestyramines preference for bile salts as the presence of other anions reduced but did not prevent the binding of cholate anion. Binding of cholate anion was reduced in direct relationship to the citrate anion concentration. Prior exposure of cholestyramine to citrate anion caused the binding of cholate anion to decrease slightly. Sequential exposure of cholestyramine to simulated gastric fluid and simulated intestinal fluid containing cholate anion resulted in a decrease in cholate binding which was attributed to competition with anions present in the gastrointestinal fluids. Components of tomato juice and orange juice, fluids commonly used to enhance ingestion of cholestyramine, also reduced the binding of cholate anion.

Effect of Anions on Adsorption of Bile Salts by Colestipol Hydrochloride

The Langmuir affinity constant and adsorptive capacity for the adsorption of citrate anion or cholate anion by colestipol hydrochloride at pH 7.5, 37°C, were similar. Prior exposure of colestipol hydrochloride to citrate anion caused the adsorption of cholate anion to decrease slightly in comparison to a control utilizing only cholate anion. The concentration of citrate anion was found to be directly related to the decrease in cholate anion adsorption. Simultaneous exposure of colestipol hydrochloride to citrate and cholate anions at pH 7.5, 37°C, resulted in the same adsorption of cholate anion as sequential exposure to citrate anion followed by cholate anion. Sequential exposure of colestipol hydrochloride to simulated gastric fluid and simulated intestinal fluid containing cholate anion resulted in a small decrease in cholate adsorption which was attributed to competition with phosphate anion in simulated intestinal fluid. Pepsin in the simulated gastric fluid did not affect adsorption of cholate anion from simulated intestinal fluid. Preexposure to components of tomato juice and orange juice also slightly reduced the adsorption of cholate anion by colestipol hydrochloride.

In vitro adsorption of bile salts by colestipol hydrochloride

The acid–base titration of colestipol hydrochloride exhibits no sharp inflection points, indicating a weakly basic anion-exchange copolymer. The swelling of colestipol hydrochloride in water and the adsorption of cholate anion are inversely related to pH and are, therefore, related to the ionization state of the copolymer. The Langmuir adsorption parameters at pH 7.5 and 37°C are similar for cholate, glycocholate, and taurocholate anions. Adsorption capacity was not related to particle size and exceeded the adsorptive capacity of the external surface by three orders of magnitude. Therefore, it is believed that the swelling of colestipol hydrochloride makes extensive internal surface area available for adsorption of bile salts. The rate of adsorption depends on the concentration of sodium cholate to which the colestipol hydrochloride is exposed. Adsorption was complete within 5 min when the concentration was below the adsorptive capacity. In contrast, adsorption at levels of sodium cholate at or above the adsorptive capacity was not complete within a 3-hr test period.

Disposition of Cefpodoxime Proxetil in Hemodialysis Patients

The disposition of cefpodoxime after single, oral 200‐mg doses of cefpodoxime proxetil (cefpodoxime equivalents) was investigated in an open‐Jabel study of six patients with end‐stage renal disease currently maintained on hemodialysis. Subjects were randomly assigned to one of two treatment groups, which differed in the sequence of the interdialytic and intradialytic periods. Doses were separated by at least 2 weeks. Blood samples were serially collected for 48 hours after each treatment; if obtainable, urine was also collected over this same period. During the intradialytic period, hemodialysis was scheduled to begin approximately 3 hours after dosing, and dialysate was collected before and until the end of dialysis. Average cefpodoxime elimination half‐life for the interdialytic period was 18.0 ± 6.5 hours; apparent total body clearance was 28.6 ± 13 mL/minute. The half‐life during hemodialysis, 2.66 ± 0.74 hours, was considerably shorter than that after hemodialysis, 19.2 ± 3.5 hours, in the intradialytic period of the study. Hemodialysis clearance of cefpodoxime was 120 ± 31 mL/minute, which was 57.1 ± 13% and 71.7 ± 25% of the hemodialysis clearance for urea nitrogen and creatinine, respectively. The 2.86 ± 0.25 hour hemodialysis session removed 22.4 ± 2.9% of the administered dose, as assessed by cefpodoxime recovery in dialysate. A maximum rebound in cefpodoxime plasma concentration of 0.41 ± 0.33 mcg/mL was observed, at about one‐half hour after the end of hemodialysis. Based on these results, dosage adjustment is not required, but extension of the dosing interval is warranted. The recommended dosing interval for cefpodoxime proxetil in patients with end‐stage renal disease is three times a week, after hemodialysis.

Systemic Absorption of Clindamycin after Intravaginal Administration of Clindamycin Phosphate Ovule or Cream

The absolute bioavailability of clindamycin phosphate vaginal ovule with comparison to a reference treatment of clindamycin phosphate sterile solution, as well as the relative bioavailability of the ovule compared to clindamycin phosphate vaginal cream, was evaluated in 12 healthy adult female volunteers. Subjects were randomly assigned to receive either the ovule or cream formulation intravaginally for 3 consecutive days during the two‐way crossover portion of the study. During a third treatment period, all subjects received 100 mg of clindamycin as a 4‐minute intravenous infusion of clindamycin phosphate sterile solution (10 mg/mL). Clindamycin concentrations in serum were assayed by a high‐performance liquid chromatography method with detection by mass spectrometry. Pharmacokinetic analyses of the serum data indicated low systemic absorption of clindamycin from the vaginal cream (about 4%), consistent with results of previous bioavailability studies. Following intravaginal administration of the clindamycin phosphate ovule, systemic absorption averaged 30%, which was approximately sevenfold greater than after dosing with the vaginal cream. The higher drug absorption for the ovule may be related to differences in formulation effects on the vaginal membrane. Nevertheless, systemic exposure to clindamycin from the ovule is still considerably lower than from a therapeutic oral dose.