Catherine A. Knupp

Pharmacokinetics of cefepime after single and multiple intravenous administrations in healthy subjects.

The pharmacokinetics of cefepime in 31 young, healthy volunteers were assessed after the administration of single and multiple 250-, 500-, 1,000-, or 2,000-mg intravenous doses. Each subject received a single dose of cefepime via a 30-min intravenous infusion on day 1 of the study. Starting from day 2, subjects received multiple doses of cefepime every 8 h for 9 days, and on the morning of day 11, they received the last dose. Serial blood and urine samples were collected after administration of the first dose and on days 1, 6, and 11. Cefepime concentrations in plasma and urine were assayed by using reverse-phase high-performance liquid chromatography with UV detection. Data were evaluated by noncompartmental methods to determine pharmacokinetic parameters. The mean half-life of cefepime was approximately 2 h and did not vary with the dose or duration of dosing. The regression analyses of peak levels (Cmax) in plasma at the end of the 30-min intravenous infusion and the area under the plasma concentration-versus-time curve (AUCo-infinity) showed a dose-proportional response. The steady-state volume of distribution (Vss) was approximately 18 liters and was independent of the administered dose. The multiple-dose pharmacokinetic data are suggestive of a lack of accumulation or change in clearance of cefepime on repeated dosing. Cefepime was excreted primarily unchanged in urine. The recovery of intact cefepime in urine was invariant with respect to the dose and accounted for over 80% of the dose. The values for renal clearance ranged from 99 to 132 ml/min and were suggestive of glomerular filtration as the primary excretion mechanism. It is concluded that cefepime linear pharmacokinetics in healthy subjects.

Pharmacokinetics of cefepime in subjects with renal insufficiency

The pharmacokinetics of intravenously administered cefepime (1000 mg over 30 minutes) were studied in 5 healthy volunteers and 20 patients with various degrees of renal impairment. Cefepime concentrations in plasma, urine, and hemodialysate were assayed using reverse‐phase HPLC with ultraviolet detection. Mean peak plasma concentrations of cefepime at the end of 30‐minute infusion ranges from 63.5 to 73.9 μg/ml and were not affected by the degree of renal impairment. The half‐life of cefepime was approximately 2.3 hours in subjects with normal kidney function; it increased proportionately as renal function decreased. Significant linear relationships between total body clearance and creatinine clearance, as well as renal clearance and creatinine clearance, were observed. The mean volume of distribution at steady state in healthy volunteers was 20.5 liters and was not significantly altered in subjects with renal insufficiency. The mean cumulative urinary recovery of cefepime in healthy volunteers was 82.9% of the administered dose and significantly decreased in subjects with creatinine clearance less than 30 ml/min. Hemodialysis significantly shortened the elimination half‐life from 13.5 hours during the predialysis period to 2.3 hours during the dialysis period. Cefepime dosage should be reduced in proportion to the decline in creatinine clearance.

Safety, tolerance, and pharmacokinetic evaluation of cefepime after administration of single intravenous doses.

In this double-blind, single-dose phase I study, the safety and tolerance of cefepime were assessed in 24 healthy male subjects, with ceftazidime as the control drug. Four subjects in each of the six dose groups (62.5, 125, 250, 500, 1,000, or 2,000 mg as a 30-min intravenous infusion) received each antibiotic, according to a crossover design, with a 2-day washout period between treatments. Blood and urine samples were obtained to characterize the pharmacokinetics of cefepime. Plasma and urine samples were assayed for intact cefepime. Samples containing ceftazidime were discarded. The adverse effects observed in the study were mild and infrequent, with prompt recovery from adverse experiences and abnormal laboratory values. The cefepime pharmacokinetic parameters for the therapeutically significant doses of 250 to 2,000 mg appeared to be proportional to dose and similar to literature values for ceftazidime. The elimination half-life of about 2 h was independent of the dose. Urinary recovery of intact cefepime was invariant with respect to dose; an overall mean value of 82% of dose was obtained for the four highest levels. Mean renal clearance was 105 ml/min and suggestive of glomerular filtration as the primary excretion mechanism. In normal humans, the safety and pharmacokinetic profiles of cefepime are very similar to those of ceftazidime.

Food-induced reduction in bioavailability of didanosine.

The effect of food on the pharmacokinetics of didanosine was evaluated in an open two‐way crossover study in eight male subjects who tested seropositive for the human immunodeficiency virus. Each subject received a single 375 mg oral dose of didanosine in a chewable tablet form with or without food. Serial blood samples and the total urinary output during 12 hours were collected and assayed for intact didanosine by validated HPLC methods. The mean (SD) values for the peak concentration (Cmax) of didanosine in plasma were 2789 (1032) ng/ml and 1291 (536) ng/ml and for the area under the plasma concentration‐time curves (AUC0‐∞) were 3902 (1316) and 2083 (922) hr · ng/ml, and the urinary excretion (%UR) accounted for 21% and 11% of dose as intact didanosine when didanosine was given under fasting conditions and with food, respectively. The values of Cmax, AUC0‐∞, and %UR were significantly lower for subjects who received didanosine with food compared with those observed for the fasted subjects. The time to reach Cmax, mean residence time, elimination half‐life, and renal clearance remained essentially the same between the two treatments. The results from this study indicated that the rates of absorption and elimination were not affected by the presence of food; however, the extent of absorption, as indicated by AUC0‐∞ and %UR, was reduced significantly in the presence of food. It is recommended that didanosine be administered under fasting conditions.

Safety, Tolerance, and Pharmacokinetics of Cefepime Administered Intramuscularly to Healthy Subjects

Steady state pharmacokinetics, absolute bioavailability, and dose proportionality of cefepime were evaluated in healthy male subjects after single (250, 500, 1000, or 2000 mg) and multiple (1000 mg every 12 hours for 10 days) intramuscular injections. Safety and tolerance were also monitored. High performance liquid chromatography/UV methodology was used to determine cefepime concentrations in plasma and urine. Key pharmacokinetic parameters were determined using noncompartmental methods. Cefepime was absorbed rapidly; mean peak times were 1.0–1.6 hours. Pharmacokinetics were linear over the 250‐mg to 2000‐mg dose range, with mean total body clearance ranging from 125 to 141 mL/min. The peak plasma concentration and area under the curve increased in a dose‐proportional manner. The apparent elimination half‐life (2 hours) did not appear to be influenced by dose or by duration of dosing. No accumulation of cefepime was observed during the multiple‐dose study. More than 80% of the administered dose was excreted in the urine as unchanged cefepime, and absolute bioavailability after intramuscular dose was 100%. Cefepime was well tolerated. Most subjects experienced none to mild pain and only minimum discomfort at the site of injection.

Effects of age and gender on pharmacokinetics of cefepime.

The effects of age and gender on the pharmacokinetics of cefepime were examined in 48 volunteers following administration of a single 1,000-mg intravenous dose. Male and female subjects were divided into four groups, each consisting of 12 subjects, according to their age and gender. The young subjects were between 20 and 40 years of age and elderly subjects were between 65 and 81 years of age. Serial blood and urine samples were collected from each subject and were analyzed for cefepime by validated high-pressure liquid chromatographic assays with UV detection. Key pharmacokinetic parameters were calculated by noncompartmental methods. There were no gender-related differences in elimination half-life (t1/2) and weight-normalized total body clearance (CLT), renal clearance (CLR), and steady-state volume of distribution (Vss). Statistically significant age-related effects were found for t1/2, CLT, CLR, and Vss parameters. In different study groups, Vss ranged from 0.21 to 0.24 liter/kg. The values for Vss were significant greater for elderly subjects than they were for young subjects. The cefepime t1/2 was significantly longer in elderly subjects (about 3 h) than that observed in young subjects (about 2.2 h). The mean values for CLT and CLR in the four study groups ranged from 1.11 to 1.56 and 0.99 to 1.44 ml/min/kg, respectively. In elderly subjects, the estimates for CLT and CLR were significantly lower than those observed in young subjects. Linear regression revealed good correlations between clearance values of cefepime and creatinine. The magnitude of age-related changes in the pharmacokinetics of cefepime is not significant enough to recommend dosage adjustment in elderly patients with kidney functions normal for their age.

Pharmacokinetics of cefepime in patients undergoing continuous ambulatory peritoneal dialysis.

The pharmacokinetics of cefepime were studied in 10 male patients receiving continuous ambulatory peritoneal dialysis therapy. Five patients received a single 1,000-mg dose and the other five received a single 2,000-mg dose; all doses were given as 30-min intravenous infusions. Serial plasma, urine, and peritoneal dialysate samples were collected; and the concentrations of cefepime in these fluids were measured over 72 h by using a high-performance liquid chromatographic assay with UV detection. Pharmacokinetic parameters were calculated by noncompartmental methods. The peak concentrations in plasma and the areas under the plasma concentration-versus-time curve for the 2,000-mg dose group were twice as high as those observed for the 1,000-mg dose group. The elimination half-life of cefepime was about 18 h and was independent of the dose. The steady-state volume of distribution was about 22 liters, and values for the 1,000- and 2,000-mg doses were not significantly different. The values for total body clearance and peritoneal dialysis clearance were about 15 and 4 ml/min, respectively. No dose dependency was observed for the clearance estimates. Over the 72-h sampling period, about 26% of the dose was excreted intact into the peritoneal dialysis fluid. For 48 h postdose, mean concentrations of cefepime in dialysate at the end of each dialysis interval exceeded the reported MICs for 90% of the isolates (MIC90s) for bacteria which commonly cause peritonitis resulting from continuous peritoneal dialysis. A parenteral dose of 1,000 or 2,000 mg of cefepime every 48 h would maintain the antibiotic levels in plasma and peritoneal fluid above the MIC90s for the most susceptible bacteria for the treatment of systemic and intraperitoneal infections [corrected].

Effect of Time of Food Administration on the Bioavailability of Didanosine From a Chewable Tablet Formulation

The effect of the time of food administration on the bioavailability of didanosine, administered as a 300‐mg dose of a chewable tablet formulation, was evaluated in 10 men seropositive for the human immunodeficiency virus (HIV), but free of any symptoms of acquired immune deficiency syndrome (AIDS). Using an open, randomized, balanced, incomplete block crossover study design, each patient received the dose of didanosine under four of the five following conditions: (1) after an overnight fastt (2) 30 minutes before a meal, (3) 1 hour before a meal, (4) 1 hour after a meal or (5) 2 hours after a meal. The meal consisted of a standard high‐fat, high‐calorie breakfast, consumed over a 15‐minute period. Serial blood samples and the total urinary output were collected over a 12‐hour interval after each dose for analysis using validated high‐pressure liquid chromatography (HPLC)/ultraviolet (UV) methods. Concentration data were used to calculate pharmacokinetic parameters using noncompartmental methods. There were no significant differences among the fasting, 30‐minute before, and 1‐hour before the meal treatments with respect to maximum peak plasma concentration (Cmax), area under the curve (AUC(0‐∞)), or urinary recovery (%UR). Values for Cmax, AUC(0‐∞), and %UR observed for the 1 and 2 hours after the meal treatments were significantly less than those obtained under either fasting conditions or before the meal. There were no significant differences among any of the treatments with respect to time to reach peak concentration (tmax), half‐life (t 1/2), or renal clearance (CLR). Based on the data from this study, it is recommended that didanosine be administered 30 minutes to 1 hour before a meal, but not within 2 hours after a meal.

Biopharmaceutics of Didanosine in Humans and in a Model for Acid-Labile Drugs, the Pentagastrin-Pretreated Dog

Didanosine is a purine nucleoside analogue approved for the treatment of human immunodeficiency virus infection. It is extremely unstable at pH values less than 3 and requires protection against gastric acid-induced hydrolysis. Beagle dogs pretreated with pentagastrin, an analogue of gastrin that reproducibly stimulates gastric acid secretion, have been used to screen different didanosine formulations. The absolute bioavailability of didanosine from a saline solution decreased from approximately 43% in untreated dogs to 8% after pretreatment with pentagastrin. Administration of buffered solution of didanosine to untreated and pretreated dogs yielded bio-availability estimates of 37 and 30%, respectively. In humans, the bioavailability from a similar buffered solution was approximately 40%. Pentagastrin-pretreated dogs were used to evaluate four new products relative to a citrate-phosphate buffer sachet, the formulation selected for large-scale clinical trials in humans. Two of these new formulations, a chewable tablet and an antacid suspension, were more bioavailable then the reference sachet. This also proved to be true in man, necessitating an adjustment in the dose of didanosine when administered as the chewable tablet. Dogs pretreated with pentagastrin accurately predicted the improved bioavailability of new didanosine formulations prior to clinical use. This animal model may be helpful in evaluating the biopharmaceutics of other acid-labile drugs.

Population Pharmacokinetic Analysis of Didanosine (2′,3′‐Dideoxyinosine) Plasma Concentrations Obtained in Phase I Clinical Trials in Patients with AIDS or AIDS‐Related Complex

Plasma didanosine concentration data from 36 patients receiving once‐a‐day therapy and from 33 patients receiving twice‐a‐day therapy were subject to population pharmacokinetic analysis with the computer program NONMEM. Once‐ or twice‐a‐day regimens of didanosine were administered intravenously (IV) (dose: 0.8–33 mg/kg) during the first 2 weeks of therapy, and orally (dose: 1.6–66 mg/kg) for the remaining 4 weeks of therapy. Plasma pharmacokinetics were determined after the first and last (steady‐state) IV and oral doses. Population pharmacokinetic parameters for the combined IV and oral steady‐state data were (mean [%CV]): systemic clearance, CL, 0.70 (5.2) L/h/kg; central compartment volume, Vc, 0.18 (32) L/kg; steady‐state distribution volume, Vdss, 0.84 (6.8) L/kg; first‐order absorption rate constant, Ka, 1.3 (9.5) hr−1; and bioavailable fraction, F, 0.34 (8.5). Interindividual variability (omega) was (%CV) 22.3 and 71.0 for CL and Vc, respectively. Intraindividual (residual) variability (sigma) in plasma concentrations (%CV) was 50.2. Body weight, sex, and age did not account for the variability in either CL or Vc, and the use of alternate pharmacokinetic models did not reduce the value of intraindividual variability. Population parameters for the combined IV and oral first‐dose data were generally similar to those for the steady‐state data. The parameters can be used to design dosing regimens in patients using the Bayesian feedback approach.