Kenneth A. Pittman

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.

Analytical methods validation: Bioavailability, bioequivalence and pharmacokinetic studies: Sponsored by the American Association of Pharmaceutical Chemists, U.S. Food and Drug Administration, Fédération Internationale Pharmaceutique, Health Protection Branch (Canada) and Association of Official Analytical Chemists

Abstract This is a summary report of the conference on ‘Analytical Methods Validation: Bioavailability, Bioequivalence and Pharmacokinetic Studies.’ The conference was held from December 3 to 5, 1990, in the Washington, DC area and was sponsored by the American Association of Pharmaceutical Scientists, U.S. Food and Drug Administration, Federation Internationale Pharmaceutique, Health Protection Branch (Canada) and Association of Official Analytical Chemists. The purpose of the report is to represent our assessment of the major agreements and issues discussed at the conference. This report is also intended to provide guiding principles for validation of analytical methods employed in bioavailability, bioequivalence and pharmacokinetic studies in man and animals. The objectives of the conference were: (1) to reach a consensus on what should be required in analytical methods validation and the procedures to establish validation; (2) to determine processes of application of the validation procedures in the bioavailability, bioequivalence and pharmacokinetic studies; and (3) to develop a report on analytical methods validation (which may be referred to in developing future formal guidelines). Acceptable standards for documenting and validating analytical methods with regard to processes, parameters or data treatments were discussed because of their importance in assessment of pharmacokinetic. bioavailability, and bioequivalence studies. Other topics which were considered essential in the conduct of pharmacokinetic studies or in establishing bioequivalency criteria, including measurement of drug metabolites and stereoselectivc determinations, were also deliberated.

High-pressure liquid chromatographic analysis of BMY-28142 in plasma and urine.

A high-pressure liquid chromatographic assay was developed for the quantitative analysis of a new cephalosporin, BMY-28142, in plasma and urine. The plasma method involved protein precipitation with acetonitrile and trichloroacetic acid followed by extraction of the acetonitrile into dichloromethane. After centrifugation, the organic phase was discarded, the aqueous solution was injected into a reverse-phase column, and peaks were detected at 280 nm. The urine method involved dilution of a urine sample with sodium acetate buffer (pH 4.25) and direct injection into the high-pressure liquid chromatography system. The assay validation data indicate that the assays for BMY-28142 in plasma and urine were specific, accurate, and reproducible. The analytical methods were applied to the determination of protein binding in human serum and to a pharmacokinetic study in rats. The results of the protein-binding study indicated that BMY-28142 was 16.3% bound to human serum proteins. In the pharmacokinetic study in rats, the maximum level in plasma of 38.7 micrograms/ml was achieved at 2.33 h after administration of a subcutaneous dose of 100 mg/kg. The levels in the plasma then declined with an elimination half-life of about 0.56 h. The mean values for the steady-state volume of distribution and total body clearance were 0.46 liters/kg and 11.9 ml/min per kg, respectively. The 0- to 24-h excretion of intact BMY-28142 in urine accounted for 88.6% of the dose.

Multiple-dose phase I study of transnasal butorphanol

The safety, tolerance, and pharmacokinetics of transnasal butorphanol were evaluated in a double‐blind, multiple‐dose phase I study. A total of 18 subjects received either placebo (n= 6) or a single transnasal dose of 2 mg butorphanol tartrate on the first day and 1, 2, and 4 mg doses of butorphanol tartrate every 6 hours on days 2 through 6, 7 through 11, and 12 through 16, respectively. Safety assessment was performed on days 7, 12, and 17. Serial blood samples were collected on days 1, 6, 11, and 16, and the plasma was analyzed for unchanged butorphanol by a validated and specific radioimmunoassay. Butorphanol was rapidly absorbed and peak levels in plasma were generally attained within 1 hour after the nasal administration. The values of maximum concentration, minimum concentration, and area under the concentration versus time curve from time zero to the dosing interval [AUC(0‐τ)] increased as the administered dose increased in a dose‐proportional manner. The values of AUC from time zero to infinity after a single dose of 2 mg butorphanol tartrate, 10.9 ng · hr/ml, were identical to the values of AUC(0‐τ) after a multiple administration of 2 mg dose, 10.4 ng · hr/ml. Mean elimination half‐life value was 5.45 hours. Steady state was reached in fewer than eight doses when given every 6 hours. Transnasal butorphanol was well tolerated by all subjects. After repeated administration of transnasal butorphanol, no significant changes were observed in the nasal examination, which included evaluation of color, wetness, and thickness of nostril membrane, air flow, airway patency, and general nasal conditions. The findings of this phase I study indicate that transnasal butorphanol is well tolerated, locally as well as systemically, and pharmacokinetics are linear within the expected therapeutic dose range.

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.

High-performance liquid chromatographic method for the determination of nefazodone and its metabolites in human plasma using laboratory robotics

A quantitative analytical method, using high-performance liquid chromatography and ultraviolet detection, has been established for the determination of nefazodone (NEF) and its metabolites, m-chlorophenylpiperazine (mCPP),p-hydroxynefazodone (PHN), and hydroxynefazodone (HO-NEF), in human plasma. The fully automated, robotic procedure consisted of addition of internal standard (aprindine), extraction with butyl chloride, followed by phase separation, organic phase evaporation, reconstitution of the residue, and injection onto the chromatographic system. The limits of detection for NEF, mCPP, PHN, and HO-NEF were 5, 1, 10, and 5 ng/ml, respectively, at a signal-to-noise ratio of 4. The method had a linear range of 10-1000 ng/ml for NEF and HO-NEF, 20-2000 ng/ml for PHN, and 2.5-250 ng/ml for mCPP. Correlation coefficients of 0.996 or greater were obtained during validation and study sample analysis.

Comparison of cefprozil and cefaclor pharmacokinetics and tissue penetration.

The pharmacokinetics and tissue penetration, as judged by skin blister fluid, of cefprozil and cefaclor were examined in 12 healthy male volunteers. Doses of 250 and 500 mg of each drug were given to fasting subjects in a crossover fashion. Serially obtained plasma, skin blister fluid, and urine samples were analyzed for cefprozil or cefaclor by validated high-pressure liquid chromatographic methods. After oral administration of 250 and 500 mg of cefprozil, mean concentrations in plasma rose to peak levels (Cmax) of 6.1 and 11.2 micrograms/ml, respectively, and those of cefaclor were 10.6 and 17.3 micrograms/ml, respectively. The elimination half-life of cefprozil (1.3 h) was significantly longer than that of cefaclor (0.6 h), and as a result, the area under the curve for cefprozil was about two times greater than that for cefaclor. Both cephalosporins were primarily excreted unchanged in urine. The mean skin blister Cmax values were 3.0 and 5.8 micrograms/ml for cefprozil and 3.6 and 6.5 micrograms/ml for cefaclor after the 250- and 500-mg oral doses, respectively. The mean Cmax values in skin blister fluid for both cephalosporins were comparable and were significantly lower than the corresponding Cmax values in plasma. However, the levels of cefprozil and cefaclor in skin blister fluid declined more slowly than they did in plasma. The skin blister fluid half-life estimates for cefprozil were significantly longer than they were for cefaclor. Parallel to the observation in plasma, the mean skin blister fluid areas under the curve for cefprozil were significantly higher than they were for cefaclor. The plasma and skin blister fluid pharmacokinetic analyses suggest that the exposure of humans to cefprozil is significantly greater than that to cefaclor at the same dose.

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.