No abstract

Imipenem combined with cilastatin and meropenem was given as intravenous infusions of 1 g to eight young, healthy males on two separate occasions. Blood and urine samples were collected for up to 12 h. The terminal half-lives in plasma were 0.98 h and 1.11 h for meropenem and imipenem, respectively. The volume of distribution was smaller for meropenem than for imipenem (12.5 l and 14.4 l, respectively). The plasma clearance for meropenem was 188 (SD 31) ml/min and for imipenem 183 (SD 25) ml/min. Renal clearance was on average 139 (SD 24) ml/min and 135 (SD 11) ml/min, respectively. About 75% of the administered dose of both compounds was eliminated unchanged in urine. Non-renal clearance accounted for approximately 25% of the total clearance for both drugs. The kinetics of meropenem are very similar to those of imipenem given with cilastatin, and meropenem is as stable against renal metabolic degradation as imipenem combined with cilastatin.

Penetration of stavudine into the cerebrospinal fluid (CSF) was studied in healthy humans. In this open, randomized study, a single oral dose of 40 mg of stavudine was given to 12 fasting volunteers > or = 18 years of age. Subjects were divided into three groups based on the time of CSF sampling (i.e., 0.75-1.25, 2-3, or 4-5 hours after dosing). Blood samples were collected over an 8-hour period after dosing and included a sample simultaneous with CSF collection to permit an estimate of CSF : plasma ratios. Stavudine concentrations in plasma and CSF were determined by a validated high-performance liquid chromatography method. Repeated measurements of vital signs, physical examination, and clinical laboratory tests indicated that the stavudine dose was well tolerated. CSF levels were not detected 0.75 to 1.25 hours after dosing. Thereafter, levels were detected in the CSF of five subjects; the mean concentration was 61 ng/ml. The mean CSF: plasma ratio increased with time, from 0.16 at 2 to 3 hours postdose in one subject to 0.40 at 4 to 5 hours postdose in four subjects. In conclusion, the mean stavudine concentration of 61 ng/ml achieved in the CSF of five subjects exceeds the ED50 of clinical isolates of HIV (230 nM, 52 ng/ml).

The pharmacokinetics of amlodipine and olmesartan in healthy volunteers after coadministration of amlodipine besylate and olmesartan medoxomil concomitantly as separate dosage forms and together in a fixed-dose combination tablet were characterized in 5 phase I, randomized, crossover studies. The mean steady-state pharmacokinetics of amlodipine and olmesartan were similar when olmesartan medoxomil 40 mg/day and amlodipine 10 mg/day were administered separately or concomitantly for 10 days. The total and maximum exposure to amlodipine and olmesartan after administration of fixed-dose combination amlodipine/olmesartan medoxomil 10 mg/40 mg was bioequivalent to amlodipine 10 mg plus olmesartan medoxomil 40 mg. The ratio of least squares mean and 90% confidence intervals for the area under the drug concentration-time curve from time zero to time t, from time zero to infinity, and the maximum observed plasma drug concentration of amlodipine and olmesartan fell within the prespecified range for bioequivalence (80.0% - 125.0%). The area under the drug concentration-time curve from time zero to time t, from time zero to infinity, and the maximum observed plasma drug concentration of both drugs also met the prespecified criterion for bioequivalence when the fixed-dose combination tablet was taken 30 minutes after a high-fat breakfast. Total exposure to amlodipine and olmesartan was dose-proportional after administration of olmesartan medoxomil 10 mg to 40 mg in the fixed-dose combination formulation with amlodipine 5 mg to 10 mg. From a pharmacokinetic perspective, the 2 drugs are well suited to coadministration in a fixed-dose combination.