Rashmi H. Barbhaiya

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.

Coadministration of nefazodone and benzodiazepines: IV. A pharmacokinetic interaction study with lorazepam.

This study was conducted to determine the potential for an interaction between nefazodone (NEF), a new antidepressant, and lorazepam (LOR) after single- and multiple-dose administration in a randomized, double-blind, parallel-group, placebo-controlled study in healthy male volunteers. A total of 12 subjects per group received either placebo (PLA) twice daily, 2 mg of LOR twice daily, 200 mg of NEF twice daily, or the combination of 2 mg of LOR and 200 mg of NEF (LOR+NEF) twice daily for 7 days. Plasma samples were collected after dosing on day 1 and day 7 and before the morning dose on days 4, 5, and 6 for the determination of LOR, NEF, and NEF metabolites hydroxy (HO)-NEF, m-chlorophenylpiperazine (mCPP), and dione by validated high-performance liquid chromatography methods. Steady-state levels in plasma were reached by day 4 for LOR, NEF, HO-NEF, mCPP, and dione. Noncompartmental pharmacokinetic analysis showed that there was no effect of LOR on the single dose or steady-state pharmacokinetics of NEF, HO-NEF, or dione after coadministration. The steady-state mCPP Cmax values decreased 36% for the LOR+NEF group in comparison to that when NEF was given alone. There was no effect of NEF on the pharmacokinetics of LOR after coadministration. The absence of an interaction appears to be attributable to LORs metabolic clearance being dependant on conjugation rather than hydroxylation. Overall, no change in LOR or NEF dosage is necessary when the two drugs are coadministered.

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.

Clinical Pharmacokinetics of Nefazodone

SummaryNefazodone is a new antidepressant drug, chemically unrelated to the tricyclic, tetracyclic or selective serotonin uptake inhibitors. Nefazodone blocks the serotonin 5-HT2 receptors and reversibly inhibits serotonin reuptake in vivo. Nefazodone is completely and rapidly absorbed after oral administration with a peak plasma concentration observed within 2 hours of administration. Nefazodone undergoes significant first-pass metabolism resulting in an oral bioavailability of approximately 20%. Although there is an 18% increase in nefazodone bioavailability with food, this increase is not clinically significant and nefazodone can be administered without regard to meals.Three pharmacologically active nefazodone metabolites have been identified: hydroxy-nefazodone, triazoledione and m-chlorophenylpiperazine (mCPP).The pharmacokinetics of nefazodone are nonlinear. The increase in plasma concentrations of nefazodone are greater than would be expected if they were proportional to increases in dose. Steady-state plasma concentrations of nefazodone are attained within 4 days of the commencement of administration.The pharmacokinetics of nefazodone are not appreciably altered in patients with renal or mild-to-moderate hepatic impairment. However, nefazodone plasma concentrations are increased in severe hepatic impairment and in the elderly, especially in elderly females. Lower doses of nefazodone may be necessary in these groups.Nefazodone is a weak inhibitor of cytochrome P450 (CYP) 2D6 and does not inhibit CYP1A2. It is not anticipated that nefazodone will interact with drugs cleared by these isozymes. Indeed, nefazodone did not affect the pharmacokinetics of theophylline, a compound cleared by CYP1A2. Nefazodone is metabolised by and inhibits CYP3A4.Clinically significant interactions have been observed between nefazodone and the benzodiazepines triazolam and alprazolam, cyclosporin and carbamazepine. The potential for a clinically significant interaction between nefazodone and other drugs cleared by CYP3A4 (e.g. terfenadine) should be considered before the coadministration of these compounds. There was an increase in haloperidol plasma concentrations when coadministered with nefazodone; nefazodone pharmacokinetics were not affected after coadministration. No clinically significant interaction was observed when nefazodone was administered with lorazepam, lithium, alcohol, cimetidine, warfarin, theophylline or propranolol.

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.

Microdialysis Studies of the Distribution of Stavudine into the Central Nervous System in the Freely-Moving Rat

AbstractPurpose. To study the extent and time course of distribution of stavudine (d4T) into the central nervous system (CNS) and to investigate the transport mechanisms of antiviral nucleosides in the CNS. Methods. Microdialysis with on-line HPLC analysis was used to measure drug concentrations in the brain extracellular fluid (ECF) and cerebrospinal fluid (CSF) in the freely-moving rat. The in vivo recovery of d4T and zidovudine (AZT) was estimated by retrodialysis, which was validated by the zero-net flux method. The CNS distribution of d4T was investigated during iv and intracerebroventricular (icv) infusion. In the subsequent studies, the effect of AZT on CNS distribution of d4T was examined. Results. During iv infusion, d4T distributed rapidly into the CNS. Its brain ECF/plasma and CSF/plasma steady-state concentration ratios were 0.33 ± 0.06 and 0.49 ± 0.12, respectively (n = 15). During icv infusion, the steady-state d4T concentrations in the brain ECF were 23-fold higher than those during iv infusion, whereas its steady-state plasma levels were about the same for these two routes. Coadministration of AZT with d4T did not alter their respective brain distribution and systemic clearance at the concentrations examined. More importantly, the steady-state brain ECF/plasma and CSF/plasma concentration ratios of d4T were about 2-fold higher than those of AZT (0.15 ± 0.04 and 0.25 ± 0.08) determined in the same animals. Conclusions. d4T readily crosses the blood-brain barrier (BBB) and blood-CSF barrier. An active efflux transport system in the BBB and blood-CSF barrier may be involved in transporting d4T out of the CNS. Direct icv administration of d4T can be used to enhance its brain delivery. Moreover, d4T exhibits a more favorable penetration into the CNS than AZT and therefore may be useful in the treatment of AIDS dementia complex.

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.

Pharmacokinetics and Bioavailability of a Metformin/Glyburide Tablet Administered Alone and with Food

Two randomized crossover studies were conducted to evaluate the pharmacokinetics (including food effect) of fixed‐combination metformin/glyburide tablets. Pharmacokinetics and bioavailability of two strengths (500 mg/2.5 mg and 500 mg/5 mg) of metformin/glyburide tablets were assessed relative to coadministered metformin and glyburide tablets in study 1. The effect of a high‐fat meal on the bioavailability of a metformin/glyburide (500 mg/5 mg) tablet was assessed relative to the fasted condition in study 2. The fixed combination metformin/glyburide tablets showed bioequivalence for the metformin component with the reference metformin tablet and comparable bioavailability for the glyburide component with the reference glyburide tablet. Food does not appear to affect the bioavailability of either component to an appreciable extent.