Debra S. Israel

Pharmacokinetic Interaction between Amprenavir and Rifabutin or Rifampin in Healthy Males

ABSTRACT The objective of this study was to determine if there is a pharmacokinetic interaction when amprenavir is given with rifabutin or rifampin and to determine the effects of these drugs on the erythromycin breath test (ERMBT). Twenty-four healthy male subjects were randomized to one of two cohorts. All subjects received amprenavir (1,200 mg twice a day) for 4 days, followed by a 7-day washout period, followed by either rifabutin (300 mg once a day [QD]) (cohort 1) or rifampin (600 mg QD) (cohort 2) for 14 days. Cohort 1 then received amprenavir plus rifabutin for 10 days, and cohort 2 received amprenavir plus rifampin for 4 days. Serial plasma and urine samples for measurement of amprenavir, rifabutin, and rifampin and their 25-O-desacetyl metabolites, were measured by high-performance liquid chromatography. Rifabutin did not significantly affect amprenavirs pharmacokinetics. Amprenavir significantly increased the area under the curve at steady state (AUCss) of rifabutin by 2.93-fold and the AUCss of 25-O-desacetylrifabutin by 13.3-fold. Rifampin significantly decreased the AUCss of amprenavir by 82%, but amprenavir had no effect on rifampin pharmacokinetics. Amprenavir decreased the results of the ERMBT by 83%. The results of the ERMBT after 2 weeks of rifabutin and rifampin therapy were increased 187 and 156%, respectively. Amprenavir plus rifampin was well tolerated. Amprenavir plus rifabutin was poorly tolerated, and 5 of 11 subjects discontinued therapy. Rifampin markedly increases the metabolic clearance of amprenavir, and coadministration is contraindicated. Amprenavir significantly decreases clearance of rifabutin and 25-O-desacetylrifabutin, and the combination is poorly tolerated. Amprenavir inhibits the ERMBT, and rifampin and rifabutin are equipotent inducers of the ERMBT.

Herbal Therapies for Perimenopausal and Menopausal Complaints

Consumer use of alternative medicines in the United States is growing rapidly. Included in this phenomenon are herbal therapies instead of or as adjuncts with traditional medicine for perimenopausal and menopausal complaints. Of significant concern is the safety of these herbs. Since many women are using herbal therapies, clinicians must be knowledgeable about their use, quality, and safety. There are currently no government standards on the quality of herbal products in the United States, and some products are either unsafe or little is known scientifically about them. Selected herbal therapies touted in the lay press for common perimenopausal and menopausal complaints are examined, with advice on their use and safety based on scientific sources. (Pharmacotherapy 1997;17(5):970–984)

Variability in activity of hepatic CYP3A4 in patients infected with HIV.

Study Objectives. To evaluate hepatic cytochrome P450 (CYP) 3A4 activity in patients infected with the human immunodeficiency virus (HIV) using the erythromycin breath test (ERMBT), and to examine the relationship of the ERMBT to plasma concentrations of indinavir and nelfinavir.

Pharmacokinetic Interaction between Amprenavir and Clarithromycin in Healthy Male Volunteers

ABSTRACT The P450 enzyme, CYP3A4, extensively metabolizes both amprenavir and clarithromycin. To determine if an interaction exists when these two drugs are coadministered, the pharmacokinetics of amprenavir and clarithromycin were investigated in healthy adult male volunteers. This was a Phase I, open-label, randomized, balanced, multiple-dose, three-period crossover study. Fourteen subjects received the following three regimens: amprenavir, 1,200 mg twice daily over 4 days (seven doses); clarithromycin, 500 mg twice daily over 4 days (seven doses); and the combination of the above regimens over 4 days (seven doses of each drug). Twelve subjects completed all treatments and the follow-up period. The erythromycin breath test (ERMBT) was administered at baseline, 2 h after the final dose of each of the three regimens and at the first follow-up visit. Coadministration of clarithromycin and amprenavir significantly increased the mean amprenavir AUCss, Cmax,ss, andCmin,ss by 18, 15, and 39%, respectively. Amprenavir had no significant effect on the AUCss of clarithromycin, but the median Tmax,ssfor clarithromycin increased by 2.0 h, renal clearance increased by 34%, and the AUCss for 14-(R)-hydroxyclarithromycin decreased by 35% when it was given with amprenavir. Amprenavir and clarithromycin reduced the ERMBT result by 85 and 67%, respectively, and by 87% when the two drugs were coadministered. The baseline ERMBT value did not correlate with clearance of amprenavir or clarithromycin. A pharmacokinetic interaction occurs when amprenavir and clarithromycin are coadministered, but the effects are not likely to be clinically important, and coadministration does not require a dosage adjustment for either drug.

Pharmacokinetic Interaction between Ketoconazole and Amprenavir after Single Doses in Healthy Men

Study Objective. To determine the effects of coadministration of amprenavir and ketoconazole on the pharmacokinetics of both drugs, and to assess the utility of the erythromycin breath test (ERMBT) to predict and explain these effects.

Pharmacokinetics and serum bactericidal titers of ciprofloxacin and ofloxacin following multiple oral doses in healthy volunteers.

Fourteen adult males participated in a randomized three-way crossover study to compare the pharmacokinetics and serum bactericidal titers (SBTs) of 500 mg of ciprofloxacin (regimen A), 750 mg of ciprofloxacin (regimen B), and 400 mg of ofloxacin (regimen C) administered every 12 h for seven doses. Mean steady-state peak concentrations in serum for regimens A, B, and C were 3.0, 4.4, and 6.5 micrograms/ml, respectively (P < 0.01, all comparisons) and mean half-lives were 4.5, 4.3, and 6.5 h, respectively (P < 0.05, C versus A and B). Mean steady-state areas under the concentration-time curve were 14.1, 21.1, and 48.1 micrograms/h/ml for regimens A, B, and C, respectively (P < 0.05, all comparisons). SBTs were determined at different times postdose for three isolates each of Streptococcus pneumoniae, Staphylococcus aureus, Escherichia coli, Enterobacter cloacae, and Pseudomonas aeruginosa. Mean steady-state peak SBTs for regimens A, B, and C, respectively, were as follows: S. pneumoniae, < 1:2, 1:8, 1:8, S. aureus, 1:16, 1:16, 1:16; E. coli, 1: > or = 128, 1: > or = 128, 1:64; E. cloacae, 1: > or = 128, 1: > or = 128, 1:64; P. aeruginosa, 1:8, 1:8, 1:2. These differences in SBTs within each genus were statistically significant. The majority of predicted SBTs were within one dilution of measured SBTs. Areas under the serum bactericidal time curves for E. coli, E. cloacae, and P. aeruginosa were significantly higher for ciprofloxacin; areas under the serum bactericidal time curves for S. pneumoniae and S. aureus were significantly greater for ofloxacin. Ofloxacin achieved higher concentrations in serum than ciprofloxacin, but differences in in vitro activity were a more important determinant of SBTs.