Pharmacokinetics and safety of oral eletriptan during different phases of the menstrual cycle in healthy volunteers.

The purpose of this study was to determine the pharmacokinetics and safety of eletriptan in different phases of the menstrual cycle. Female volunteers (n = 16) with a regular menstrual cycle (28 +/- 4 days) received a single oral dose of 80 mg eletriptan during each of the four cycle phases: phase 1 (menses), days 1 to 4; phase 2 (follicular), days 6 to 10; phase 3 (ovulatory), days 11 to 13; and phase 4 (luteal), days 21 to 24. Eletriptan plasma concentrations were determined from serial plasma samples taken during a 24-hourperiod after dosing. Blood pressure, pulse rate, and ECG measurements were performed at baseline, 1 and 24 hours after dosing. No significant differences between phases were observed for maximum plasma concentration (cmax, range of means = 188-234 ng/ml), time to maximum concentration (tmax, range of means = 1.8-2.5 h), or systemic exposure (area under the curve [AUC], range of means = 1194-1514 ng x h/ml). Although there was a statistically significant difference in the terminal phase elimination rate constant (kel) between phases 1 and2 (0.175/h vs. 0.158/h, p = 0.044), the corresponding difference in terminal phase half-life (t 1/2) (4.0 h vs. 4.4 h) was not considered to be clinicallyrelevant. No clinically relevant differences in blood pressure, pulse rate, or ECG were observed, and the incidence, nature, and severity of adverse events were similar in all phases. The different phases of the menstrual cycle had no clinically significant effect on the pharmacokinetics, safety, or tolerability of oral 80 mg eletriptan in healthy females.

Practical considerations regarding the influence of the menstrual cycle on leukocyte parameters in clinical trials.

Variations in hormone levels during different phases of the menstrual cycle have been shown to alter the pharmacokinetics of some medications and are known to exert significant effects on seemingly unrelated physiologic parameters. Numerous studies have been undertaken to examine the effects of different phases of the menstrual cycle on leukocyte and differential counts, but results have often been inconclusive and contradictory. This study endeavored to reexamine these parameters, measured by standard laboratory assays, in healthy ovulating females to determine whether the menstrual cycle may have clinically relevant effects on leukocyte counts. Twenty-one women, aged 18 to 35 years and not taking hormonal contraception, were enrolled in an outpatient study within 12 hours after the onset of normal menses. The women reported to the clinical pharmacology unit for a complete blood count with differential on days 1, 2, 7, 10 through 17, 22, and 25 through 32. Blinded duplicate samples were obtained on day 2 to assess variability at the analytic site, and levels of luteinizing hormone and estradiol were measured on days 11 through 16 to determine the day of ovulation. Eighteen women completed the study, with cycle lengths ranging from 24 to 31 days (28.2 +/- 1.9 days, mean +/- SD). Evaluations of the data revealed a trend toward higher leukocyte counts and absolute neutrophil counts at the onset of menses but no significant or clinically relevant effects of different phases of the menstrual cycle on these parameters. Some split samples showed considerable variation in the assays (eg, a 42% increase in absolute neutrophil counts), suggesting that errors at the analytic facility may be a more important consideration than hormonal effects.

The effect of azithromycin on the pharmacokinetics of indinavir.

This study was performed to examine the effect of the coadministration of azithromycin on the pharmacokinetics of the protease inhibitor indinavir (Crixivan). In an open-label, parallel-design study, 32 healthy male and female volunteers were given indinavir (800 mg tid) for 5 days. One hour prior to the first dose of indinavir on day 5, 18 subjects received 1200 mg azithromycin (Zithromax), and 14 subjects received matching placebo. Serial samples of plasma were obtained for 8 hours following the morning dose of indinavir on days 4 and 5 and assayed for indinavir by HPLC/UV. Twenty-seven subjects completed the study. Following coadministration of azithromycin with indinavir, there was no significant change between day 5 and day 4 in AUC (20.7 mg.hr/ml and 23.1 mg.hr/ml; 90% CI on the ratio 81%-100%) or Cmax (9.88 mg/ml and 10.3 mg/ml; 90% CI 86%-108%). The day 5 to day 4 difference in indinavir concentrations following coadministration with azithromycin was not significantly different from the day 5 to day 4 difference with placebo (AUC p = 0.68; Cmax p = 0.074). Therefore, azithromycin does not significantly alter the kinetics of indinavir.

Comparison of azithromycin and clarithromycin in their interactions with rifabutin in healthy volunteers.

A 14-day, randomized, open, phase I clinical trial was designed to examine possible pharmacokinetic interactions between rifabutin and two other antibiotics, azithromycin and clarithromycin, used in the treatment of Mycobacterium avium complex infections. Thirty healthy male and female volunteers were divided into five groups of six participants each: 18 received 300 mg/day of rifabutin, 12 in combination with therapeutic doses of either azithromycin or clarithromycin; the remaining 12 received azithromycin or clarithromycin alone. On day 10 the study was terminated because of adverse events, including severe neutropenia. Fourteen participants who received rifabutin developed neutropenia, including all 12 participants who received azithromycin or clarithromycin concomitantly. Analyses of serum revealed no apparent pharmacokinetic interaction between azithromycin and rifabutin. However, the mean concentrations of rifabutin and 25-O-desacetyl-rifabutin (an active metabolite) in participants who received clarithromycin and rifabutin concomitantly were more than 400% and 3,700%, respectively, of concentrations in those who received rifabutin alone. Physicians should be aware that recommended prophylactic doses of rifabutin may be associated with severe neutropenia within 2 weeks after initiation of therapy, and all patients receiving rifabutin, especially with clarithromycin, should be monitored carefully for neutropenia.