Search

Observations of predose spikes in transaminases from a phase I study prompted our review of other clinical trials, including 250 healthy participants from 4 studies at 3 sites. Six of these participants (2.4%) displayed elevated alanine aminotransferase/aspartate aminotransferase (ALT/AST) levels immediately predose despite normal values

Casopitant, an antiemetic, is a neurokinin-1 receptor antagonist metabolized primarily by cytochrome P450 3A4 (CYP3A4). Three phase 1 studies with 131 healthy subjects examined the impact of a strong CYP3A inhibitor (ketoconazole) and inducer (rifampin) on the pharmacokinetics and safety of casopitant. Oral casopitant was administered alone (study 1, 100-mg single dose; study 2, 150 mg on day 1, 50 mg on days 2 and 3; study 3, 150-mg single dose) with either 400 mg daily of oral ketoconazole or 600 mg daily of oral rifampin. Ketoconazole increased the maximum observed plasma concentration (C(max)) and area under the plasma concentration time curve to the last sampling time, t (AUC(0-t)) of single-dose casopitant 2.7-fold and 12-fold and increased the C(max) of 3-day casopitant 2.5-fold on day 1 and 2.9-fold on day 3, whereas AUC((0-tau)) increased 4.3-fold on day 1 and 5.8-fold on day 3. Neither safety signals nor prolongation of Fredericia-corrected QT was observed at these increased exposures in study 2. Repeat-dose rifampin reduced the C(max) and AUC((0-t)) of casopitant 96% and 90%, respectively. These clinical studies confirmed the role of CYP3A in the metabolism and disposition of casopitant. Coadministration of casopitant with strong inhibitors of CYP3A is likely to increase plasma exposure of casopitant, whereas coadministration with strong inducers of CYP3A is likely to decrease casopitant exposure and compromise efficacy.

Eleven subjects completed a clinical trial to determine the safety/tolerability of freeze-dried black raspberries (BRB) and to measure, in plasma and urine, specific anthocyanins-cyanidin-3-glucoside, cyanidin-3-sambubioside, cyanidin-3-rutinoside, and cyanidin-3-xylosylrutinoside, as well as ellagic acid. Subjects were fed 45 g of freeze-dried BRB daily for 7 days. Blood samples were collected predose on days 1 and 7 and at 10 time points postdose. Urine was collected for 12 hours predose on days 1 and 7 and at three 4-hour intervals postdose. Maximum concentrations of anthocyanins and ellagic acid in plasma occurred at 1 to 2 hours, and maximum quantities in urine appeared from 0 to 4 hours. Overall, less than 1% of these compounds were absorbed and excreted in urine. None of the pharmacokinetic parameters changed significantly between days 1 and 7. In conclusion, 45 g of freeze-dried BRB daily are well tolerated and result in quantifiable anthocyanins and ellagic acid in plasma and urine.

In phase I clinical trials intended for healthy volunteers, testing for human immunodeficiency virus (HIV) is often times part of a routine screening procedure to determine eligibility. The rationale is to safeguard volunteers, to protect the scientific integrity of a clinical trial, and/or to facilitate the process of drug development. Asymptomatic HIV-positive individuals are at increased risk for adverse events, and participating in a phase I clinical trial could also interfere with effective treatment for their disease. Although the Food and Drug Administration has not established a policy regarding HIV testing in clinical trials, some institutional review boards (IRBs) impose restrictions. The role of an IRB is to protect the rights and welfare of human subjects in clinical trials. Restricting testing does not protect subjects and may in fact harm them; therefore, an IRB should not restrict testing proposed by a pharmaceutical sponsor in agreement with a clinical investigator.

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 ofplasma 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 C max (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; C max p = 0.074). Therefore, azithromycin does not significantly alter the kinetics of indinavir.

An open-label, placebo-controlled study was conducted to determine the effects of sertraline on the steady-state levels and renal clearance of lithium in 20 healthy volunteers. Subjects received 600 mg of lithium twice daily for 9 days. On the evening of day 8, subjects received orally either placebo or 100 mg of sertraline; these were administered twice, 8 hours apart, beginning 2 hours after the evening dose of lithium. In a comparison of day 8 with day 9 (before administration of the morning doses of lithium), sertraline was associated with only a 0.01 mEq/L (1.4%) decrease in steady-state levels and a 0.11 L/hour (6.9%) increase in the renal clearance of lithium. Neither change was statistically significant relative to placebo. Four subjects were excluded from analysis because of protocol violations or laboratory abnormalities unrelated to sertraline. Seven subjects who received lithium plus sertraline experienced side effects, mainly tremors, possibly related to treatment, whereas none of those administered lithium plus placebo experienced side effects. No sertraline-related laboratory abnormalities were observed.