Atazanavir increases the plasma concentrations of 1200 mg raltegravir dose.

Raltegravir is a human immunodeficiency virus (HIV)-1 integrase strand transfer inhibitor currently marketed at a dose of 400 mg twice-daily (b.i.d.). Raltegravir 1200 mg once-daily (q.d.) (investigational q.d. formulation of 2 × 600 mg tablets; q.d. RAL) was found to be generally well tolerated and non-inferior to the marketed 400 mg b.i.d. dose at 48 weeks in a phase 3 trial. Since raltegravir is eliminated mainly by metabolism via a uridine diphosphate glucuronosyltransferase (UGT) 1A1-mediated glucuronidation pathway, co-administration of UGT1A1 inhibitors may increase the plasma levels of q.d. RAL. To assess this potential, the drug interaction of 1200 mg raltegravir using atazanavir, a known UGT1A1 inhibitor, was studied. An open-label, randomized, 2-period, fixed-sequence phase 1 study was performed in adult healthy male and female (non-childbearing potential) subjects ≥ 19 and ≤ 55 years of age, with a body mass index (BMI) ≥ 18.5 and ≤ 32.0 kg/m2 . Subjects (n = 14) received a single oral dose of 1200 mg raltegravir in period 1. After a washout period of at least 7 days, the subjects received oral doses of 400 mg atazanavir q.d. for 9 consecutive days, with a single oral dose of 1200 mg raltegravir co-administered on day 7 of period 2. Serial blood samples were collected for 72 h following raltegravir dosing and analysed using a validated bioanalytical method to quantify raltegravir plasma concentrations. Co-administration with atazanavir yielded GMRs (90% CIs) for raltegravir AUC0-∞ , Cmax and C24 of 1.67 (1.34, 2.10), 1.16 (1.01, 1.33) and 1.26 (1.08, 1.46), respectively. There was no effect of raltegravir on serum total bilirubin. In contrast, atazanavir increased the mean bilirubin by up to 200%, an effect that was preserved in the atazanavir/raltegravir treatment group. Administration of single q.d. RAL alone and co-administered with multiple oral doses of atazanavir were generally well tolerated in healthy subjects. The results show that atazanavir increased the PK exposure of raltegravir; therefore, co-administration of atazanavir with raltegravir q.d. is not recommended. Copyright © 2016 John Wiley & Sons, Ltd.

Pharmacokinetics of laropiprant, a selective prostaglandin D2 receptor 1 antagonist, in patients with moderate hepatic impairment.

This open-label study evaluated the influence of hepatic insufficiency on the pharmacokinetics of laropiprant (LRPT), a prostaglandin D(2) receptor-1 antagonist, to guide clinicians in the event of inadvertent dosing in patients with hepatic insufficiency. A single oral 40-mg dose of LRPT was administered to 8 patients with moderate hepatic insufficiency and 8 healthy control participants matched for important baseline characteristics. Blood samples were collected predose and up to 96 hours postdose to assess LRPT pharmacokinetics. No clinically significant effect of hepatic insufficiency would be declared if the 90% confidence interval (CI) for the estimated geometric mean ratio (GMR; hepatic insufficiency patients/healthy participants) of AUC(0-∞) was contained within the prespecified bounds of (0.50-3.00). Estimated GMRs of AUC(0-∞) and C(max) (90% CIs) were 2.78 (1.71, 4.50) and 2.17 (1.33, 3.53), respectively. The median time to C(max) and apparent terminal t(1/2) of LRPT were comparable between the 2 populations (P > .100). Single-dose LPRT 40 mg was generally well tolerated in all patients. The plasma pharmacokinetics of a single 40-mg oral dose of LRPT is not similar between patients with moderate hepatic insufficiency and matched healthy participants. The GMR (90% CI) of AUC(0-∞) for patients with moderate hepatic insufficiency versus matched controls was 2.78 (1.71, 4.50).

Effect of raltegravir on the pharmacokinetics of methadone.

A randomized, placebo-controlled, 2-period crossover study in subjects on methadone maintenance therapy was conducted to assess the effect of the HIV-1 integrase inhibitor, raltegravir, on the pharmacokinetics of methadone. Twelve HIV-negative male and female subjects stabilized on an oral methadone program were enrolled. Subjects maintained their prescribed oral doses of methadone throughout the study and, in each of 2 periods, received either 400 mg of raltegravir or matching placebo every 12 hours on days 1 through 10 of each treatment period with a washout of 7 days between periods. Plasma samples for analysis of methadone pharmacokinetics were collected over 24 hours postdose on day 10 of each treatment period. Safety and tolerability were assessed throughout the study. The geometric mean ratio (90% confidence interval) for methadone when administered with raltegravir relative to methadone alone was 1.00 (0.93-1.09) for area under the methadone concentration time curve from time 0 to 24 hours and 1.00 (0.94-1.07) for maximal concentration. There were no serious clinical or laboratory adverse experiences. There were no discontinuations due to an adverse experience. Coadministration of raltegravir and methadone is generally well tolerated. Raltegravir has no clinically meaningful effect on methadone pharmacokinetics. No dose adjustment is required for methadone when coadministered with raltegravir.

Short-acting T-type calcium channel antagonists significantly modify sleep architecture in rodents.

A novel phenyl acetamide series of short-acting T-type calcium channel antagonists has been identified and evaluated using in vitro and in vivo assays. Heterocycle substitutions of the 4-position of the phenyl acetamides afforded potent and selective antagonists that exhibited desired short plasma half-lives across preclinical species. Lead compound TTA-A8 emerged as a compound with excellent in vivo efficacy as indicated by its significant modulation of rat sleep architecture in an EEG telemetry model, favorable pharmacokinetic properties, and excellent preclinical safety. TTA-A8 recently progressed into human clinical trials, and in line with our predictions, preliminary studies (n = 12) with a 20 mg oral dose afforded a high C max of 1.82 ± 0.274 µM with an apparent terminal half-life of 3.0 ± 1.1 h.