Doravirine and the Potential for CYP3A-Mediated Drug-Drug Interactions.

Identifying and understanding potential drug-drug interactions (DDIs) are vital for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. This article discusses DDIs between doravirine, a nonnucleoside reverse transcriptase inhibitor (NNRTI), and cytochrome P450 3A (CYP3A) substrates and drugs that modulate CYP3A activity. Consistent with previously published in vitro data and DDI trials with the CYP3A substrates midazolam and atorvastatin, doravirine did not have any meaningful impact on the pharmacokinetics of the CYP3A substrates ethinyl estradiol and levonorgestrel. Coadministration of doravirine with CYP3A inhibitors (ritonavir or ketoconazole) increased doravirine exposure approximately 3-fold. However, these increases were not considered clinically meaningful. Conversely, previously published trials showed that coadministered CYP3A inducers (rifampin and rifabutin) decreased doravirine exposure by 88% and 50%, respectively (K. L. Yee, S. G. Khalilieh, R. I. Sanchez, R. Liu, et al., Clin Drug Investig 37:659-667, 2017 [https://doi.org/10.1007/s40261-017-0513-4]; S. G. Khalilieh, K. L. Yee, R. I. Sanchez, R. Liu, et al., J Clin Pharmacol 58:1044-1052, 2018 [https://doi.org/10.1002/jcph.1103]), while doravirine exposure following prior efavirenz administration led to an initial reduction in doravirine exposure of 62%, but the reduction became less pronounced with time (K. L. Yee, R. I. Sanchez, P. Auger, R. Liu, et al., Antimicrob Agents Chemother 61:e01757-16, 2017 [https://doi.org/10.1128/AAC.01757-16]). Overall, the coadministration of doravirine with CYP3A inhibitors and substrates is, therefore, supported by these data together with efficacy and safety data from clinical trials, while coadministration with strong CYP3A inducers, such as rifampin, cannot be recommended. Concomitant dosing with rifabutin (a CYP3A inducer less potent than rifampin) is acceptable if doravirine dosing is adjusted from once to twice daily; however, the effect of other moderate inducers on doravirine pharmacokinetics is unknown.

Assessment of the CYP3A-mediated drug interaction potential of anacetrapib, a potent cholesteryl ester transfer protein (CETP) inhibitor, in healthy volunteers.

In this study, midazolam was used as a probe-sensitive CYP3A substrate to investigate the effect of anacetrapib on CYP3A activity, and ketoconazole was used as a probe-inhibitor to investigate the effect of potent CYP3A inhibition on the pharmacokinetics of anacetrapib, a novel cholesteryl ester transfer protein inhibitor in development for the treatment of dyslipidemia. Two partially blinded, randomized, 2-period, fixed-sequence studies were performed. Safety, tolerability, and midazolam and anacetrapib plasma concentrations were assessed. All treatments were generally well tolerated. The geometric mean ratios (90% confidence interval) of midazolam with anacetrapib/midazolam alone for AUC0-infinity and Cmax were 1.04 (0.94, 1.14) and 1.15 (0.97, 1.37), respectively. Exposure to anacetrapib was increased by ketoconazole--specifically, the geometric mean ratios (90% confidence interval) of anacetrapib with ketoconazole/anacetrapib alone for AUC0-infinity and Cmax were 4.58 (3.68, 5.71) and 2.37 (2.02, 2.78), respectively. The study showed that anacetrapib does not inhibit or induce CYP3A activity. Furthermore, anacetrapib appears to be a moderately sensitive substrate of CYP3A.

Single-dose pharmacokinetics and pharmacodynamics of anacetrapib, a potent cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects.

AIMS: Anacetrapib is an orally active and potent inhibitor of CETP in development for the treatment of dyslipidaemia. These studies endeavoured to establish the safety, tolerability, pharmacokinetics and pharmacodynamics of rising single doses of anacetrapib, administered in fasted or fed conditions, and to preliminarily assess the effect of food, age, gender and obesity on the single-dose pharmacokinetics and pharmacodynamics of anacetrapib. METHODS: Safety, tolerability, anacetrapib concentrations and CETP activity were evaluated. RESULTS: Anacetrapib was rapidly absorbed, with peak concentrations occurring at approximately 4 h post-dose and an apparent terminal half-life ranging from approximately 9 to 62 h in the fasted state and from approximately 42 to approximately 83 h in the fed state. Plasma AUC and C(max) appeared to increase in a less than approximately dose-dependent manner in the fasted state, with an apparent plateau in absorption at higher doses. Single doses of anacetrapib markedly and dose-dependently inhibited serum CETP activity with peak effects of approximately 90% inhibition at t(max) and approximately 58% inhibition at 24 h post-dose. An E(max) model best described the plasma anacetrapib concentration vs CETP activity relationship with an EC(50) of approximately 22 nm. Food increased exposure to anacetrapib; up to approximately two-three-fold with a low-fat meal and by up to approximately six-eight fold with a high-fat meal. Anacetrapib pharmacokinetics and pharmacodynamics were similar in elderly vs young adults, women vs men, and obese vs non-obese young adults. Anacetrapib was well tolerated and was not associated with any meaningful increase in blood pressure. CONCLUSIONS: Whereas food increased exposure to anacetrapib significantly, age, gender and obese status did not meaningfully influence anacetrapib pharmacokinetics and pharmacodynamics.

On-the-road driving performance the morning after bedtime use of suvorexant 15 and 30 mg in healthy elderly.

RATIONALE: Suvorexant is a first-in-class orexin receptor antagonist for treating insomnia. There is a general concern that hypnotics may impair next-morning driving ability. OBJECTIVE: The objective of this study was to evaluate next-morning driving performance in older adults after single and repeated doses of suvorexant. METHODS: Double-blind, randomized, placebo-controlled, 4-period crossover study in 24 healthy volunteers (10 females), aged 65-80 years. Subjects were treated with suvorexant (15 and 30 mg) for eight consecutive nights, zopiclone 7.5 mg nightly on days 1 and 8, and placebo. Driving performance was assessed on days 2 and 9 (9 h after dosing) using a 1-h standardized highway driving test in normal traffic, measuring standard deviation of lateral position (SDLP). Drug-placebo differences in SDLP >2.4 cm were considered to reflect clinically meaningful driving impairment. RESULTS: Driving performance as measured by SDLP was not impaired following suvorexant. Mean drug-placebo differences in SDLP following suvorexant 15 and 30 mg on day 2 and 9 were 0.6 cm or less. Their 90 % CIs were all below the threshold of 2.4 cm for clinical relevance and included zero, indicating effects were not clinically meaningful or statistically significant. Symmetry analysis showed no significant differences between the number of participants who had SDLP differences >2.4 cm and those who had SDLP differences <-2.4 cm following suvorexant. CONCLUSIONS: There was no clinically meaningful residual effect of suvorexant 15 and 30 mg on next-morning driving (9 h after bedtime dosing) in healthy older adults, as assessed by mean changes in SDLP and by the number of participants on drug versus placebo that exceeded a predetermined threshold for clinically meaningful impairment.

A randomized, crossover, placebo-controlled clinical trial to assess the sensitivity of the CRCDS Mini-Sim to the next-day residual effects of zopiclone.

OBJECTIVES: We sought to validate Cognitive Research Corporation's Driving Simulator (CRCDS Mini-Sim) for studies of drug safety with respect to driving ability. METHODS: A total of 30 healthy subjects were randomized to receive placebo or 7.5 mg zopiclone, a hypnotic known to impair driving, in random order during the 2 treatment periods of a 2 period crossover design. RESULTS: Evening administration of 7.5 mg zopiclone increased next-day standard deviation of lateral lane position (SDLP) by 2.62 cm on average compared with evening administration of placebo, and caused significant effects on symmetry analysis. The magnitude of the change in SDLP is highly similar to changes previously observed using on-the-road driving methods. CONCLUSIONS: Further validation of the CRCDS Mini-Sim is warranted to develop this platform for drug safety studies.

On-the-Road Driving Performance the Morning after Bedtime Use of Suvorexant 20 and 40 mg: A Study in Non-Elderly Healthy Volunteers.

STUDY OBJECTIVE: To evaluate next-morning driving performance in adults younger than 65 years, after single and repeated doses of suvorexant 20 and 40 mg. DESIGN: Double-blind, placebo-controlled, 4-period crossover study. SETTING: Maastricht University, The Netherlands. PARTICIPANTS: 28 healthy volunteers (15 females), aged 23 to 64 years. INTERVENTIONS: Suvorexant (20 and 40 mg) for 8 consecutive nights; zopiclone 7.5 mg nightly on day 1 and 8; placebo. MEASUREMENTS: Performance on day 2 and 9 (9 h after dosing) using a one-hour standardized highway driving test in normal traffic, measuring standard deviation of lateral position (SDLP). Drug-placebo changes in SDLP > 2.4 cm were considered to reflect meaningful driving impairment. RESULTS: Mean drug-placebo changes in SDLP following suvorexant 20 and 40 mg were 1.01 and 1.66 cm on day 2, and 0.48 and 1.31 cm on Day 9, respectively. The 90% CIs of these changes were all below 2.4 cm. Symmetry analysis showed that more subjects had SDLP changes > 2.4 cm than < -2.4 cm following suvorexant 20 and 40 mg on day 2, and following suvorexant 40 mg on day 9. Four female subjects requested that a total of 5 driving tests--all following suvorexant--stop prematurely due to self-reported somnolence. CONCLUSIONS: As assessed by mean changes in standard deviation of lateral position (SDLP), there was no clinically meaningful residual effect of suvorexant in doses of 20 and 40 mg on next-morning driving (9 h after bedtime dosing) in healthy subjects < 65 years old. There may be some individuals who experience next-day effects, as suggested by individual changes in SDLP and prematurely stopped tests. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov NCT01311882.

Image-derived input function for [11C]flumazenil kinetic analysis in human brain.

PURPOSE: We describe a method for analysis of [11C]flumazenil data using an input curve directly derived from the positron emission tomography (PET) images. PROCEDURE: The shape of the tracer plasma curve was obtained from the product of the intact flumazenil fraction in plasma in six arterial samples and the internal carotid artery time-activity curve (TAC). The resulting curve was calibrated using the [11C]flumazenil concentration in three of the six samples. The curve peak was recovered by adding an exponential function to the scaled curve whose parameters were estimated from simultaneous fittings of several tissue TACs assuming that all regions share the same input. RESULTS: Good agreement was found between the image-derived and the experimental plasma curves in six subjects. Distribution volumes were highly correlated with linear regression slope and intercept values between [0.94, 1.03] and [-0.10, 0.16], respectively. CONCLUSION: The proposed method is suitable for benzodiazepine receptor quantification requiring only a few blood samples.

Single- and multiple-dose pharmacokinetics and tolerability of telcagepant, an oral calcitonin gene-related peptide receptor antagonist, in adults.

Telcagepant is a novel, orally active, and selective calcitonin gene-related peptide receptor antagonist being developed for acute treatment of migraine with and without aura. Three separate clinical studies were conducted to evaluate the pharmacokinetics and tolerability of telcagepant following single oral doses in healthy young and elderly men and women and multiple oral doses in men. Telcagepant was rapidly absorbed with a time to maximum concentration of approximately 1.5 hours. The terminal half-life was approximately 6 hours. A greater than dose-proportional increase was observed in the area under the plasma concentration versus time curve from zero to infinity. Following twice-daily dosing, with each dose separated by 2 hours, steady state was achieved in approximately 3 to 4 days with an accumulation ratio of approximately 2. There were no clinically meaningful pharmacokinetic differences when compared across age and gender. Telcagepant was generally well tolerated up to single doses of 1200 mg and multiple doses of 400 mg twice daily.

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.