Effects of Lemborexant on the Pharmacokinetics of Oral Contraceptives: Results From a Phase 1 Drug-Drug Interaction Study in Healthy Females.

Lemborexant is a dual orexin receptor antagonist approved in multiple countries including the United States, Canada, and Japan for the treatment of insomnia in adults. As women of childbearing potential may be prescribed insomnia drugs, a drug-drug interaction study was conducted. This single-center, open-label, fixed-sequence study examined potential drug-drug interactions between lemborexant and an oral contraceptive (OC) in healthy females (18-44 years, n = 20). The purpose of this study was to determine the effect of lemborexant 10 mg (at steady state) on the pharmacokinetics of a single dose of OC (0.03 mg ethinyl estradiol and 1.5 mg norethindrone acetate), assess the effect of a single dose of OC on lemborexant pharmacokinetics, and evaluate safety and tolerability of lemborexant and OC coadministration. Ethinyl estradiol maximum plasma drug concentration was not altered by lemborexant coadministration; area under the curve from zero time to the last quantifiable concentration was slightly increased, by 13%. No clinically relevant effects on norethindrone acetate pharmacokinetics were observed. Coadministration of OC with lemborexant had no clinically relevant effect on the steady-state pharmacokinetics of lemborexant. Adverse events were consistent with the known safety profile. These results support the conclusion that lemborexant and OC can be coadministered without dose adjustment.

Landry I ，Aluri J ，Hall N ，Filippov G ，Dayal S ，Moline M ，Reyderman L ... -  《Clinical Pharmacology in Drug Development》

Evaluation of the CYP3A and CYP2B6 Drug-Drug Interaction Potential of Lemborexant.

Lemborexant is approved for treating insomnia and is under investigation for treating irregular sleep-wake rhythm disorder. Based on in vitro drug-drug interaction (DDI) characteristics, phase 1, open-label DDI studies were conducted to evaluate lemborexant's cytochrome P450 3A (CYP3A) and CYP2B6 interaction potential. Interactions between lemborexant 10 mg and strong and moderate CYP3A inhibitors (itraconazole and fluconazole), a strong CYP3A inducer (rifampin), and CYP3A (midazolam) and CYP2B6 substrates (bupropion) were evaluated. Coadministration of lemborexant with itraconazole or fluconazole resulted in 1.4- to 1.6-fold and 3.7- to 4-fold increases in lemborexant maximum observed concentration (Cmax ) and area under the concentration-time curve from zero time extrapolated to infinity (AUC0-inf ), respectively. Coadministration of lemborexant with rifampin resulted in >90% decreases in lemborexant Cmax and AUC0-inf . Midazolam exposure was not affected. Coadministration of lemborexant with bupropion resulted in 49.9% and 45.5% decreases in S-bupropion Cmax and AUC0-inf , respectively.Comparison of estimated exposures for patients in phase 3 trials who were/were not receiving concomitant weak CYP3A inhibitors substantiated the DDI pharmacokinetic findings. Lemborexant was generally well tolerated in the phase 1 studies. In summary, lemborexant does not affect the pharmacokinetics of CYP3A substrates and has potential to induce CYP2B6. Consistent with in vitro findings, moderate and strong CYP3A inhibitors and inducers affected the pharmacokinetics of lemborexant; hence, patients taking lemborexant 5 or 10 mg should avoid coadministration with moderate and strong CYP3A inhibitors and inducers.

Landry I ，Aluri J ，Nakai K ，Hall N ，Miyajima Y ，Ueno T ，Dayal S ，Filippov G ，Lalovic B ，Moline M ，Reyderman L ... -  《Clinical Pharmacology in Drug Development》

Effect of vicriviroc with or without ritonavir on oral contraceptive pharmacokinetics: a randomized, open-label, parallel-group, fixed-sequence crossover trial in healthy women.

Because women of childbearing potential represent 20% to 25% of the HIV population, it is important to determine any potential drug interactions between vicriviroc, an antiretroviral agent, and an oral contraceptive (OC) to provide guidance on any potential dose adjustments. The primary study objective was to determine the effect of vicriviroc, a C-C chemokine receptor type 5 inhibitor, alone or in the presence of ritonavir, on the pharmacokinetics (AUC and C(max)) of the study OC (ethinyl estradiol [EE] 0.035 mg + norethindrone [NET] 1 mg). A secondary objective was to monitor the safety and tolerability of vicriviroc plus an OC with and without ritonavir. This was a randomized, open-label, parallel-group, single-center study with a fixed-sequence crossover design. Female subjects were randomized into 2 groups and treated for 2 menstrual cycles. In cycle 1, all received the OC alone, per standard 28-day pack instructions. On the first 10 days of cycle 2, group 1 received OC + vicriviroc and group 2 received OC + ritonavir; on the following 11 days, both groups received OC + vicriviroc + ritonavir. Blood samples were collected up to 24 hours after dosing on prespecified days. Pharmacokinetic parameters, including AUC(0-24), C(max), and C(min), were calculated using noncompartmental methods, and drug interactions were evaluated using an ANOVA model by treatment group. Adverse events were collected using physical examination, vital sign measurements, clinical laboratory analysis, electrocardiography, and questioning at predefined time points throughout the study to assess the safety profile. Twenty-seven subjects were enrolled (26 white, 1 black). The median age and body mass index were 21 years (range, 18-36 years) and 24.5 kg/m(2) (range, 19.1-31.3 kg/m(2)), respectively. Twenty-one subjects completed the study and were included in the pharmacokinetic analysis; 4 discontinued for reasons unrelated to study drug and 2 discontinued because of adverse events. Vicriviroc had little effect on the pharmacokinetics of the OC. EE mean ratio estimates for C(max) and AUC(0-24) compared with OC administered alone were 91% and 97%, respectively, and for NET were 106% and 93%. Subjects receiving ritonavir, alone or with vicriviroc, experienced decreases in exposure of EE (C(max) mean ratio estimates, 89% and 76%; AUC(0-24) mean ratio estimates, 71% each, for ritonavir alone and ritonavir with vicriviroc, respectively) and, to a lesser extent, decreases in NET (C(max) mean ratio estimates 89% each; AUC(0-24) mean ratio estimates: 93% and 83%, for ritonavir alone and ritonavir with vicriviroc, respectively). Twenty-two of 27 (81%) subjects reported ≥1 treatment-emergent adverse event (TEAE). During cycle 1, TEAEs were reported for 18 of 27 (67%) subjects while receiving OC alone and for 3 of 24 (13%) subjects while receiving placebo OC. During cycle 2, TEAEs were reported for 8 of 12 (67%) subjects while receiving vicriviroc with OC, 4 of 12 (33%) subjects while receiving ritonavir with OC, 7 of 22 (32%) subjects while receiving vicriviroc + ritonavir with OC, and 2 of 22 (9%) subjects while receiving placebo OC. The most commonly reported TEAE was headache (vicriviroc + OC, n = 1; ritonavir + OC, n = 3; vicriviroc + ritonavir + OC, n = 2; OC alone, n = 12; placebo OC, n = 2). No TEAEs were considered severe. In this population of healthy female subjects, vicriviroc had little effect on the pharmacokinetics of EE or NET, whereas ritonavir, alone or with vicriviroc, was associated with consistent decrease in exposure of EE and a lesser decrease in NET.

Kasserra C ，Li J ，March B ，O'Mara E ... -  《-》

Effect of severe renal impairment on pharmacokinetics, safety, and tolerability of lemborexant.

The primary aim of this study was to examine the effect of severe renal impairment (SRI) on the pharmacokinetics of lemborexant, a dual orexin receptor antagonist indicated for the treatment of insomnia. A phase 1 multicenter, single-dose, open-label, parallel-group study was conducted in subjects with SRI not requiring dialysis (estimated glomerular filtration rate 15-29 ml/min/1.73 m2 ; n = 8) compared with demographically matched healthy subjects with normal renal function (n = 8). Plasma levels of lemborexant and its metabolites were measured over 240 h following a single oral 10-mg dose administered in the morning. Relative to subjects with normal renal function, lemborexant maximum plasma concentration (Cmax ) was similar, whereas area under the plasma concentration-time curve from zero to time of last quantifiable concentration (AUC(0-t) ) and AUC from zero to infinity (AUC(0-inf) ) were about 1.5-fold higher in subjects with SRI. The geometric mean ratios (90% confidence interval) were 104.8 (77.4-142.0), 150.5 (113.2-200.3), and 149.8 (113.1-198.6) for Cmax , AUC(0-t) , and AUC(0-inf) , respectively. In both groups, the median lemborexant time to Cmax (tmax ) was 1 h, and the mean unbound fraction of lemborexant was ~7%. For the M4, M9, and M10 metabolites, Cmax was reduced ~20% and exposure (AUC(0-t) and AUC(0-inf) ) was ~1.4- to 1.5-fold higher in subjects with SRI versus healthy subjects; tmax was delayed ~1.5-2 h for M4 and M10. All treatment-emergent adverse events were mild or moderate. Lemborexant pharmacokinetics were not sufficiently altered to warrant a dose adjustment for subjects with renal impairment.

Landry I ，Aluri J ，Hall N ，Filippov G ，Dayal S ，Moline M ，Reyderman L ... -  《Pharmacology Research & Perspectives》

Effect of steady-state ambrisentan on the pharmacokinetics of a single dose of the oral contraceptive norethindrone (norethisterone) 1 mg/ethinylestradiol 35 microg in healthy subjects: an open-label, single-sequence, single-centre study.

Spence R ，Mandagere A ，Walker G ，Dufton C ，Boinpally R ... -  《CLINICAL DRUG INVESTIGATION》