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》

Physiologically-based pharmacokinetic modeling to predict drug interactions of lemborexant with CYP3A inhibitors.

Lemborexant, a recently approved dual orexin receptor antagonist for treatment of adults with insomnia, is eliminated primarily by cytochrome P450 (CYP)3A metabolism. The recommended dose of lemborexant is 5 mg once per night, with a maximum recommended dose of 10 mg once daily. A physiologically-based pharmacokinetic (PBPK) model for lemborexant was developed and applied to integrate data obtained from in vivo drug-drug interaction (DDI) assessments, and to further explore lemborexant interaction with CYP3A inhibitors and inducers. The model predictions were in good agreement with observed pharmacokinetic data and with DDI results from clinical studies with CYP3A inhibitors, itraconazole and fluconazole. The model further predicted that DDI effects of weak CYP3A inhibitors (fluoxetine and ranitidine) are weak, and effects of moderate inhibitors (erythromycin and verapamil) are moderate. Based on the PBPK simulations and clinical efficacy and safety data, the maximum daily recommended lemborexant dose when administered with weak CYP3A inhibitors is 5 mg; co-administration of moderate and strong inhibitors should be avoided except in countries where 2.5 mg has been approved.

Ueno T ，Miyajima Y ，Landry I ，Lalovic B ，Schuck E ... -  《-》

Clinical Drug-Drug Interaction Studies to Evaluate the Effects of a P-Glycoprotein Inhibitor, CYP3A Inhibitors, and a CYP3A Inducer on the Pharmacokinetics of Naldemedine in Healthy Subjects.

Fukumura K ，Kawaguchi N ，Ishibashi T ，Kubota R ，Tada Y ，Ogura E ... -  《-》

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》

Assessment of Clinical Drug-Drug Interactions of Elagolix, a Gonadotropin-Releasing Hormone Receptor Antagonist.

Elagolix is an oral gonadotropin-releasing hormone receptor antagonist indicated for the management of endometriosis-associated pain and in combination with estradiol/norethindrone acetate indicated for the management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women. Elagolix coadministered with estradiol/norethindrone acetate is in late-stage development for the management of heavy menstrual bleeding associated with uterine fibroids. Based on the in vitro profile of elagolix metabolism and disposition, 9 drug-drug interaction (DDI) studies evaluating the victim and perpetrator characteristics of elagolix were conducted in 144 healthy volunteers. As a victim of cytochrome P450 (CYPs) and transporter-mediated DDIs, elagolix area under the curve (AUC) increased by ∼2-fold following coadministration with ketoconazole and by ∼5- and ∼2-fold with single and multiple doses of rifampin, respectively. As a perpetrator, elagolix decreased midazolam AUC (90% confidence interval) by 54% (50%-59%) and increased digoxin AUC by 32% (23%-41%). Elagolix decreased rosuvastatin AUC by 40% (29%-50%). No clinically significant changes in exposure on coadministration with sertraline or fluconazole occurred. A elagolix 150-mg once-daily regimen should be limited to 6 months with strong CYP3A inhibitors and rifampin because of the potential increase in bone mineral density loss, as described in the drug label. A 200-mg twice-daily regimen is recommended for no more than 1 month with strong CYP3A inhibitors and not recommended with rifampin. Elagolix is contraindicated with strong organic anion transporter polypeptide B1 inhibitors (eg, cyclosporine and gemfibrozil). Consider increasing the doses of midazolam and rosuvastatin when coadministered with elagolix, and individualize therapy based on patient response. Clinical monitoring is recommended for P-glycoprotein substrates with a narrow therapeutic window (eg, digoxin). Dose adjustments are not required for sertraline, fluconazole, bupropion (or any CYP2B6 substrate), or elagolix when coadministered.

Polepally AR ，Ng JW ，Salem AH ，Dufek MB ，Parikh A ，Carter DC ，Kamradt K ，Mostafa NM ，Shebley M ... -  《-》