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This report describes polysomnography and sleep diary exposure-response analyses from Study E2006-G000-304 (Study 304), a 1-month trial of 5- or 10-mg lemborexant, zolpidem, or placebo; and Study E2006-G000-303 (Study 303), a 6-month trial of 5- or 10-mg lemborexant or placebo. Studies 304 and 303 included 1006 (86%) and 956 (68%) (female) participants, respectively; >40% were ≥65 years, with individual lemborexant exposures derived from a previously described pharmacokinetic model. Linear mixed-effects analyses of polysomnography: latency to persistent sleep (LPS), sleep efficiency (SE), and wake after sleep onset (WASO) quantified the change from baseline given lemborexant exposure, time, and covariates, guided by consensus recommendations regarding clinical significance. A small impact of sex, body weight, and race was predicted for LPS and SE, irrespective of treatment. Effect of age on LPS was small; baseline SE was estimated to be 8% higher for a 50-year-old versus an 80-year-old, decreasing to 6% by 1 month. Baseline WASO was 13 minutes longer for Black versus White subjects, corresponding to a 5-minute lower change from baseline at the end of the study. For subjective end points, the statistically significant covariate effects for age, sex, and race were not deemed therapeutically relevant, likely reflecting physiologic sleep pattern changes across age and study subgroups. Both polysomnography and subjective analyses indicated clinically meaningful differences from baseline for both lemborexant treatments, with effects being greater for 10-mg versus 5-mg lemborexant, while indicating that covariate-specific lemborexant dose adjustments are not warranted., (© 2022, The American College of Clinical Pharmacology.)

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., (© 2021 Eisai Inc. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

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 (C max ) and area under the concentration-time curve from zero time extrapolated to infinity (AUC 0-inf ), respectively. Coadministration of lemborexant with rifampin resulted in >90% decreases in lemborexant C max and AUC 0-inf . Midazolam exposure was not affected. Coadministration of lemborexant with bupropion resulted in 49.9% and 45.5% decreases in S-bupropion C max and AUC 0-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., (© 2021 Eisai Co., Ltd. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Lemborexant is a novel orexin receptor antagonist approved in the United States and Japan for the treatment of insomnia. This article describes the population pharmacokinetics (PK) of lemborexant and the relationship of its daily steady-state exposure (C av,ss ) to the probability of most frequent treatment-emergent adverse events (TEAEs). The 12 230-observation, 1892-subject PK data set included data from 12 clinical studies with predominantly female subjects (66%) ranging in age from 18 to 88 years and from 37 to 168 kg in body weight. The 1664-subject exposure-response data set included data from 3 late-stage studies. Lemborexant pharmacokinetics were described by a 3-compartment model with combined first- and zero-order absorption with lag time and linear elimination. Oral clearance decreased with increasing body mass index (exponent, -0.428), increasing alkaline phosphatase levels (exponent, -0.118), and was 26% lower in the elderly (≥65 years). Across the adverse event analysis, the frequency of subjects experiencing TEAEs during active treatment ranged from approximately 3% to 8%, in the range estimated for placebo. With and without adjustment for age, lemborexant exposure (C av,ss ) was not a clinically meaningful linear predictor of the probability of specific TEAEs: somnolence, nasopharyngitis, flu/influenza, urinary tract infection, upper respiratory tract infection, or headache. Given the small effect sizes of covariates of the PK model and a low degree of association of lemborexant TEAEs and exposure over the range of phase 3 (therapeutic) 5- and 10-mg doses, lemborexant can be safely administered without the need for dose adjustment., (© 2020 Eisai Inc. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Infants and young children with severe acute malnutrition (SAM) are treated with empiric broad-spectrum antimicrobials. Parenteral ceftriaxone is currently a second-line agent for invasive infection. Oral metronidazole principally targets small intestinal bacterial overgrowth. Children with SAM may have altered drug absorption, distribution, metabolism, and elimination. Population pharmacokinetics of ceftriaxone and metronidazole were studied, with the aim of recommending optimal dosing. Eighty-one patients with SAM (aged 2-45 months) provided 234 postdose pharmacokinetic samples for total ceftriaxone, metronidazole, and hydroxymetronidazole. Ceftriaxone protein binding was also measured in 190 of these samples. A three-compartment model adequately described free ceftriaxone, with a Michaelis-Menten model for concentration and albumin-dependent protein binding. A one-compartment model was used for both metronidazole and hydroxymetronidazole, with only 1% of hydroxymetronidazole predicted to be formed during first-pass. Simulations showed 80 mg/kg once daily of ceftriaxone and 12.5 mg/kg twice daily of metronidazole were sufficient to reach therapeutic targets., (© 2018 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Lemborexant is a novel dual orexin receptor antagonist being developed to treat insomnia. Its potential to cause QT prolongation was evaluated using plasma concentration-response (CR) modeling applied to data from 2 multiple ascending-dose (MAD) studies. In the primary MAD study, placebo or lemborexant (2.5 to 75 mg) was administered for 14 consecutive nights. In another MAD study designed to "bridge" pharmacokinetic and safety data between Japanese and non-Japanese subjects (J-MAD), placebo or lemborexant (2.5, 10, or 25 mg) was administered for 14 consecutive nights. QT intervals were estimated using a high-precision measurement technique and evaluated using a linear mixed-effects CR model, for each study separately and for the pooled data set. When each study was analyzed separately, the slopes of the CR relationship were shallow and not statistically significant. In the pooled analysis, the slope of the CR relationship was -0.00002 milliseconds per ng/mL (90%CI, -0.01019 to 0.01014 milliseconds). The highest observed C max was 400 ng/mL, representing a margin 8-fold above exposures expected for the highest planned clinical dose. The model-predicted QTc effect at 400 ng/mL was 1.1 milliseconds (90%CI, -3.49 to 5.78 milliseconds). In neither the J-MAD study nor the pooled analysis was an effect of race identified. CR modeling of data from early-phase clinical studies, including plasma levels far exceeding those anticipated clinically, indicated that a QT effect >10 milliseconds could be excluded. Regulatory agreement with this methodology demonstrates the effectiveness of a CR modeling approach as an alternative to thorough QT studies., (© 2016, The American College of Clinical Pharmacology.)

The circadian timing system plays a critical role in the regulation of seasonal modifications in reproductive function. By detecting and transducing changes in the day-length (photoperiod), the neural substrates of the circadian system, including the supra-chiasmatic nuclei of the hypothalamus, trigger reproductive activity or quiescence at the appropriate seasons of the year in photoperiodic species. The circadian system also plays a role in the expression of endocrine changes that occur with seasonal breeding. Surges in luteinizing hormone secretion in female hamsters, for example, are either expressed daily during reproductive quiescence or suppressed on three out of the four days of the cycle during the breeding season. By such mechanisms a daily timer can be used in the regulation of cyclic events of much longer period.