ABSTRACT
Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor targeting vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor (FGF) receptors 1-4, platelet-derived growth factor receptor-α (PDGFRα), KIT, and RET that have been implicated in pathogenic angiogenesis, tumor growth, and cancer. The primary objective of this work was to evaluate, by establishing quantitative relationships, whether lenvatinib exposure and longitudinal serum biomarker data (VEGF, Ang-2, Tie-2, and FGF-23) are predictors for change in longitudinal tumor size which was assessed based on data from 558 patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC) receiving either lenvatinib or placebo treatment. Lenvatinib PK was best described by a 3-compartment model with simultaneous first- and zero-order absorption and linear elimination from the central compartment with significant covariates (body weight, albumin <30 g/dL, ALP>ULN, RR-DTC, RCC, HCC subjects, and concomitant CYP3A inhibitors). Except for body weight, none of the covariates have any clinically meaningful effect on exposure to lenvatinib. Longitudinal biomarker measurements over time were reasonably well defined by a PK/PD model with common EC50, Emax, and a slope for disease progression for all biomarkers. Longitudinal tumor measurements over time were reasonably well defined by a tumor growth inhibition Emax model, which in addition to lenvatinib exposure, included model-predicted relative changes from baseline over time for Tie-2 and Ang-2 as having significant association with tumor response. The developed PK/PD models pave the way for dose optimization and potential prediction of clinical response.
Subject(s)
Iodine Radioisotopes , Phenylurea Compounds , Quinolines , Thyroid Neoplasms , Humans , Quinolines/pharmacokinetics , Quinolines/administration & dosage , Quinolines/therapeutic use , Quinolines/blood , Quinolines/pharmacology , Phenylurea Compounds/pharmacokinetics , Phenylurea Compounds/administration & dosage , Phenylurea Compounds/therapeutic use , Phenylurea Compounds/blood , Phenylurea Compounds/pharmacology , Thyroid Neoplasms/drug therapy , Thyroid Neoplasms/blood , Thyroid Neoplasms/pathology , Male , Female , Middle Aged , Adult , Iodine Radioisotopes/pharmacokinetics , Iodine Radioisotopes/therapeutic use , Aged , Biomarkers, Tumor/blood , Models, Biological , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/blood , Vascular Endothelial Growth Factor A/blood , Receptor, TIE-2/blood , Young Adult , Angiopoietin-2/bloodABSTRACT
AIMS: The aim of this study is to determine the cumulative amount of lemborexant (a competitive dual orexin receptor antagonist approved to treat adults with insomnia) excreted in human breast milk and the relative infant dose (RID) as a proportion of daily maternal dose. METHODS: E2006-A001-010 was a single-centre, open-label study that enrolled lactating women (≥18 years) who breastfed for ≥5 weeks postpartum. After overnight fasting, subjects received a single 10-mg oral dose of lemborexant. Using a standardized electric pump, milk was sampled before and ≤240 h (10 days) after dosing; combined and total volume were recorded. The cumulative total amount of lemborexant excreted, fraction of dose excreted, daily infant dose and RID were calculated. Lemborexant concentration in human milk was assessed by liquid chromatography with tandem mass spectrometry. RESULTS: Eight subjects completed the study. The mean cumulative total amount of lemborexant reached 0.0174 mg (coefficient of variation [CV] 54.5%; 0.174% of lemborexant 10 mg administered) in breast milk at 240 h (10 days); ~70% of excreted lemborexant accumulated in the first 24 h. For an infant weighing 6 kg, the daily infant dose was 0.00290 mg kg-1 (CV 54.5%) and the RID was 1.96% (CV 63.1%) of daily maternal dose. Mild treatment-emergent adverse events were reported in 4 subjects; these all resolved by end of study. CONCLUSION: Trace quantities of lemborexant were found in human breast milk. Lemborexant was well tolerated by healthy lactating women.
Subject(s)
Lactation , Milk, Human , Adult , Infant , Humans , Female , Milk, Human/chemistry , Pyridines/adverse effects , Breast FeedingABSTRACT
The first-in-human phase I study for E6742, a dual toll-like receptor (TLR) 7 and TLR8 antagonist, has been conducted to assess the safety, tolerability, and pharmacokinetics of E6742 in healthy volunteers. In a single ascending dose (SAD) study, 42 subjects received 10-800 mg of E6742 in the fasted state, as well as a 100-mg cohort in the fed state for evaluating the effect of food. In a multiple ascending dose (MAD) study, 18 subjects received 100-400 mg of E6742 twice daily for 7 days. E6742 was rapidly absorbed with a median tmax ranging from 1.50 to 2.50 hours across dose groups under the fasted condition, and eliminated with a median t½ ranging from 2.37 to 14.4 hours. After multiple oral doses, a steady state was reached by day 7. In the SAD study, dose proportionality was observed for Cmax , AUC(0-t) , and AUC(0-inf) values of E6742 up to 800 mg, but these values were slightly less than dose proportional at 10 mg. In the MAD study, the Cmax and AUC(0-12h)ss of E6742 appeared to be almost dose proportionally increased between 100 and 200 mg, while these parameters showed more than a dose proportional increase at 400 mg. In addition to safety and good tolerability, this study demonstrated cytokine concentrations in cultured peripheral blood in response to E6742 were suppressed in a dose-dependent manner. Further clinical studies targeting systemic lupus erythematosus patients are currently underway.
Subject(s)
Fasting , Toll-Like Receptor 7 , Humans , Area Under Curve , Healthy Volunteers , Double-Blind MethodABSTRACT
BACKGROUND: E2814 is a human IgG1 antibody that binds to microtubule binding region of tau (MTBR-tau), a critical domain for the seeding and spreading of tau pathology in Alzheimer's Disease (AD). It is being developed for the treatment of AD by stopping tau propagation and slowing the associated cognitive decline. E2814 has been evaluated in healthy and Dominantly Inherited Alzheimer's Disease (DIAD) participants for safety, pharmacokinetics (PK), and cerebrospinal fluid (CSF) target engagement. METHOD: Seventy-two healthy participants were enrolled in single and multiple ascending dose cohorts of Study 001 (NCT04231513) and received randomized, double-blind, placebo-controlled treatment of E2814. Intravenous infusion of single and multiple doses (once every 4 weeks for three times) were administered. In Study 103 (NCT04971733), 7 DIAD participants with confirmed mutations and mild to moderate cognitive impairment were enrolled and received open-label treatment of E2814. Four sequential doses were evaluated as intravenous infusion every 4 weeks. Serum and CSF PK, and CSF target engagement (by analyzing both bound and unbound MTBR-tau299 and MTBR-tau354 [containing the epitopes of E2814]) were measured in both healthy and DIAD participants, as well as safety assessments. CSF MTBR-tau243 recapitulating AD tau pathology was also measured in DIAD participants using methods previously described (Horie et al., J Prev Alz Dis 2022). RESULT: E2814 was safe and well-tolerated over a wide dose range. No infusion-related reactions or other clinically significant safety signals were observed with single or repeated dose administration for up to 15 months. E2814 showed a dose-related increase in serum and CSF exposure with CSF-to-serum ratio of â¼0.2%, comparable between healthy and DIAD participants. CSF target engagement was demonstrated by concentration-related and sustained MTBR-tau299 and MTBR-tau354 binding in healthy and DIAD participants. More importantly, E2814 elicited a rapid and robust reduction on MTBR-tau243, a neurofibrillary tangle-specific biomarker, in DIAD participants. CONCLUSION: E2814 demonstrated promising safety, PK and CSF target engagement profile in DIAD participants, and showed evidence of downstream effects on tangle-specific biomarker MTBR-tau243. Data supports further evaluation in the ongoing Ph2/3 DIAN-TU Tau NexGen Platform Study in DIAD (NCT05269394) and future exploration in sporadic AD.
Subject(s)
Alzheimer Disease , tau Proteins , Humans , tau Proteins/cerebrospinal fluid , Alzheimer Disease/drug therapy , Double-Blind Method , Male , Female , Middle Aged , Adult , Cognitive Dysfunction , Antibodies, Monoclonal, Humanized/pharmacokinetics , Antibodies, Monoclonal, Humanized/administration & dosage , AgedABSTRACT
BACKGROUND: E2027 is a novel, highly selective and potent inhibitor of phosphodiesterase9 (PDE9) being evaluated as a treatment for dementia with Lewy bodies. METHODS: Phase 1, randomized, double-blind, single ascending dose (SAD, n=96) and multiple ascending dose (MAD, n=68) studies evaluated E2027 doses (5 to 1200 mg) in healthy subjects. The impact of age, race (Japanese/non-Japanese), and food on pharmacokinetics (PK)/pharmacodynamics were evaluated. Serial cerebrospinal fluid (CSF) samples were collected to assess the target engagement. RESULTS: E2027 PK profiles were biphasic (elimination half-life: ~30 hours. Approximately 3-fold accumulation was observed following multiple once-daily dosing. E2027 single doses of 50 to 400 mg resulted in mean maximum increases in CSF cyclic guanosine monophosphate ranging from 293% to 461% within 5.37 to 12.9 hours after dose administration to assess target engagement. Dose-response modelling of steady-state predose CSF cyclic guanosine monophosphate concentrations showed ≥200% increase from baseline is maintained with doses of ≥50 mg QD. The most common adverse events with E2027 were post-LP syndrome and back pain. PK profiles were similar between Japanese and non-Japanese. Higher exposure observed in fed versus fasted state was not considered clinically significant. PK exposure was higher in elderly subjects. CONCLUSIONS: S.E2027 was well-tolerated following single and multiple administration. E2027 achieved maximal and sustained target engagement at 50 mg QD, the dose selected for the phase 2 clinical trial.
Subject(s)
Lewy Body Disease , Phosphodiesterase Inhibitors , Aged , Area Under Curve , Clinical Trials, Phase II as Topic , Dose-Response Relationship, Drug , Double-Blind Method , Guanosine Monophosphate , Healthy Volunteers , Humans , Lewy Body Disease/drug therapy , Phosphodiesterase Inhibitors/therapeutic use , Phosphoric Diester HydrolasesABSTRACT
BACKGROUND: Lemborexant (LEM) is a dual orexin receptor antagonist approved for the treatment of insomnia in adults in multiple countries including the the United States, Japan, Canada, Australia and several Asian countries. PROCEDURES: This was a randomized, single-dose, single-center, double-blind, active-control, 6-way crossover study to evaluate LEM abuse potential. The study assessed oral doses of LEM 10 mg (LEM10), 20 mg (LEM20), and 30 mg (LEM30) compared with placebo (PBO), zolpidem (ZOL) immediate release 30 mg, and suvorexant (SUV) 40 mg. Subjects were healthy, nondependent, recreational sedative users able to discriminate/like the effects of both SUV and ZOL from PBO during a qualification phase. RESULTS: Abuse potential endpoints were analyzed in qualified subjects who received and completed all treatments (n = 32). On the "at this moment" drug-liking visual analog scale (VAS), mean maximum (peak) effect (primary endpoint) values were 78.4, 80.5, and 83.6 for LEM10, LEM20, and LEM30, respectively, which were all significantly greater than PBO (57.8; all P > 0.05) but not different from SUV (76.1) or ZOL (78.3). Similarly, for secondary endpoints overall drug-liking VAS and take-drug-again VAS, mean maximum (peak) effect values for all LEM doses were significantly greater than PBO ( P > 0.05) but not different compared with ZOL or SUV. CONCLUSIONS: For all doses, LEM demonstrated abuse potential versus PBO and appeared to have a similar abuse potential profile to ZOL and SUV in this study population. Lemborexant was well tolerated. Lemborexant has been placed in Schedule IV, the same drug schedule as ZOL and SUV.
Subject(s)
Hypnotics and Sedatives , Orexin Receptor Antagonists , Adult , Azepines , Cross-Over Studies , Double-Blind Method , Humans , Hypnotics and Sedatives/adverse effects , Orexin Receptor Antagonists/adverse effects , Pyridines , Pyrimidines , Triazoles , Zolpidem/adverse effectsABSTRACT
Intravenous (IV) drug administration enables treatment of epilepsy when oral administration is temporarily not feasible. Perampanel is a once-daily antiseizure medication currently available as oral formulations. Study 050 (NCT03376997) was an open-label, randomized, single-dose, crossover study to evaluate the interchangeability of oral and IV perampanel in healthy subjects (N = 48). Bioequivalence of single 12-mg doses of IV (30-, 60-, or 90-minute infusion) and oral perampanel, ≥6 weeks apart, was assessed. Analyses indicated bioequivalence of area under the plasma concentration-time curve extrapolated to infinity for 30- and 60-minute IV infusions and oral perampanel doses (geometric mean ratio [90% confidence interval], 0.93 [0.84-1.02] and 1.03 [0.97-1.09], respectively); however, IV maximum observed drug concentration (Cmax ) values were 1.35- to 1.61-fold higher than Cmax . Simulated plasma concentration-time profiles using pooled pharmacokinetic data further supported oral and IV perampanel interchangeability in two scenarios: 12-mg per day IV dosing during a temporary 7-day switch from oral steady-state maintenance therapy, and treatment initiation with 2-mg perampanel. Thirty-four (70.8%) subjects experienced treatment-related adverse events. The IV perampanel safety profile was similar to that of oral perampanel without new safety concerns. Perampanel IV infusions may be a suitable temporary alternative to oral perampanel for treatment maintenance and/or initiation.
Subject(s)
Nitriles , Pyridones , Area Under Curve , Cross-Over Studies , Humans , Nitriles/adverse effects , Pyridones/adverse effectsABSTRACT
BACKGROUND: Lemborexant is a dual orexin receptor antagonist approved to treat insomnia in adults in several countries including the USA, Canada, and Japan. AIMS: This study was conducted to investigate effects of lemborexant and alcohol coadministration on postural stability, cognitive performance, and the pharmacokinetics, safety, and tolerability of lemborexant. METHODS: This was a Phase 1, double-blind, placebo-controlled, four-period crossover study in 32 healthy adults. Individuals were randomized into one of four treatment sequences to receive single doses of placebo, lemborexant 10 mg (LEM10), alcohol (males, 0.7 g/kg; females, 0.6 g/kg), and LEM10 plus alcohol, each separated by a 14-day washout. Postural stability (body sway) was measured by ataxiameter and a cognitive performance assessment battery evaluated four domains of attention and memory. RESULTS: Pharmacodynamic outcomes were analyzed for the 18 participants who completed all four treatments. Change from baseline in body sway showed no significant differences between lemborexant plus alcohol versus alcohol alone. Compared with alcohol alone, coadministration of lemborexant with alcohol showed additive negative effects on cognitive performance domains, corresponding approximately with peak plasma lemborexant concentrations (median = 1.5 h). Cognitive performance was also impaired with lemborexant alone at 0.5 and 2 h in this experimental paradigm with morning dosing. Alcohol increased plasma lemborexant exposure by 70% based on area under the curve to 72 h, and increased peak plasma lemborexant concentrations by 35%. The most commonly reported treatment-emergent adverse event was somnolence. CONCLUSION: Coadministration of lemborexant with alcohol showed additive negative effects on cognitive measures, but not on postural stability, compared with alcohol alone. Lemborexant exposure was increased with alcohol. Lemborexant alone or with alcohol was well tolerated. Patients are advised not to consume alcohol with lemborexant.
Subject(s)
Orexin Receptor Antagonists , Pyridines , Adult , Cross-Over Studies , Ethanol/adverse effects , Female , Humans , Male , Orexin Receptor Antagonists/adverse effects , Orexin Receptor Antagonists/pharmacokinetics , Pyridines/pharmacology , Pyrimidines/pharmacologyABSTRACT
BACKGROUND: E2027 is a novel, highly selective and potent inhibitor of phosphodiesterase 9 in development for dementia with Lewy bodies. Cardiac safety assessments for emerging agents are essential to avoid drug-induced QT interval prolongation, which may predispose individuals to potentially fatal ventricular arrhythmias. To evaluate the cardiac safety of E2027 and to inform dose selection for the phase 2 study of E2027 in dementia with Lewy bodies, we evaluated concentration-response modeling of pooled electrocardiogram data. PATIENTS AND METHODS: A post hoc concentration-QTc analysis evaluated potential QT effects using data from 2 randomized, double-blind studies in healthy subjects: a single ascending dose (SAD) study and a multiple ascending dose (MAD) study. Daily E2027 doses ranged from 5 to 1200 mg. RESULTS: A linear mixed-effects model was used to establish the relationship between plasma concentrations of E2027 and change from the baseline of QTcF (ΔQTcF). A significant but shallow relationship was observed in the estimated slope of the concentration-ΔQTcF: 0.002 ms/ng/mL (90% confidence interval: 0.0007-0.0031) with a small, nonsignificant treatment effect-specific intercept of -0.6 ms. Based on this pooled concentration-QTc analysis, an effect on the QTcF interval >10 ms can be excluded up to E2027 plasma concentrations of â¼3579 ng/mL, corresponding to a dose at least 4-fold larger than the 50 mg phase 2 dose. CONCLUSION: This pooled post hoc analysis evaluating cardiac safety of E2027 demonstrated that clinically concerning QTcF prolongation and related cardiac complications are highly unlikely with proposed E2027 doses planned for phase 2.
Subject(s)
Lewy Body Disease , Long QT Syndrome , Phosphodiesterase Inhibitors , Dose-Response Relationship, Drug , Double-Blind Method , Electrocardiography , Humans , Lewy Body Disease/drug therapy , Long QT Syndrome/chemically induced , Phosphodiesterase Inhibitors/adverse effects , Randomized Controlled Trials as TopicABSTRACT
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.
Subject(s)
Ethinyl Estradiol/administration & dosage , Norethindrone/administration & dosage , Pyridines/administration & dosage , Pyrimidines/administration & dosage , Adolescent , Adult , Area Under Curve , Contraceptives, Oral, Combined/administration & dosage , Contraceptives, Oral, Combined/pharmacokinetics , Contraceptives, Oral, Combined/pharmacology , Drug Interactions , Ethinyl Estradiol/pharmacokinetics , Ethinyl Estradiol/pharmacology , Female , Humans , Norethindrone/pharmacokinetics , Norethindrone/pharmacology , Orexin Receptor Antagonists/administration & dosage , Orexin Receptor Antagonists/pharmacokinetics , Orexin Receptor Antagonists/pharmacology , Pyridines/pharmacokinetics , Pyridines/pharmacology , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Young AdultABSTRACT
Lemborexant, a dual orexin receptor antagonist, is approved in the United States, Japan, and Canada for the treatment of insomnia in adults. This phase I, multicenter, open-label, parallel-group study assessed the impact of mild or moderate hepatic impairment (HI) on lemborexant pharmacokinetics and metabolism. The pharmacokinetics, tolerability, and safety of lemborexant were evaluated in subjects with mild (Child-Pugh class A) or moderate (Child-Pugh class B) HI and healthy age-, sex-, and body mass index (BMI)-matched control subjects (n = 8 subjects/group). Subjects received a single oral dose of lemborexant 10 mg (LEM10). Blood samples were collected up to 312 hours post dosing for lemborexant pharmacokinetics assessments. Median time to maximum plasma concentration was similar across all groups. Compared with healthy subjects, exposure measures (maximum plasma concentration [Cmax ] and area under the curve extrapolated to infinity [AUC0-inf ]) increased by ~58% (Cmax ) and ~25% (AUC0-inf ) in subjects with mild HI and ~22% (Cmax ) and ~54% (AUC0-inf ) in subjects with moderate HI. Clearance decreased by 20% and 35% in subjects with mild and moderate HI, respectively, versus healthy subjects. Lemborexant unbound fraction was similar in all groups (range: 0.060-0.065). All treatment-emergent adverse events (TEAEs) were mild in severity; no serious TEAEs occurred. In conclusion, following a single LEM10 dose, lemborexant exposure was similar in subjects with mild HI and increased in subjects with moderate HI versus healthy subjects. No dose adjustment is required in subjects with mild HI. Dosing in subjects with moderate HI should be restricted to 5 mg. Lemborexant was well tolerated in all groups.
Subject(s)
Hepatic Insufficiency/metabolism , Hepatobiliary Elimination/physiology , Pyridines/pharmacokinetics , Pyrimidines/pharmacokinetics , Sleep Aids, Pharmaceutical/pharmacokinetics , Administration, Oral , Adolescent , Adult , Aged , Area Under Curve , Female , Healthy Volunteers , Hepatic Insufficiency/diagnosis , Hepatic Insufficiency/physiopathology , Humans , Male , Middle Aged , Pyridines/administration & dosage , Pyridines/adverse effects , Pyrimidines/administration & dosage , Pyrimidines/adverse effects , Severity of Illness Index , Sleep Aids, Pharmaceutical/administration & dosage , Sleep Aids, Pharmaceutical/adverse effects , Sleep Initiation and Maintenance Disorders/drug therapy , Young AdultABSTRACT
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.
Subject(s)
Orexin Receptor Antagonists/pharmacokinetics , Pyridines/pharmacokinetics , Pyrimidines/pharmacokinetics , Renal Elimination/physiology , Renal Insufficiency/metabolism , Sleep Initiation and Maintenance Disorders/drug therapy , Adolescent , Adult , Aged , Area Under Curve , Female , Glomerular Filtration Rate/physiology , Half-Life , Humans , Male , Middle Aged , Orexin Receptor Antagonists/administration & dosage , Orexin Receptor Antagonists/adverse effects , Pyridines/administration & dosage , Pyridines/adverse effects , Pyrimidines/administration & dosage , Pyrimidines/adverse effects , Renal Insufficiency/diagnosis , Renal Insufficiency/physiopathology , Severity of Illness Index , Young AdultABSTRACT
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.
Subject(s)
Cytochrome P-450 CYP2B6/drug effects , Cytochrome P-450 CYP3A/drug effects , Orexin Receptor Antagonists/administration & dosage , Pyridines/administration & dosage , Pyrimidines/administration & dosage , Adult , Area Under Curve , Cytochrome P-450 CYP2B6/metabolism , Cytochrome P-450 CYP3A/metabolism , Cytochrome P-450 CYP3A Inhibitors/pharmacology , Cytochrome P-450 Enzyme Inducers/pharmacology , Drug Interactions , Female , Humans , Male , Middle Aged , Orexin Receptor Antagonists/pharmacokinetics , Orexin Receptor Antagonists/pharmacology , Pyridines/pharmacokinetics , Pyridines/pharmacology , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Young AdultABSTRACT
Lemborexant is a novel dual orexin receptor antagonist recently approved for the treatment of insomnia in the United States and Japan. Here, disposition and metabolic profiles were investigated in healthy human subjects. After single oral administration of 10 mg [14C]lemborexant (100 µCi), plasma concentrations of lemborexant and radioactivity peaked at 1 hour postdose and decreased biphasically. Cumulative recovery of the administered radioactivity within 480 hours was 86.5% of the dose, with 29.1% in urine and 57.4% in feces. Unchanged lemborexant was not detected in urine but accounted for 13.0% of the dose in feces, suggesting that the main elimination pathway of lemborexant was metabolism. Metabolite analyses revealed that the major metabolic pathways of lemborexant are oxidation of the dimethylpyrimidine moiety and subsequent further oxidation and/or glucuronidation. In plasma, lemborexant was the dominant component, accounting for 26.5% of total drug-related exposure. M4, M9, M10, and M18 were detected as the major radioactive components; M10 was the only metabolite exceeding 10% of total drug-related exposure. Although M4, M9, and M10 showed binding affinity for orexin receptors comparable to that of lemborexant, their contributions to the sleep-promoting effects of lemborexant are likely low because of the limited brain penetration by P-glycoprotein. Exposure comparison between humans and nonclinical toxicology species confirmed that plasma exposure of M10 was higher in at least one animal species compared with that in humans, indicating that there is no disproportionate metabolite in humans, as defined by International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use M3(R2) and U.S. Food and Drug Administration Metabolite in Safety Testing guidance; therefore, no additional toxicology studies are needed. SIGNIFICANCE STATEMENT: This study provides detailed data of the disposition and metabolism of lemborexant, a novel therapeutic drug for insomnia, in humans, as well as a characterization of the circulating metabolites and assessment of their contributions to efficacy and safety. The information presented herein furthers our understanding of the pharmacokinetic profiles of lemborexant and its metabolites and will promote the safe and effective use of lemborexant in the clinic.
Subject(s)
Drug Monitoring/methods , Pyridines , Pyrimidines , Sleep Initiation and Maintenance Disorders/drug therapy , Administration, Oral , Healthy Volunteers , Humans , Metabolic Networks and Pathways , Orexin Receptor Antagonists/blood , Orexin Receptor Antagonists/pharmacokinetics , Pharmacokinetics , Pyridines/blood , Pyridines/pharmacokinetics , Pyrimidines/blood , Pyrimidines/pharmacokinetics , RadioactivityABSTRACT
Lemborexant, a dual orexin receptor antagonist, is approved for the treatment of insomnia and is under investigation for treating other sleep disorders. Here we summarize pharmacokinetic, pharmacodynamic, and safety data from 3 randomized, double-blind, placebo-controlled phase 1 studies: single ascending doses in healthy adults (Study 001; 1-200 mg; N = 64), multiple ascending doses in healthy and elderly adults (Study 002; 2.5-75 mg; N = 55), and multiple doses in healthy white and Japanese adults (Study 003; 2.5-25 mg; N = 32). Lemborexant exposure increased with increasing dose. The time to maximum concentration ranged from approximately 1 to 3 hours for the 5- and 10-mg doses. The mean effective half-life was 17 hours for lemborexant 5 mg and 19 hours for lemborexant 10 mg. The plasma concentration at 9 hours postdose was 27% of the maximum concentration following multiple dosing with lemborexant 10 mg. There were no clinically relevant effects on next-morning residual sleepiness (Karolinska Sleepiness Scale, Digital Symbol Substitution Test, Psychomotor Vigilance Test) for doses through 10 mg/day, indicating no effect of residual plasma concentrations on next-day residual effects. Lemborexant was well tolerated across the doses tested. There were no clinically relevant effects of age, sex, or race on lemborexant pharmacokinetics, pharmacodynamics, or safety. These results suggest that lemborexant at doses through 25 mg provides an overall pharmacokinetic, pharmacodynamic, and safety profile suitable for obtaining the target pharmacologic effect supporting treatment of insomnia while minimizing residual effects during wake time.
Subject(s)
Orexin Receptor Antagonists/administration & dosage , Pyridines/administration & dosage , Pyrimidines/administration & dosage , Adult , Age Factors , Aged , Asian People , Dose-Response Relationship, Drug , Double-Blind Method , Female , Half-Life , Humans , Male , Middle Aged , Orexin Receptor Antagonists/adverse effects , Orexin Receptor Antagonists/pharmacokinetics , Pyridines/adverse effects , Pyridines/pharmacokinetics , Pyrimidines/adverse effects , Pyrimidines/pharmacokinetics , Sex Factors , White PeopleABSTRACT
Lemborexant is a dual orexin receptor antagonist approved for treating insomnia. As the solubility of lemborexant is pH-sensitive, the impact of the gastric acid-reducing agent (ARA), famotidine, on lemborexant pharmacokinetics was evaluated in a Phase 1 study. Additionally, post hoc analysis of data from Phase 3 studies examined the potential effect of concomitant ARAs on patient-reported/subjective sleep onset latency (sSOL) in subjects with insomnia. Coadministration of lemborexant 10 mg with famotidine decreased the maximum observed concentration by 27% and delayed time of maximum observed concentration by 0.5 hours. Famotidine did not affect overall lemborexant exposure based on comparison of area under the concentration curves. Concomitant ARA use in the Phase 3 studies did not impact the effect of lemborexant on sSOL; the change from baseline during the last 7 nights of 1 month of treatment with lemborexant 10 mg was -17.1 minutes with vs -17.9 minutes without ARAs. Collectively, these results indicate that lemborexant can be coadministered with ARAs.
Subject(s)
Famotidine/pharmacokinetics , Gastric Acid/metabolism , Histamine H2 Antagonists/pharmacokinetics , Orexin Receptor Antagonists/pharmacokinetics , Pyridines/pharmacokinetics , Pyrimidines/pharmacokinetics , Adult , Double-Blind Method , Drug Interactions/physiology , Famotidine/administration & dosage , Female , Histamine H2 Antagonists/administration & dosage , Humans , Male , Orexin Receptor Antagonists/administration & dosage , Pyridines/administration & dosage , Pyrimidines/administration & dosage , Treatment OutcomeABSTRACT
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 (Cav,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 (Cav,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.
Subject(s)
Orexin Receptor Antagonists/adverse effects , Orexin Receptor Antagonists/pharmacokinetics , Pyridines/adverse effects , Pyridines/pharmacokinetics , Pyrimidines/adverse effects , Pyrimidines/pharmacokinetics , Sleep Initiation and Maintenance Disorders/drug therapy , Administration, Oral , Adolescent , Adult , Aged , Aged, 80 and over , Area Under Curve , Clinical Trials as Topic , Drug Elimination Routes , Female , Humans , Male , Middle Aged , Orexin Receptor Antagonists/administration & dosage , Orexin Receptor Antagonists/blood , Pyridines/administration & dosage , Pyridines/blood , Pyrimidines/administration & dosage , Pyrimidines/blood , Young AdultABSTRACT
BACKGROUND AND OBJECTIVE: Lenvatinib is a multikinase inhibitor that inhibits enzyme activity but induces gene expression of cytochrome P450 3A4 (CYP3A4), an important enzyme for drug metabolism. We evaluated the impact of lenvatinib on CYP3A4 using midazolam as a probe substrate in patients with advanced solid tumors. The primary objective was to determine the pharmacokinetic effects of lenvatinib on midazolam, and the secondary objective was to assess the safety of lenvatinib. METHODS: This multicenter, open-label, nonrandomized, phase 1 study involved patients with advanced cancer that progressed after treatment with approved therapies or for which no standard therapies were available. RESULTS: Compared with baseline, coadministration of lenvatinib decreased the geometric mean ratio of the area under the concentration-time curve for midazolam on day 1 to 0.914 (90% confidence interval [CI] 0.850-0.983) but increased it on day 14 to 1.148 (90% CI 0.938-1.404). Coadministration of lenvatinib also decreased the geometric mean ratio of the maximum observed concentration for midazolam on day 1 to 0.862 (90% CI 0.753-0.988) but increased it on day 14 to 1.027 (90% CI 0.852-1.238). There was little change in the terminal elimination phase half-life of midazolam when administered with lenvatinib. The most common treatment-related adverse events were hypertension (20.0%), fatigue (16.7%), and diarrhea (10.0%). CONCLUSIONS: Coadministration of lenvatinib had no clinically relevant effect on the pharmacokinetics of midazolam, a CYP3A4 substrate. The adverse events were consistent with the known safety profile of lenvatinib, and no new safety concerns were identified. CLINICALTRIALS. GOV IDENTIFIER: NCT02686164.
Subject(s)
Antineoplastic Agents/pharmacology , Cytochrome P-450 CYP3A/metabolism , Midazolam/pharmacokinetics , Phenylurea Compounds/pharmacology , Quinolines/pharmacology , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/administration & dosage , Area Under Curve , Cytochrome P-450 CYP3A/drug effects , Cytochrome P-450 CYP3A/genetics , Drug Interactions , Female , Half-Life , Humans , Male , Middle Aged , Neoplasms/drug therapy , Phenylurea Compounds/administration & dosage , Phenylurea Compounds/adverse effects , Quinolines/administration & dosage , Quinolines/adverse effectsABSTRACT
AIMS: Avatrombopag, a thrombopoietin receptor agonist, is a substrate of cytochrome P450 (CYP) 2C9 and CYP3A. We assessed three drug-drug interactions of avatrombopag as a victim with dual or selective CYP2C9/3A inhibitors and inducers. METHODS: This was a three-part, open-label study. Forty-eight healthy subjects received single 20 mg doses of avatrombopag alone or with one of 3 CYP2C9/3A inhibitors or inducers: fluconazole 400 mg once daily for 16 days, itraconazole 200 mg twice daily on Day 1 and 200 mg once daily on Days 2-16, or rifampicin 600 mg once daily for 16 days. Pharmacokinetics, pharmacodynamics (platelet count) and safety of avatrombopag were evaluated. RESULTS: Coadministration of a single 20-mg dose of avatrombopag with fluconazole at steady-state resulted in 2.16-fold increase of AUC of avatrombopag, prolonged terminal elimination phase half-life (from 19.7 h to 39.9 h) and led to a clinically significant increase in maximum platelet count (1.66-fold). Itraconazole had a mild increase on both avatrombopag pharmacokinetics and pharmacodynamics compared to fluconazole. Coadministration of rifampicin caused a 0.5-fold decrease in AUC and shortened terminal elimination phase half-life (from 20.3 h to 9.84 h), but has no impact on maximum platelet count. Coadministration with interacting drugs was found to be generally safe and well-tolerated. CONCLUSIONS: The results from coadministration of fluconazole or itraconazole suggest that CYP2C9 plays a more predominant role in metabolic clearance of avatrombopag than CYP3A. To achieve comparable platelet count increases when avatrombopag is coadministered with CYP3A and CYP2C9 inhibitors, an adjustment in the dose or duration of treatment is recommended, while coadministration with strong inducers is not currently recommended.
Subject(s)
Drug Interactions , Fluconazole/pharmacology , Itraconazole/pharmacology , Rifampin/pharmacology , Thiazoles/pharmacology , Thiazoles/pharmacokinetics , Thiophenes/pharmacology , Thiophenes/pharmacokinetics , Adolescent , Adult , Cytochrome P-450 CYP2C9 Inducers/pharmacology , Cytochrome P-450 CYP2C9 Inhibitors/pharmacology , Cytochrome P-450 CYP3A Inducers/pharmacology , Cytochrome P-450 CYP3A Inhibitors/pharmacology , Female , Healthy Volunteers , Humans , Male , Middle Aged , Platelet Count/statistics & numerical data , Receptors, Thrombopoietin/agonists , Thiazoles/adverse effects , Thiazoles/blood , Thiophenes/adverse effects , Thiophenes/blood , Young AdultABSTRACT
Avatrombopag, an orally administered, small-molecule thrombopoietin receptor (c-Mpl) agonist, is currently in clinical development for the potential treatment of severe thrombocytopenia in patients with chronic liver disease undergoing an elective procedure. The objectives of this study were to characterize and compare the pharmacokinetics (including the food effect) and pharmacodynamics (platelet count) of avatrombopag following single doses in Japanese and white subjects. Following single dosing under fasted and fed conditions, mean peak concentrations occurred at 5 to 8 hours and subsequently declined with a half-life of 16 to 18 hours in Japanese and white subjects. Administration with food did not alter the rate or extent of avatrombopag absorption but substantially reduced pharmacokinetic variability relative to the fasted state. CYP2C9 polymorphism (*2, *3) was associated with higher pharmacokinetic variability but not with any clinically important effect on variability in platelet response. Plasma exposures of avatrombopag increased in a dose-proportional manner over the dose range tested. After a single dose, platelet count increased in a dose-related manner, reaching a maximum by day 11 and returning to baseline levels by day 27. No clinically important differences were found when avatrombopag pharmacokinetics and pharmacodynamics were compared between Japanese and white subjects. Administration of avatrombopag was generally well tolerated.