Lemborexant levels in breast milk after single doses in healthy, lactating women.

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.

Clinical assessment of gepotidacin (GSK2140944) as a victim and perpetrator of drug-drug interactions via CYP3A metabolism and transporters.

Gepotidacin is a novel triazaacenaphthylene antibiotic in phase III development. Based on nonclinical in vitro characterization of gepotidacin metabolism, two phase I studies were conducted in healthy participants to investigate clinical drug-drug interactions (DDIs). We assessed gepotidacin as a DDI victim with a potent cytochrome P450 (CYP) 3A4/P-glycoprotein (P-gp) inhibitor (itraconazole), potent CYP3A4 inducer (rifampicin), and nonspecific organic cation transporter (OCT)/multidrug and toxic extrusion transporter (MATE) renal transport inhibitor (cimetidine) via single doses of gepotidacin before and after co-administration with multiple doses of the modulator drugs. Gepotidacin DDI perpetrator potential for P-gp inhibition (digoxin) and CYP3A4 inhibition (midazolam) was evaluated via single doses of the two-drug cocktail without and with gepotidacin. The DDI magnitudes were interpreted based on area under the concentration-time curve (AUC). A weak DDI (AUC increase 48%-50%) was observed for gepotidacin co-administered with itraconazole. A clinically significant decrease in gepotidacin plasma AUC (52%) was observed with rifampicin coadministration, indicating a moderate DDI. There was no DDI for gepotidacin with cimetidine; a unique biomarker approach showed increased serum creatinine (24%), decreased renal clearance of creatinine (21%), and N1-methylnicotinamide (39%), which confirmed extensive MATE inhibition and partial OCT2 inhibition. Gepotidacin was not a P-gp DDI perpetrator, although the maximum plasma concentration of digoxin increased (53%) and is potentially clinically relevant given its narrow therapeutic index. Gepotidacin demonstrated weak CYP3A4 inhibition with midazolam (<2-fold AUC increase). There were no new safety-risk profile findings. These results will inform the safe and efficacious clinical use of gepotidacin when co-administered with other drugs.

Pharmacokinetic, Safety, and Tolerability Evaluations of Gepotidacin (GSK2140944) in Healthy Japanese Participants.

Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibiotic in late-phase development for uncomplicated urinary tract infection and uncomplicated urogenital gonorrhea. Two clinical studies were conducted to assess the pharmacokinetics (PK) and interethnic comparisons of oral gepotidacin (free-base and to-be-marketed mesylate formulations) administered as single doses ranging from 1500 to 3000 mg in fed and fasted states, and as 2 × 3000-mg doses given 12 hours apart under fed conditions in healthy participants of Japanese ancestry. Dose proportionality was observed in plasma exposures, and comparable area under the concentration-time curve (AUC) and maximum concentration were observed in fed and fasted states. Interethnic comparisons for Japanese versus non-Japanese participant data showed slightly higher plasma maximum concentration (7%-30%) yet similar plasma AUCs; slightly lower urine AUCs (11%-18%) were observed. The slightly higher plasma exposures in healthy Japanese versus White participants in the same study were attributed to lower mean body weights (64 kg versus ≈80 kg). Adverse events were primarily gastrointestinal, and when administered with food, gastrointestinal tolerability was improved. Overall, the gepotidacin PK and safety-risk profiles in healthy Japanese support potential evaluation of the global clinical doses in future studies.

Pharmacokinetics of Oral Formulations of Gepotidacin (GSK2140944), a Triazaacenaphthylene Bacterial Type II Topoisomerase Inhibitor, in Healthy Adult and Adolescent Participants.

Gepotidacin is a novel, first-in-class triazaacenaphthylene antibiotic that may provide a new treatment option for antibiotic-resistant pathogens. Two pharmacokinetic evaluations of oral gepotidacin are presented: a relative bioavailability study that guided formulation development, followed by an adult and adolescent study of the final formulation. In the relative bioavailability study, after gepotidacin administration to 26 healthy adults as free-base roller-compacted (RC) tablets, free-base high-shear wet granulation (HSWG) tablets, and mesylate salt reference capsules, the RC tablet exposure ratios and 90% confidence intervals (CIs) were within the 0.80-to-1.25 confidence bounds; however, the HSWG tablet maximum observed concentration (Cmax) was higher than the reference (ratio, 1.15; 90% CI, 1.0113, 1.3047). In the healthy adult (n = 16) and adolescent (n = 17) study, a gepotidacin mesylate salt tablet was evaluated as a 1,500-mg single dose or 2 doses administered 6 or 12 h apart (6,000 mg total), or placebo was administered. The single-dose mean Cmax was ∼27% higher in adolescents than in adults, and area under the concentration-time curve (AUC) values were comparable in both populations. After 2 doses were administered, the mean Cmax values were similar for both age groups, and the mean AUC was ∼35% higher in adolescents than in adults. Concentrations increased proportionally with dose. Safety-risk profiles were similar for both age groups. Across studies, the most common adverse events were gastrointestinal. Overall, the pharmacokinetics of the final gepotidacin mesylate salt tablet have been well characterized, enrollment of adolescents into the pivotal trials is supported, and dosing intervals were determined that should provide adequate exposures for microbiological efficacy. (This study has been registered at ClinicalTrials.gov under identifiers NCT02853435 and NCT04079790.).

A phase 1, open-label study to evaluate the drug interaction between islatravir (MK-8591) and the oral contraceptive levonorgestrel/ethinyl estradiol in healthy adult females.

INTRODUCTION: Hormonal contraceptives are among the most effective forms of reversible contraception, but many other compounds, including some antiretrovirals, have clinically meaningful drug-drug interactions (DDIs) with hormonal contraceptives. Islatravir is a novel human immunodeficiency virus nucleoside reverse transcriptase translocation inhibitor currently in clinical development for treatment and prevention of HIV infection. A phase 1 clinical trial was conducted to evaluate the DDI of islatravir and the combination of oral contraceptive levonorgestrel (LNG)/ethinyl estradiol (EE). METHODS: This was an open-label, two-period, fixed-sequence, DDI clinical trial in healthy, postmenopausal or bilaterally oophorectomized females aged 18 through 65 years in the United States between October 2016 and January 2017. A single dose of LNG 0.15 mg/EE 0.03 mg was given followed by a 7-day washout. Islatravir, 20 mg, was then dosed once weekly for 3 weeks; a single dose of LNG 0.15 mg/EE 0.03 mg was given concomitantly with the third dose of islatravir. Pharmacokinetic samples for plasma LNG and EE concentrations were collected pre-dose and up to 120 hours post-dose in each period. Safety and tolerability were assessed throughout the trial by clinical assessments, laboratory evaluations and examination of adverse events. RESULTS AND DISCUSSION: Fourteen participants were enrolled. The pharmacokinetics of LNG and EE were not meaningfully altered by co-administration with islatravir. For the comparison of (islatravir + LNG/EE)/(LNG/EE alone), the geometric mean ratios (GMRs) (90% confidence intervals [CIs]) for LNG AUC0-inf and Cmax were 1.13 (1.06, 1.20) and 0.965 (0.881, 1.06), respectively. For EE, the GMRs (90% CI) for AUC0-inf and Cmax were 1.05 (0.981, 1.11) and 1.02 (0.971, 1.08), respectively. Co-administration of all three drugs was generally well tolerated. CONCLUSIONS: The results of this trial support the use of LNG/EE contraceptives in combination with islatravir without dose adjustment.

Randomised, phase I pharmacokinetic study of adalimumab biosimilar CT-P17 (40 mg/0.4 mL) by autoinjector and prefilled syringe in healthy subjects.

AIMS: To evaluate pharmacokinetic equivalence and preliminary safety of the adalimumab biosimilar CT-P17 administered via autoinjector (CT-P17 AI) or prefilled syringe (CT-P17 PFS) in healthy subjects. METHODS: This phase I, open-label study (ClinicalTrials.gov: NCT04295356) randomised subjects (1:1) to receive a single 40-mg (100 mg/mL) dose of CT-P17 AI or CT-P17 PFS. Primary endpoint was pharmacokinetic equivalence of CT-P17 AI to CT-P17 PFS for: area under the concentration-time curve from time zero to infinity (AUC0-inf ); area under the concentration-time curve from time zero to the last quantifiable concentration (AUC0-last ); maximum serum concentration (Cmax ). Equivalence was determined if the 90% confidence interval for the geometric least-squares mean ratio was within the 80-125% equivalence margin. Additional pharmacokinetic endpoints, safety and immunogenicity were evaluated. RESULTS: Of 193 subjects who were randomised (98 CT-P17 AI; 95 CT-P17 PFS), 180 received study drug. Pharmacokinetic equivalence was demonstrated: 90% confidence intervals were within the 80-125% equivalence margin (AUC0-inf : 93.98-114.29; AUC0-last : 91.09-121.86; Cmax : 94.08-111.90). Mean serum CT-P17 concentrations, secondary pharmacokinetic parameters and numbers of subjects with antidrug antibodies (ADAs) or neutralising ADAs were comparable between groups. AUC0-inf , AUC0-last and Cmax were numerically lower for ADA-positive than for ADA-negative subjects (both groups); pharmacokinetic equivalence was also demonstrated among ADA-positive subjects. CT-P17 AI and CT-P17 PFS were well tolerated, with comparable overall safety profiles. CONCLUSIONS: CT-P17 AI and CT-P17 PFS were pharmacokinetically equivalent. Overall safety and immunogenicity were comparable between the 2 delivery devices.

Relative Bioavailability of a Single 4-mg Dose of Somatropin Administered by Subcutaneous Injection or by Needle-free Device and Coadministered With the Growth Hormone Inhibitor Octreotide Acetate in Healthy Adult Subjects.

PURPOSE: Somatropin, used to treat growth hormone deficiency, has been traditionally administered by subcutaneous (SC) injection with needle and syringe. Needle-free devices offer ease of administration and may improve adherence and outcomes. This study evaluated the relative bioavailability of somatropin delivered with a needle-free device compared with traditional SC injection. METHODS: In this randomized, single-dose, crossover study, healthy adults aged 18 to 35 years received single 4-mg doses of somatropin via a needle-free device or SC injection, along with octreotide to suppress endogenous growth hormone production. Blood samples were analyzed for serum somatropin and insulin-like growth factor-1 (IGF-1) concentrations over 24 hours after somatropin dosing. Pharmacokinetic and pharmacodynamic parameters were evaluated by using noncompartmental methods, and bioequivalence was determined based on ln transformation of the AUC0-24, AUC0-∞, Cmax, area under the effect-time curve from time 0 to 24 hours (AUEC0-24), and maximum effect concentration (Emax). Bioequivalence was concluded if the 90% CIs of the needle-free device compared with the SC injection, constructed by using the two 1-sided hypotheses at the α = 0.05 level, for these pharmacokinetic/pharmacodynamic parameters fell within the 80.00% to125.00% regulatory acceptance range. FINDINGS: A total of 57 subjects completed both study periods and were included in the pharmacokinetic analyses. Point estimates (90% CIs) of the geometric mean ratio (needle-free device/SC injection) based on serum somatropin were 1.013 (0.987-1.040) for AUC0-24, 1.012 (0.986-1.038) for AUC0-∞, and 1.200 (1.137-1.267) for Cmax. For IGF-1, baseline-corrected point estimates (90% CIs) were 0.901 (0.818-0.993) for AUEC0-24 and 0.867 (0.795-0.946) for Emax. Non-baseline-corrected values were 0.978 (0.953-1.004) for AUEC0-24 and 0.953 (0.923-0.984) for Emax. Both treatments were well tolerated; blood glucose levels increased in nearly all subjects (98.3%). All adverse events were mild and resolved spontaneously within 24 hours. IMPLICATIONS: Bioequivalence was shown for a single 4-mg dose of somatropin delivered by using a needle-free device compared with SC injection based on ln-transformed AUC0-24 and AUC0-∞ but not ln-transformed Cmax.

A randomized, three-treatment, three-period, six-sequence-crossover, single-center, bioequivalence study to evaluate the impact of different 10-mg crystalline forms on the pharmacokinetics of lenvatinib in healthy volunteers.

OBJECTIVE: This study assessed the impact of varying lenvatinib crystalline forms in 10-mg lenvatinib capsules on drug bioavailability in healthy volunteers. MATERIALS: Lenvatinib 10-mg capsules (low C and high C forms). METHODS: This randomized, three-period- crossover study compared the pharmacokinetics and safety of two crystalline forms of capsules (low C-form, <4% crystalline; high C-form, 38% crystalline) to a standard (ref Cform, 15% crystalline). RESULTS: 59 subjects were evaluable for pharmacokinetics. Test/reference ratios of the geometric least squares means (LSM) and 90% confidence intervals (CI) for AUC0-t (t up to 120 hours), AUC0-∞, and Cmax for low C-form vs. ref C-form were 101 (94.8, 107), 101 (95.3, 107), and 98.7 (88.6, 110), respectively; and for high C-form vs. ref C-form were 96.0 (92.1, 100), 96.5 (92.5, 101), and 90.6 (83.5, 98.4), respectively. The incidence of treatment-emergent adverse events (TEAE) and treatment-related adverse events (TRAE) were comparable between all formulations (TEAE range 20-24%; TRAE range 15-19%). One serious TRAE (spontaneous abortion) occurred in the low C-form group. CONCLUSIONS: For both comparisons, the 90% CIs of the test/reference ratios were within the regulatory acceptance range (80-125%), suggesting that both test formulations (low Cform and high C-form) were bioequivalent to the reference formulation for Cmax, AUC0-t, and AUC0-∞.