Assessment of pharmacokinetics, safety, and tolerability following twice-daily administration of molnupiravir for 10 days in healthy participants.

Molnupiravir is an orally administered, small-molecule ribonucleoside prodrug of ß-D-N4-hydroxycytidine (NHC) that has demonstrated potent, broad-spectrum preclinical activity against RNA viruses and has a high barrier to the development of resistance. A double-blind, placebo-controlled, phase I trial was conducted to evaluate the pharmacokinetics (PKs), safety, and tolerability of 10.5-day administration of multiple doses of molnupiravir and its metabolites in healthy, adult participants. Participants were randomly assigned (3:1) to receive molnupiravir (400 mg [n = 6], 600 mg [n = 6], and 800 mg [n = 12]) or matching placebo (n = 8) every 12 h (q12h) for 10.5 days. Blood was collected to evaluate the PKs of NHC in plasma and of its active metabolite, NHC-triphosphate (NHC-TP), in peripheral blood mononuclear cells (PBMCs). Molnupiravir was generally well-tolerated. All adverse events were mild or moderate in severity and none led to treatment discontinuation. No clinically meaningful dose-related safety findings were observed. Mean time to maximal concentration was ~1.50 to 1.98 h for plasma NHC and ~4.00 to 8.06 h for PBMC NHC-TP. Accumulation was minimal (<1.2) for NHC and ~2- to 2.5-fold for NHC-TP. Plasma NHC PKs was generally dose proportional, and PBMC NHC-TP PKs was less than dose proportional over the dose range studied. NHC and NHC-TP PK support twice-daily administration. Overall, molnupiravir administered at up to 800 mg q12h for 10.5 days was generally well-tolerated in healthy participants with dose-linear PKs, supporting the evaluation of longer molnupiravir dosing up to 10 days in future clinical trials.

A Phase 1 Trial to Evaluate the Relationship Between Fluoride Intake and Urinary Fluoride Excretion in Healthy Participants.

Chronic overexposure to fluoride can have deleterious effects in the musculoskeletal system. Some fluorine-containing therapeutics, such as voriconazole, release fluoride through metabolism. Therefore, drug-related fluoride exposure should be assessed for novel therapeutics suspected of releasing fluoride through metabolism. Two trials were conducted to identify the optimal method of assessing drug-related fluoride exposure. In trial 1, designed to assess reproducibility of fluoride pharmacokinetics in urine and plasma, 14 participants were administered a fluoride-restricted diet and once-daily doses of sodium fluoride (2.2 mg [1 mg of fluoride] on days 1 and 2; and 13.2 mg of sodium fluoride [6 mg of fluoride] on days 3 and 4). In trial 2, designed to confirm the selected method for fluoride detection, 12 participants were administered a fluoride-restricted diet and randomized to receive voriconazole (400 mg twice, 12 hours apart, on day 1 [131 mg/d of fluoride maximum], then 3 doses of 200 mg every 12 hours [65.3 mg/d of fluoride maximum]) or placebo. Plasma fluoride concentrations and urinary fluoride excretion were assessed in each trial. Assessment of plasma fluoride concentrations in trial 1 was limited by 301 of 854 samples (35.2%) below the lower limit of quantitation. Urine fluoride excretion was readily measured and demonstrated a decrease from baseline during the fluoride-restricted diet phase, as well as dose-proportional increases with fluoride administration. In trial 2, increases in urine fluoride were successfully observed in participants administered voriconazole. In conclusion, fluoride exposure was optimally assessed by urinary fluoride excretion in conjunction with strict dietary fluoride restrictions, as measurements were consistent and reproducible.

Fluoride Pharmacokinetics in Urine and Plasma Following Multiple Doses of MK-8507, an Investigational, Oral, Once-Weekly Nonnucleoside Reverse Transcriptase Inhibitor.

MK-8507 is an investigational HIV-1 nonnucleoside reverse transcriptase inhibitor being developed for the treatment of HIV-1 infection. MK-8507 contains 2 trifluoromethyl groups that may result in fluoride release through metabolism, but the extent of MK-8507-related fluoride release in humans has yet to be determined. This double-blind, placebo-controlled, 2-period, parallel-group, multiple-dose trial in healthy participants without HIV-1 who were administered a fluoride-restricted diet and once-weekly doses of MK-8507 aimed to estimate the relationship between MK-8507 dose and fluoride exposure. A total of 15 adult male and 3 adult female (of non-childbearing potential) participants were randomized to receive MK-8507 200 mg (n = 6), MK-8507 800 mg (n = 6), or placebo (n = 6). Change from baseline in mean daily fluoride excretion averaged over 7 days following the administration of MK-8507 200 mg resulted in a net mean increase of 19.8 µmol (90% confidence interval, 12.2-27.4) relative to placebo and did not exceed 57 µmol, a threshold related to the mean difference between the daily reference dose set by the US Environmental Protection Agency and the average dietary fluoride intake in the United States. However, daily urinary fluoride excretion exceeded the threshold following administration of 800 mg MK-8507 (75.1 µmol [90% confidence interval, 67.5-82.7]). Assuming a linear relationship between MK-8507 dose and estimated mean daily fluoride released at steady-state, data interpolation suggests that the US Environmental Protection Agency reference dose for fluoride would not be exceeded in most patients when administering MK-8507 at doses currently under clinical investigation (≤400 mg once weekly).

Effects of Bedtime Dosing With Suvorexant and Zolpidem on Balance and Psychomotor Performance in Healthy Elderly Participants During the Night and in the Morning.

PURPOSE/BACKGROUND: This study was designed as an early assessment of the safety of the orexin receptor antagonist suvorexant, but also included exploratory assessments of balance and psychomotor performance that are the focus of this report. METHODS/PROCEDURES: This was a double-blind, randomized, 3-period, crossover, phase 1 study. Balance and psychomotor performance were evaluated during the night in 12 healthy elderly participants after bedtime administration of suvorexant 30 mg (a supratherapeutic dose), the GABAergic agonist zolpidem 5 mg (the recommended dose in the elderly), or placebo. Balance (body sway measured by platform stability) and psychomotor performance (measured by choice reaction time) were assessed predose and at 1.5, 4, and 8 hours postdose in each period. Memory (measured by word recall) was assessed predose and at 4 hours postdose. FINDINGS/RESULTS: At 1.5 hours after nighttime administration of each drug (the approximate time of their anticipated maximal plasma concentrations), both zolpidem and suvorexant increased body sway versus placebo, with a greater increase for zolpidem than suvorexant. Suvorexant increased choice reaction time compared with placebo or zolpidem at 1.5 hours. There were no treatment differences on body sway or choice reaction time at 4 or 8 hours, or on word recall at 4 hours. IMPLICATIONS/CONCLUSIONS: These exploratory data suggest that a 30-mg dose of suvorexant (supratherapeutic) and a 5-mg dose of zolpidem (recommended dose in the elderly) impaired balance at 1.5 hours in healthy elderly people, with potentially less impairment for suvorexant relative to zolpidem, but no treatment differences on body sway or psychomotor performance at 4 and 8 hours. Because of their exploratory nature, these findings and their clinical relevance, if any, require confirmation in a prospective study.

Golimumab induction and maintenance for moderate to severe ulcerative colitis: results from GO-COLITIS (Golimumab: a Phase 4, UK, open label, single arm study on its utilization and impact in ulcerative Colitis).

OBJECTIVE: GO-COLITIS aimed to measure the effectiveness of subcutaneous golimumab in tumour necrosis factor-α antagonist-naive patients with moderate to severe ulcerative colitis (UC) despite conventional treatment. DESIGN: GO-COLITIS was an open label, single arm, phase 4 study with a pragmatic design which reflected UK clinical practice. Adult patients were eligible if diagnosed with UC ≥3 months, partial Mayo score (PMS) 4-9. Patients received subcutaneous golimumab induction (200 mg initially and 100 mg at week 2) followed at week 6 by 50 mg or 100 mg (depending on weight) every 4 weeks until week 54 with a 12-week follow-up. Efficacy was measured by PMS at baseline, week 6, 30, 54 and 66. Health-related quality of life (HRQoL; Inflammatory Bowel Disease Questionnaire (IBDQ) and EuroQol Group 5 Dimensions Health Questionnaire (EQ-5D)) was assessed at baseline, week 6 and week 54. All safety adverse events (AEs) were recorded. RESULTS: 207 patients were enrolled and 205 received golimumab (full analysis set (FAS)205). At week 6, 68.8% (95% CI 62.0% to 75.1%) and 38.5% (95% CI 31.8% to 45.6%) of patients were in response and remission, respectively, using PMS. At the end of the induction phase, 140/141 patients in clinical response continued into the maintenance phase (Maintenance FAS). Sustained clinical response through week 54 was achieved in 51/205 (24.9%) of the FAS205 population and 51/140 (36.4%) of the Maintenance FAS population. Statistically significant improvements from baseline to week 6 were observed for the IBDQ total score and for each IBDQ domain score (bowel symptoms, emotional function, systemic symptoms and social function), as well as the EQ-5D index score and associated visual analogue scale score (p<0.0001). Improvement of HRQoL was sustained through week 54. Serious AEs leading to treatment discontinuation occurred in 8.8% of patients. CONCLUSION: In this study measuring patient-reported outcomes in patients with moderate to severe UC, golimumab induced and maintained response as measured by PMS and significantly improved quality of life measures. TRIAL REGISTRATION NUMBER: NCT02092285; 2013-004583-56.