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A Single and Multiple Dose Clinical Study to Evaluate the Safety, Tolerability and Pharmacokinetics of MK-4482 in Healthy Japanese Adult Participants(COVID-19)

Single and Multiple Dose Study of MK-4482 in Healthy Japanese Adults

65

Healthy Japanese male participants, aged between 20 and 60 years (inclusive) and body mass index (BMI) between>= 18.5 and =< 24.9 kg/m2 at screening.

The trial consisted of 2 parts (Part 1: single oral dose administration of MK-4482 final market image capsules or placebo under fasted and fed states [high-fat meal]; Part 2: multiple oral dose administration of MK-4482 final market image capsules or placebo). In Part 1, participants were randomized to one of 3 Panels (A, B, and C) and received a single oral dose of MK-4482 200 mg, 400 mg or 800 mg (N=6 per panel), respectively, or placebo (N=2 per panel) in a blinded fashion in the fasted state in Period 1. In Period 2, Panel A participants received a single oral dose of MK-4482 1600 mg (N=6) or placebo (N=2) and Panel C participants received a single oral dose of MK-4482 800 mg (N=6) or placebo (N=2) following consumption of high-fat breakfast. In Part 2, participants were randomized to Panels E and F and received multiple oral doses of 400- or 800-mg MK-4482 (N=15 per panel), respectively, or placebo (N=5 per panel) every 12 hours for 5.5 days (total of 11 doses per participant) in a blinded fashion. The first and last dose of study interventions (on Day 1 am and Day 6 am, respectively) were administered in the fasted condition. In both Part 1 and Part 2, plasma and peripheral blood mononuclear cells (PBMC) samples were collected for assessment of N-hydroxycytidine (NHC) and N-hydroxycytidine triphosphate (NHC-TP), respectively. Participants in both of Part 1 and Part 2 were followed for safety throughout the study, until approximately 14 days following administration of the last dose of study intervention. In addition, the participants were verbally contacted to confirm contraceptive requirements 90 days (within + 1 week) after the last study intervention.

-Single doses of MK-4482 up to 1600 mg and multiple doses of MK-4482 400 mg and 800 mg Q12H for 5.5 days were generally well tolerated in healthy Japanese male adult participants. -In Part 1 (single dose), 2 participants out of 25 (8.0%) reported 3 AEs. In Part 2 (multiple dose), 13 participants out of 40 (32.5%) reported 15 AEs. There were no serious adverse events (SAEs) or events of clinical interest (ECIs). -Drug-related AEs were reported for 1 and 5 participants who received MK-4482 in Part 1 and Part 2, respectively. Of these, toxic skin eruption was the most frequently reported (3 participants in the MK-4482 800 mg group in Part 2). There were no drug-related AEs in both of the placebo groups in Part 1 and Part 2. -All the AEs were mild in intensity except 2 events: 1 moderate dermatitis reported in 1 participant who received a single dose of MK-4482 200 mg in Period 1 of Part 1, and 1 moderate toxic skin eruption reported in 1 participant who received multiple doses of MK-4482 800 mg Q12H for 5 days in Part 2. The participant who reported moderate dermatitis also received a single dose of MK-4482 1600 mg in Period 2 of Part 1 without recurrence of dermatitis. -In Part 1, the reported AEs in the MK-4482 group were dermatitis, increased lipase and increased amylase (1 participant each). There were no AEs in the placebo group. In Part 2, the most frequently reported AE (>=3 participants) in the total MK-4482 group was toxic skin eruption (3 participants). In the placebo group in Part 2, only decreased haemoglobin (1 participant) was reported. -There was 1 AE (moderate toxic skin eruption) resulting in discontinuation of study intervention in Panel F (multiple doses of MK-4482 800 mg Q12H for 5.5 days). The toxic skin eruption occurred on Day 4 pm before dosing of study intervention and resolved on Day 14 following treatment with betamethasone butyrate propionate and fexofenadine hydrochloride. The participant received 10 doses of MK-4482 800 mg and discontinued study intervention after the Day 5 pm dosing. -No clinically meaningful trends were observed for changes in clinical laboratory values, vital signs, or 12-lead ECGs as a function of dose or treatment.

Safety See "Adverse Events" Section. Pharmacokinetics Part 1 Following single oral dose administration of MK-4482 final market image capsules in the fasted state to healthy Japanese male participants, NHC appeared rapidly in plasma and reached Cmax with a median Tmax between 1.00 and 2.00 hours. AUC0-inf and Cmax of plasma NHC increased approximately in a dose proportional manner across the dose levels of 200 to 1600 mg. Part 2 Following multiple oral dose administration of MK-4482 every 12 hours for 5.5 days, the GM apparent terminal t1/2 of plasma NHC was 11.5 hours and 10.2 hours after the last dose of 400 mg and 800 mg, respectively. No meaningful accumulation of NHC was observed following multiple oral dose administration of MK-4482 every 12 hours for 5.5 days, indicating that the terminal phase does not contribute meaningfully to accumulation after multiple dose administration.

Safety -Single doses of MK-4482 up to 1600 mg, and Multiple doses of MK-4482 400 mg and 800 mg Q12H for 5.5 days were generally well tolerated in healthy Japanese male adult participants. Pharmacokinetics -NHC appeared rapidly in plasma following MK-4482 administration, with median Tmax between 1.00 and 2.00 hours. -AUC0-inf and Cmax of plasma NHC increased approximately in a dose proportional manner following single doses. -No meaningful accumulation of NHC was observed following multiple doses.

Yes

http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

https://jrct.mhlw.go.jp/latest-detail/jRCT2031210010

Tanaka Yoshiyuki

MSD K.K.

KITANOMARU SQUARE,1-13-12,Kudan-kita,Chiyoda-ku,Tokyo 102-8667,Japan

msdjrct@msd.com

inquiry mailbox MSDJRCT

MSD K.K.

KITANOMARU SQUARE,1-13-12,Kudan-kita,Chiyoda-ku,Tokyo 102-8667,Japan

+81-3-6272-1957

msdjrct@msd.com

Complete

April. 09, 2021

Interventional

randomized controlled trial

double blind

placebo control

single assignment

other

Healthy Japanese male between the ages of 20 and 60 years with BMI of 18.5 to 24.9 kg/m2

Has a history of clinically significant abnormalities or diseases.

Male

Coronavirus disease caused by severe acute respiratory syndrome coronavirus 2

- Drug: MK-4482 (molnupiravir)
MK-4482 100-1600 mg administered orally in capsule form once or twice daily (every 12 hours for 5.5 days, 11 doses in total)
- Drug: Placebo
Placebo matching MK-4482 administered orally in capsule form once or twice daily (every 12 hours for 5.5 days, 11 doses in total)

1. Adverse events, vital signs, laboratory safety tests, 12-lead electrocardiograms, physical examinations following a single or multiple oral doses of MK-4482
2. Cmax, Tmax, t1/2, AUC0-12, AUC0-last and AUC0-inf of N-hydroxycytidine in plasma following a single oral dose of MK-4482
3. Ctrough, Cmax, Tmax, t1/2, AUC0-tau, accumulation ratio for Cmax and AUC0-tau of N-hydroxycytidine following multiple oral doses of MK-4482

1. AUC0-inf and Cmax of N-hydroxycytidine in plasma following a single oral dose of MK-4482 with food
2. Cmax, Tmax, t1/2, AUC0-12, AUC0-last and AUC0-inf of N-hydroxycytidine triphosphate in peripheral blood mononuclear cells following a single oral dose of MK-4482
3. Ctrough, Cmax, Tmax, t1/2, AUC0-tau, accumulation ratio for Cmax and AUC0-tau of N-hydroxycytidine triphosphate in peripheral blood mononuclear cells following multiple oral doses of MK-4482

+81-42-625-5216

April. 07, 2021

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