Decoding safety, tolerability, and pharmacokinetics of Molnupiravir

This is a first-in-human, phase 1, randomized, double-blind,placebo-controlled study to determine the safety, tolerability, and pharmacokinetics of single and multiple ascending oral doses of molnupiravir in healthy subjects.

Study Design

• Inclusion criteria and Randomization: Healthy subjects, of any ethnic origin, race, or sex, aged between 18 and 60 years, with BMI between 18 and 30 kg/m². Eligible subjects were randomized in a 3:1 ratio to either molnupiravir or placebo in single- and multiple-ascending-dose. Each dose escalation cohort comprised 8 subjects, of whom 6 were administered molnupiravir and 2 were administered a placebo.
• Dosing Regimen: Single oral doses of 50 to 1,600mg molnupiravir or placebo were administered in single-ascending-dose part and BID doses of between 50 and 800mg molnupiravir or placebo were administered for 5 days with a final dose on the morning of day 6 in the multiple-ascending dose.
• Endpoints: Primary objectives (i) to determine the safety and tolerability of single and multiple ascending doses of molnupiravir,(ii) to assess the effect of food on the pharmacokinetics of molnupiravir and EIDD-1931 following a single dose. Secondary objective: to define the pharmacokinetics of molnupiravir and EIDD-1931 in plasma and urine following single and multiple doses in healthy subjects.
• Criteria for evaluation: Following single doses, plasma and urine samples for pharmacokinetic analysis were collected up to 72 and 48 h postdose, respectively. Following multiple doses, plasma and urine samples were collected up to 12 h after first dose and up to 192 and 72 h postdose, respectively, after the final dose.

Results:

Subjects were aged between 19 and 60 years, with a mean BMI between 24.4 and 25.4 kg/m². The majority of the subjects were male Caucasians.

Tolerability

Single ascending doses: A greater proportion of subjects reporting adverse events (AE) following administration of placebo vs Molnupiravir (43.8% vs 35.4%). The most frequently reported AE was a headache - 18.8% in placebo vs 12.5% in molnupiravir.

Multiple ascending doses: A greater proportion of subjects reporting AE following administration of placebo vs Molnupiravir (50% vs 43.9%). The most frequently reported AE was diarrhea, which was similar in both groups (7.1%). One subject discontinued study drug administration on day 4 because of rash.

Food effect evaluation: Three subjects in the food effect evaluation each reported 1 AE, all of which were mild (grade 1) in severity.

Safety

No clinically significant findings or dose-related trends in the clinical laboratory, vital signs, hematological parameters, and electrocardiogram data are seen in this study.

Pharmacokinetics

EIDD-1931appeared rapidly in plasma, with a median time of maximum observed concentration of 1.00 to 1.75 h, and declined with a geometric half-life of approximately 1 h, with a slower elimination phase apparent following multiple doses or higher single doses(7.1 h at the highest dose tested).

Mean maximum observed concentration (Cmax) and area under the plasma concentration versus time curve (AUC) increased in a dose-proportional manner, and there was no accumulation following multiple doses.

When administered in a fed state, there was a decrease in the rate of absorption, but no decrease in overall exposure.

Molnupiravir has demonstrated good tolerability with no serious adverse effects and dose-proportional pharmacokinetics the following administration to healthy volunteers at clinically relevant doses.

                                                                                                Take away
• Molnupiravir is well absorbed after oral administration and minimally affected by food intake.
• Plasma exposure to EIDD-1931 is essentially dose proportional across the range of doses tested and these plasma exposures may be adequate to provide prophylactic and therapeutic benefit in the treatment of these respiratory infections.
• No accumulation was observed in the multiple-ascending dose part of this study
• Very little molnupiravir or EIDD-1931 was detected in urine
• Molnupiravir was well tolerated, and no subjects experienced serious adverse events

Reference:

Painter WP, Holman W, Bush JA, Almazedi F, Malik H, Eraut NCJE, Morin MJ, Szewczyk LJ, Painter GR. Human Safety, Tolerability, and Pharmacokinetics of Molnupiravir, a Novel Broad-Spectrum Oral Antiviral Agent with Activity Against SARS-CoV-2. Antimicrob Agents Chemother. 2021 Mar 1;65(5):e02428-20.