Decoding safety, tolerability, and pharmacokinetics of Molnupiravir

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.