Comprehensive Nonclinical Safety Assessment of Nirmatrelvir Supporting Timely Development of the SARS-COV-2 Antiviral Therapeutic, Paxlovid™

Abstract

COVID-19 is a potentially fatal infection caused by the SARS-CoV-2 virus. The SARS-CoV-2 3CL protease (Mpro) is a viral enzyme essential for replication and is the target for nirmatrelvir. Paxlovid (nirmatrelvir co-administered with the pharmacokinetic enhancer ritonavir) showed efficacy in COVID-19 patients at high risk of progressing to hospitalization and/or death. Nonclinical safety studies with nirmatrelvir are essential in informing benefit-risk of Paxlovid and were conducted to support clinical development. In vivo safety pharmacology assessments included a nervous system/pulmonary study in rats and a cardiovascular study in telemetered monkeys. Potential toxicities were assessed in repeat dose studies of up to 1 month in rats and monkeys. Nirmatrelvir administration (1,000 mg/kg, p.o.) to male rats produced transient increases in locomotor activity and respiratory rate but did not affect behavioral endpoints in the functional observational battery. Cardiovascular effects in monkeys were limited to transient increases in blood pressure and decreases in heart rate, observed only at the highest dose tested (75 mg/kg per dose b.i.d; p.o.). Nirmatrelvir did not prolong QTc-interval or induce arrhythmias. There were no adverse findings in repeat dose toxicity studies up to 1 month in rats (up to 1,000 mg/kg daily, p.o.) or monkeys (up to 600 mg/kg daily, p.o.). Nonadverse, reversible clinical pathology findings without clinical or microscopic correlates included prolonged coagulation times at ≥60 mg/kg in rats and increases in transaminases at 600 mg/kg in monkeys. The safety pharmacology and nonclinical toxicity profiles of nirmatrelvir support clinical development and use of Paxlovid for treatment of COVID-19.

Paxlovid (Nirmatrelvir/Ritonavir): A new approach to Covid-19 therapy?

“…In monkeys, the max dose of nirmatrelvir caused the blood pressure to transiently elevate, the pulse rate to drop, and the transaminase levels to increase, but there were no arrhythmic changes. Taken together, they concluded that nirmatrelvir seems reasonably safe for use in human cases [68] .…”

“…Sathish et al used rats and monkeys to evaluate the safety profile of nirmatrelvir [68] . The duration of oral nirmatrelvir administration was one month for both species, and the max dose was 1000 mg/kg.day for rats and 600 mg/kg.day for the monkeys.…”

Developmental safety of nirmatrelvir in zebrafish (Danio rerio) embryos

“…Pharmacological safety assessments of nirmatrelvir have failed to reveal evidence of adverse effects on nervous, cardiovascular or pulmonary systems after up to 1 month of repeated doses using non pregnant animal models (rats and monkeys), then demonstrating a good safety profile out of pregnancy (Sathish et al, 2022).…”

How to use COVID-19 antiviral drugs in patients with chronic kidney disease

“…No direct nephrotoxicity has been reported against nirmatrelvir. Preclinical studies suggest that nirmatrelvir is safe up to 1000 mg/kg per day which is 8 times more than the dose recommended for humans ( Sathish et al, 2022 ).…”