By Raman Sharma
PAXLOVID (nirmatrelvir[PF-07321332]/ritonavir – 300/100 mg) is the first oral SARS-CoV-2 main protease inhibitor to receive emergency use authorization (EUA) for the treatment of COVID-19. Because of the pressing need for new drugs to address the COVID pandemic, novel methods had to be employed to hasten the development of PAXLOVID. For any new medicine, an overall understanding of the disposition of the active compound in humans is a requirement for regulatory registration. Historically, a human absorption, distribution, metabolism and excretion (hADME) study has been used to establish the disposition of a compound. These studies are typically performed via the administration of a radiolabeled analog of the parent compound followed by the collection of plasma, urine and feces. A radiolabel is used because of the low background and universal analytical response. Radiolabeled compounds can often be costly and require long lead times. Following the administration of the radiolabeled compound; urine, feces and plasma samples are analyzed for total drug content by liquid scintillation counting (LSC) to determine mass balance. Subsequently, pooled samples of the three matrices are profiled for metabolites by liquid chromatography/mass spectrometry (LC/MS). In conjunction with the LC/MS analysis fractions are collected and analyzed by LSC to create a radiochromatogram.
Because of the long lead time for the synthesis of [14C]nirmatrelvir a conventional hADME study was not an option. Hence, for the hADME, alternative analytical detection methods were evaluated. Because 19F qNMR has a universal response independent of chemotype and because nirmatrelvir contains a trifluoroacetamide, 19F qNMR was used as a detection technique for the hADME study. Using 19F qNMR we were able to evaluate the disposition of nirmatrelvir within a first-in-human study following the administration of a single dose of nirmatrelvir. Mass balance was reached with approximately 84.9 ± 8.9% of the dose recovered (urine 47.0% and feces 33.9%). Nirmatrelvir was the only drug-related compound observed in plasma. These data were accepted by the FDA for the EUA of PAXLOVID. To the best of our knowledge, this is the first time a regulatory agency accepted the use of 19F-qNMR data in lieu of a radiolabeled study for hADME characterization. Notably, because of the 19F qNMR approach, the hADME data was delivered much sooner to regulatory agencies and facilitated a rapid approval of a critical medicine that is helping address the worldwide COVID pandemic.