Sarang Mishra (1), Katharina Rox (1,2)
(1) Department of Chemical Biology, Helmholtz Centre for Infection Research, Braunschweig, (2) German Centre for Infection Research (DZIF), partner site Hannover/Braunschweig, Braunschweig, Germany
Introduction: Although the end of COVID-19 pandemic has been declared, SARS-CoV-2 infection cases are still being reported worldwide [1]. During the pandemic, drugs like remdesivir, Molnupiravir were repurposed at the same time a new drug combination Paxlovid® (Nirmatrelvir/Ritonavir) was approved. However, in case of populations taking CYP3A4-sensitive medication, Paxlovid® cannot be prescribed as the drug-drug-interaction potential is a contraindication. In particular for outpatients, an orally administered drug, like Molnupiravir is much more preferred. The pharmacokinetic (PK) parameters of Molnupiravir are not fully understood yet because of its prodrug nature and non-CYP metabolism. Unavailability of any clinical trials of Molnupiravir in pediatrics poses challenge to recommend potential effective doses for these subpopulations. Physiologically based pharmacokinetic (PBPK) modelling can be employed to predict an effective and safe dosage regimen in pediatrics while considering metabolism parameters and enzyme ontogeny [2]. This is also of particular relevance as it had emerged that Molnupiravir might exert cartilage and bone toxicity when exceeding certain concentrations.
Objectives: The aim of this study was to investigate effective dose levels of the Molnupiravir for pediatric subpopulations of Neonates (0-27 days), Infants (28 days-1 year), Early childhood (1-12 years) with the help of PBPK modelling. At the same time, we aimed to evaluate if concentrations used might result in concentrations conferring potential bone toxicity.
Methods: A whole-body PBPK model of Molnupiravir and its metabolite N-hydroxycytidine (NHC) was developed using PK-Sim® for human adult population with in-house generated esterase (CES1) based plasma and liver metabolism of Molnupiravir and NHC hepatic clearance, plasma protein binding data of parent and active metabolite. The clearance as well as information from different oral formulations (i.e. capsule) parameters were optimized by Monte-Carlo simulation. Finally, the model was verified using different stages of single and multiple doses in the same population [3]. The validated adult model was extrapolated to three pediatric subpopulations by integrating CES1 ontogeny [4] and PK-Sim® inbuilt scaling parameters. The pediatric models simulated doses up to 14 mg/kg BID to achieve T>EC50 and Cmax equivalent to clinically recommended adult dose of 800 mg BID for 5.5 days. In addition, safe levels of Molnupiravir, NHC were calculated for pediatric populations to estimate if concentrations were reached that might cause irreversible bone or cartilage toxicity. The maximal concentration for this safety window was based on data from a toxicity study in dogs by scaling to human equivalent dose [5,6].
Results: The whole body Molnupiravir-NHC PBPK model was developed for adults. All models for the adult single and multiple dose passed the acceptance criteria of observed data points falling under 95% confidence interval of predicted plasma concentration, and AUC and Cmax predicted to the observed ratio were also in the acceptable 2-fold error range (0.5 to 2). To estimate the dose level at which bone and cartilage toxicity would be observed, the doses and levels from the dog toxicity study were converted by calculation of the human equivalent dose, resulting in a dose of 27.8 mg/kg [6]. Therefore, models were developed for highest possible dose of 14 mg/kg BID for all three pediatric subpopulations. The T>EC50 at adult clinically recommended dose of 800 mg BID was 4.75 hours at EC50 value of 1.43 for delta variant [7]. While T>EC50 of the highest possible safe dose of 14 mg/kg for neonates, infants, early childhood pediatrics models generated T>EC50 between 2.5 and 3.75 hours. Likewise, Cmax values for 14 mg/kg pediatric subpopulations models were between 12.98 and 18.83 µM, while adult model Cmax was 11.73 µM. The Ctrough values for pediatric models were all below 0.010 µM in comparison to high values of 0.05 µM for adult model.
Conclusions: The Molnupiravir-NHC PBPK model was developed for the first time by integrating plasma and liver clearance data. The EC50 and PK parameters of developed pediatric models for different age ranges indicate that the highest possible and safe dose to avoid bone and cartilage toxicity was not able to achieve T>EC50 equivalent to adult dose. Future studies will investigate if the model might predict efficacy in treating infections when it is integrated into a PD model.
References:
[1] https://who.int/publications/m/item/covid-19-epidemiological-update-16-february-2024.
[2] Edginton, A.E.; et. al. CPT Pharmacometrics Syst Pharmacol. 2019 Nov; 8(11): 835–844.
[3] Boberg, M.; et. al. Drug Metab Dispos. 2017 Feb; 45(2): 216–223.
[4] Painter, W.P; et. al. Antimicrob Agents Chemother 65:10.1128/aac.02428-20.
[5] https://www.fda.gov/media/157300/download.
[6] Nair, A.; et. al. J Basic Clin Pharm. March 2016-May 2016; 7(2): 27–31.
[7] Chang, CH.; et. al. Commun Med 3, 150 (2023).
Reference: PAGE 32 (2024) Abstr 10953 [www.page-meeting.org/?abstract=10953]
Poster: Drug/Disease Modelling - Absorption & PBPK