Favipiravir pharmacokinetics in immunocompromised infants and children with chronic RNA viral infections
I. Cheng [1,2], C. Solas [3] , E. Howley [2], O. Mcgarrity [2], K. Rajani [2], J. Breuer [2], J. Standing [2], A. Kreins[1,2].
[1] UCL Great Ormond Street Institute of Child Health [2] Great Ormond Street Hospital [3] Aix-Marseille Univ, APHM, Unité des Virus Émergents (UVE, IRD 190, INSERM 1207)
Introduction
Favipiravir is a broad-spectrum antiviral licensed to treat influenza in adults and is currently not licensed in children [1,2]. It is a purine analog prodrug converted by intracellular enzymes aldehyde oxidase (AO) into its active form [3]. The incorporation of this active metabolite prevents the further extension of the viral RNA strands, thereby halting viral replication [2]. Favipiravir is reported to have a complex, nonlinear, time-, dose- and weight-dependent pharmacokinetics in adults [4]. There are limited studies investigating the pharmacokinetic properties in children. Since the activity of AO reaches adult capacity in the first year of life and is known to have large inter-individual differences, the study of pharmacokinetics in children is of great interest. We have used favipiravir, in combination with other antivirals, in severely immunocompromised children with life-threatening RNA virus infections which currently has no licensed antiviral treatment for. As an unlicensed indication, favipiravir pharmacokinetics were routinely monitored at our institution.
Objective
To describe the pharmacokinetic properties of favipiravir in infants and young children using population pharmacokinetics.
Method
All patients receiving favipiravir and had therapeutic drug levels taken between January 2020 to December 2021 were included in this study. Blood samples were collected in 1mL EDTA. Quantification of favipiravir in plasma was performed by a sensitive and selective ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) method (UPLC-TQD, Waters, USA) with a lower limit of quantification of 0.5 μg/mL. Parameter estimation using the first-order conditional estimation method with interaction (‘FOCEI’) was undertaken using nlmixr2 (v2.0.71) hosted in R. Assessment of model simulation properties (visual predictive check) were undertaken using Rxode (v2.0.7). One- and two-compartment structural models were compared and the influence of weight and length of treatment on estimated parameters were evaluated. As it is a retrospective study using anonymised data, the ethics committee has confirmed that ethics approval and parent and patient consent can be exempted (17/LO/0008).
Result
10 patients (mean age = 4 years (0.8-16 years)) were analysed retrospectively (97 samples). The median weight is 15.4kg (7.88 to 38.9 kg) and the duration of treatment since first start of therapy was between 4 to 127 days. All patients received favipiravir 600mg or 1200mg per day in two- to three-divided doses and had at least one plasma level 45 minutes (peak), 3 hours, and 8 hours (trough) post-dose. A one-compartment model with allometric scaling using a fixed exponent of 0.75 on clearance terms and linear scaling on volume terms best describes the data. The elimination clearance= 3.79 L/h/70kg, volume of distribution=43.51 L/70kg and estimated half-life = 7.43 hours.
Conclusions
We have explored the favipiravir pharmacokinetic parameters in infants and young children. We observe similar predicted pharmacokinetic parameters in children compared to those reported in adults. Weight significantly improves the model fit as a covariate. The introduction of the length of treatment did not improve the model, suggesting the clearance will reach an equilibrium after chronic use. Dosing simulations demonstrated that the current regime will not yield the effective plasma concentrations required to achieve viral clearance or viral load reduction for RSV or norovirus, indicating higher doses and/or combinations with other antivirals are required. This result was used to inform local dosing guideline.
References:
[1] Japan: Toyama Chemical Co Ltd Tokyo. Avigan (favipiravir) [prescribing information], 2019
[2] Yousuke Furuta, Takashi Komeno, and Takaaki Nakamura. Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proceedings of the Japan Academy. Series B, Physical and Biological Sciences, 93(7):449–463, 2017
[3] Leen Delang, Rana Abdelnabi, and Johan Neyts. Favipiravir as a potential countermeasure against neglected and emerging RNA viruses. 153:85–94, 2018
[4] Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau and Ministry of Health, Labour and Welfare. Report on the Deliberation Results, 2014