Background
Favipiravir (FVP) is an anti-influenza agent but preclinical data support broad spectrum antiviral activity against RNA viruses including SARS-CoV-2 and haemorrhagic fevers. Pharmacokinetic (PK) data on the active form, favipiravir ribofuranosyl-5’-triphosphate (FRTP), are lacking in humans. We measured liquid plasma (LPL) FVP and intracellular FRTP measurements in PBMC and compared this with HemaSep filter cards that separate cells (HC) and plasma (HPL) upon contact.
Methods
AGILE CST-6 (NCT04746183) is a phase Ib dose escalation study to evaluate intravenous FVP for treatment of COVID-19. Patients (n=6/cohort) with SARS-CoV-2 were randomised 2:1 to receive FVP (600 mg, 1200mg, 1800mg, 2400 mg BD) or standard of care. LPL and HemaSep were collected on Day (d) 1, 3 and 5 over 0-12 hours post-completion of infusion and PBMC at 6-12 hours. FVP was quantified in LPL and HPL, and FRTP from HC and PBMC using validated LC-MS/MS methods. FRTP concentrations were expressed as pmol/sample (12mm punch, HC) and pmol/106 cells (PBMC). PK parameters were calculated using WinNonlin.
Results
16 patients [7 female at birth; median (range) age, weight: 77 years (52-93), 79kg (52-125)] were enrolled. Analysis included 153 HemaSep|38 PBMC, of which 47 (31%)|25 (66%) had quantifiable FRTP. In PBMC, there was high interindividual variability and limited evidence for accumulation of FRTP from d1-d5, confounded by sampling issues (26% haemolysed). PBMC FRTP ranged from 20.8-141.4 pmol/106 cells. In HC, all d1 samples were <LLQ and FRTP accumulation was observed from d3-d5 [C6-12 GMR (95% CI) 1.71(1.07,2.74)]. FRTP exposures were dose linear (r2= 0.83). Median FRTP AUClast on d3 were 74.6|209.7|228.1|618.9 h*pmol/sample for 600|1200|1800|2400mg, respectively. FRTP d3 exposures were correlated with both LPL (r2= 0.816,p<0.005) and DP (r2=0.750,p=0.001). The ratio of peak-to-trough (P:T) FVP concentrations in HPL on d3 was 1.0-5.1 while for FRTP HC the ratio was 1.0-2.2.
Conclusions
This is the first report of FRTP PK in humans. Formation of FRTP increased with escalating doses but appeared to saturate at doses beyond 1800 mg. P:T ratios support an extended intracellular half-life of FRTP compared to the parent form, in line with prior in vitro studies. Correlation between plasma FVP and FRTP was better using HC compared to PBMC indicating that dried filter spots may be more robust than PBMC for the purpose of intracellular FRTP quantitation and offer a pragmatic alternative to venepuncture in field settings.