Population pharmacokinetic analysis of peficitinib in patients with rheumatoid arthritis

Abstract

Aims: To analyse the population pharmacokinetics (PK) of peficitinib in patients with rheumatoid arthritis (RA) and assess the potential PK covariates to identify the requirement for dose adjustment in RA patients.

Methods: The analysis incorporated 2464 observations from 98 healthy volunteers and 4919 observations from 989 RA patients. A population PK model for peficitinib in RA patients was constructed by a nonlinear mixed effect model using NONMEM with prior information from a healthy volunteer model.

Results: A 2-compartment model with sequential zero- and first-order absorption and lag time was constructed for RA patients. Covariate exploration in the RA patient model revealed that estimated glomerular filtration rate (eGFR) and lymphocyte count had a significant effect on apparent total systemic clearance (CL), which was 91.7 L/h (2.3% relative standard error). Compared with the mean population CL, the model predicted mean changes in CL of 12.3 and -10.7% in patients with observed minimum and maximum lymphocyte count of 500 and 4600 10⁶ /L, respectively, and mean changes in CL of -17.8 and 16.7% in patients with minimum and maximum eGFR of 36.4 and 188 mL/min/1.73m² , respectively. The simulated population mean area under plasma concentration-time curve for 24 hours after dosing showed a 1.35-fold increase in patients with severe renal impairment (eGFR 22.5 mL/min/1.73m² ) compared with patients with reference eGFR (91.5 mL/min/1.73m² ).

Conclusion: The population PK model identified eGFR and lymphocyte count as covariates for CL. The magnitude of changes was not considered clinically relevant, indicating no requirement for dose adjustment.

Trial registration: ClinicalTrials.gov NCT02586194 NCT02603497 NCT02760342 NCT02531191 NCT02308163 NCT02305849 NCT01565655.

Keywords: pharmacokinetics; population analysis; rheumatoid arthritis.