Population pharmacokinetic analysis of peficitinib in patients with rheumatoid arthritis

Abstract

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 10 6 /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/1.73m 2 , 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/1.73m 2) compared with patients with reference eGFR (91.5 mL/min/1.73m 2). 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. K E Y W O R D S population analysis, pharmacokinetics, rheumatoid arthritis * Affiliation at the time of analysis. This manuscript was a nonclinical modelling study, and there was no associated clinical responsibility for patients. As such, there is no Principal Investigator on this publication.

Exposure–response modeling of peficitinib efficacy in patients with rheumatoid arthritis

“…On the other hand, the mechanism behind the significant effect of baseline total bilirubin in the final ACR20 model was unknown, as it was not selected as a significant covariate in a previous population PK model of peficitinib. 17 The simulation results using our final ACR20 and DAS28-CRP models suggested no requirement for dose adjustment based on DAS28-CRP, concomitant MTX treatment, CRP, or total bilirubin at baseline. Caution should be used when applying these models to predict covariate effects in non-Asian patients, as the models were constructed using PK data from an Asian population.…”

“…Considering that the peficitinib package insert carries the precaution that the product should be used in patients who have previously been treated with at least one antirheumatic drug, including methotrexate, but apparently still have disease‐attributed symptoms, the concomitant use of MTX with peficitinib is feasible. On the other hand, the mechanism behind the significant effect of baseline total bilirubin in the final ACR20 model was unknown, as it was not selected as a significant covariate in a previous population PK model of peficitinib 17 . The simulation results using our final ACR20 and DAS28‐CRP models suggested no requirement for dose adjustment based on DAS28‐CRP, concomitant MTX treatment, CRP, or total bilirubin at baseline.…”

“…A population pharmacokinetic (PK) model for peficitinib in RA patients was previously constructed as a two‐compartment model with sequential zero‐ and first‐order absorption and lag time using NONMEM ® 17 . This model was utilized to obtain individual post hoc area under the plasma concentration–time curve for the 24‐hour period after dosing (AUC 24 h ) at steady state, based on the concentrations obtained in the above phase 2 and phase 3 studies, as an exposure parameter for this analysis.…”

“…A population pharmacokinetic (PK) model for peficitinib in RA patients was previously constructed as a two-compartment model with sequential zero-and first-order absorption and lag time using NONMEM ® . 17 This model was utilized to obtain individual post hoc What is already known about this subject?…”

Efficacy of peficitinib in two patients with rheumatoid arthritis on maintenance hemodialysis

“…These values were not significantly different from those observed in the patients with normal renal function 12 ) . However, although this drug has the lowest urinary excretion rate of all Janus kinase inhibitors, some reports have raised concerns regarding the increased AUC in patients with severely impaired renal function 11 , 13 ) . Unlike in patients with impaired renal function, there are no reports on the pharmacokinetics of peficitinib in patients on maintenance dialysis, and it is possible that the pharmacokinetics of peficitinib may not be similar to those in patients with impaired renal function.…”