# Physiologically Based Pharmacokinetic Simulation of Tofacitinib in Humans Using Extrapolation from Single-Species Renal Failure Model

## TL;DR

This study shows that PBPK simulations can accurately predict tofacitinib levels in patients with kidney failure, helping to adjust dosing for better treatment.

## Contribution

The study demonstrates the effectiveness of single-species PBPK extrapolation for predicting tofacitinib pharmacokinetics in renal failure patients.

## Key findings

- PBPK simulations matched observed plasma concentration profiles and pharmacokinetic parameters for tofacitinib in renal failure patients.
- Simulated to observed ratios for tofacitinib were within a 0.5–2.0-fold error range.
- PBPK simulations outperformed Dedrick plot analysis due to incorporating more comprehensive data.

## Abstract

Background/Objectives: Tofacitinib is a Janus kinase 1 and 3 inhibitor that was developed to treat rheumatoid arthritis. Accordingly, this study aimed to predict plasma tofacitinib concentrations and pharmacokinetic parameters in patients with renal failure through physiologically based pharmacokinetic (PBPK) simulations. Methods: PK-Sim and Simcyp simulators were used, as well as conventional Dedrick plot analysis, employing a single animal extrapolation method. The predictions were compared with previously published data. Results: PBPK simulations of tofacitinib in patients with renal failure closely matched the observed plasma concentration profiles and pharmacokinetic results, including the area under the plasma concentration–time curve (AUC), maximum plasma concentration (Cmax), and time to reach Cmax (Tmax). The ratios of the simulated to observed plasma concentrations and pharmacokinetic parameters for tofacitinib were within a 0.5–2.0-fold error range. Although the results from the Dedrick plot were reasonably good, they were less accurate than those of the PBPK simulations. This was because the Dedrick plot relied solely on preclinical plasma concentration data without incorporating drug physicochemical properties, in vitro data, or physiological and pathophysiological variables. Conclusions: The findings suggest that PBPK simulations using single-species extrapolation effectively provide preliminary estimates of plasma tofacitinib concentration profiles and pharmacokinetic parameters in humans under specific conditions, including renal failure. Furthermore, the results provide a foundation for adjusting tofacitinib dosage and dosing schedules to maintain effective plasma concentrations by considering the pathophysiological characteristics of patients according to their specific diseases.