Population Pharmacokinetics of Abrocitinib in Healthy Individuals and Patients with Psoriasis or Atopic Dermatitis

Abstract

Background and objective: Abrocitinib is a Janus kinase 1 inhibitor in development for the treatment of atopic dermatitis (AD). This work characterized orally administered abrocitinib population pharmacokinetics in healthy individuals, patients with psoriasis, and patients with AD and the effects of covariates on abrocitinib exposure.

Methods: Abrocitinib concentration measurements (n = 6206) from 995 individuals from 11 clinical trials (seven phase I, two phase II, and two phase III) were analyzed, and a non-linear mixed-effects model was developed. Simulations of abrocitinib dose proportionality and steady-state accumulation of maximal plasma drug concentration (Cmax) and area under the curve (AUC) were conducted using the final model.

Results: A two-compartment model with parallel zero- and first-order absorption, time-dependent bioavailability, and time- and dose-dependent clearance best described abrocitinib pharmacokinetics. Abrocitinib coadministration with rifampin resulted in lower exposure, whereas Asian/other race coadministration with fluconazole and fluvoxamine, inflammatory skin conditions (psoriasis/AD), and hepatic impairment resulted in higher exposure. After differences in body weight are accounted for, Asian participants demonstrated a 1.43- and 1.48-fold increase in Cmax and AUC, respectively. The overall distribution of exposures (Cmax and AUC) was similar in adolescents and adults after accounting for differences in total body weight.

Conclusions: A population pharmacokinetics model was developed for abrocitinib that can be used to predict abrocitinib steady-state exposure in the presence of drug-drug interaction effects or intrinsic patient factors. Key covariates in the study population accounting for variability in abrocitinib exposures are Asian race and adolescent age, although these factors are not clinically meaningful.

Clinical trial numbers: NCT01835197, NCT02163161, NCT02201524, NCT02780167, NCT03349060, NCT03575871, NCT03634345, NCT03637790, NCT03626415, NCT03386279, NCT03937258.

Conflict of interest statement

Jessica Wojciechowski, Bimal K. Malhotra, Xiaoxing Wang, Luke Fostvedt, Hernan Valdez, and Timothy Nicholas are employees and shareholders of Pfizer Inc.

© 2022. The Author(s).

Figures

Fig. 1

Schematic representation of the final abrocitinib population pharmacokinetic model. AK1 and FK1 are the amount and fraction of the total dose absorbed by first-order processes, respectively. F1 and F2 are the fractions of the total bioavailable (Fi) dose that enters the depot/absorption compartment (for first-order absorption, F1) and the central compartment (for zero-order absorption, F2), respectively. The rate of absorption is dictated by the first-order rate constant (ka) and the zero-order absorption process is dictated by the zero-order absorption rate (k0). Absorption delays, ALAG1 for first-order absorption lag and ALAG2 for zero-order absorption lag, assume the zero-order process starts at the same time as the first-order process (i.e., where ALAG1 = ALAG2 and the processes occur in parallel) or after the first-order process has commenced (i.e., where ALAG2 = ALAG1 + ALAG2 and the processes occur sequentially). For a two-compartment model, CL is clearance from the central compartment (L/h), Vc is the volume of central compartment (L), Q is the inter-compartmental clearance (L/h), and Vp is the volume of peripheral compartment (L). Fabs fraction absorbed

Fig. 2

Prediction-corrected visual predictive check. The prediction-corrected observed data against time after dose (a) and time after first dose (c) are represented by blue circles and dashed black lines (median, 5th and 95th percentiles). The prediction-corrected simulated abrocitinib concentration (200 mg) based on the index population (n = 1000 simulations) are represented by the red lines and red shaded ribbons (median and 95% prediction interval of the median, respectively) and the blue lines and blue shaded ribbons (median and 95% prediction intervals of the 5th and 95th percentiles, respectively). The black dashed lines represent the proportion of observed BLQ concentrations over time after dose (b) and time after first dose (d), and the green solid line and green shaded ribbons are the median and 90% prediction intervals, respectively, of simulated BLQ concentrations (n = 1000) based on the index population. Yellow indicators in the x-axis represent the time bins for summarizing the data. BLQ below limit of quantification

Fig. 3

Ratios of steady-state Cmax (a) and 24-h AUC (b) after abrocitinib 200 mg QD for given covariates. For each covariate scenario on the left y-axis, concentration-time profiles for 1000 trials of 30 randomly assigned participants administered 200 mg QD were simulated using the full model and summarized by Cmax (a) or 24-h AUC (b) at steady state. The geometric mean ratio of Cmax or 24-h AUC compared with the reference scenario (healthy, White, adult males, 70 kg, fasted status, phase III tablet) was calculated for each trial. The gray-colored density distributions represent the geometric mean ratios across all trials; red numbers are the proportion of trials with ratios of < 0.8 (left) or > 1.25 (right). Black numbers on the right y-axis are the median (5th and 95th percentiles) of ratios for the covariate scenario. The blue shaded region is the range of geometric mean ratios from 0.8 to 1.25, and the black vertical dashed line is a geometric mean ratio of 1. Reference low and high body weights are the 5th and 95th percentiles of the analysis population. AUC area under the plasma concentration-time curve, Cmax maximal concentration, DDI drug–drug interaction, QD once daily

Fig. 4

Evaluation of race on abrocitinib 200 mg QD steady-state Cmax (a) and 24-h AUC (b) for all individuals. Red circles represent the distribution of 200 mg once-daily steady-state Cmax (a) and AUC (b) based on the EBE for all participants in the analysis population (irrespective of what dose they received), and blue box and whisker plots depict newly simulated participants (n = 200) based on the final population PK model. The model provides an appropriate depiction of the observed differences between the race categories. AUC area under the plasma concentration-time curve, Cmax maximal concentration, EBE empirical Bayes estimates, PK pharmacokinetics, QD once daily

Fig. 5

Weight-based simulations on abrocitinib 200 mg QD steady-state Cmax (a) and 24-h AUC (b) in adolescents. Red circles represent the EBE of steady-state Cmax (a) and AUC (b) for participants from the two phase III studies who received abrocitinib 200 mg, and blue box and whisker plots depict new simulated populations (n = 200) based on the final population PK model, with representative weights observed in the two phase III studies (adolescent and adult categories), test weights (25, 30, 35, or 40 kg), or reference weight (70 kg). AUC area under the plasma concentration-time curve, Cmax maximal concentration, EBE empirical Bayes estimates, PK pharmacokinetics, QD once daily