Population pharmacokinetic-pharmacodynamic modelling of platelet time-courses following administration of abrocitinib

Abstract

Aims: Abrocitinib is a selective Janus kinase 1 inhibitor for the treatment of moderate-to-severe atopic dermatitis. Herein we describe the time-course of drug-induced platelet reduction following abrocitinib administration, identify covariates affecting platelet counts, and determine the probability of patients experiencing thrombocytopaenia while receiving abrocitinib.

Methods: This analysis included data from two Phase 2 and three Phase 3 studies in psoriasis and atopic dermatitis patient populations administered abrocitinib 10-400 mg QD orally for up to 12 weeks, with platelet counts determined up to week 16. A semi-mechanistic model was developed to assess the impact of baseline platelet counts (170, 220 and 270 × 1000/μL), age and race on the platelet nadir and week 12 counts with once-daily abrocitinib 200 mg or 100 mg.

Results: Decreases in platelet counts were transient with the nadir occurring on average 24 days (95% prediction interval, 23-24) after continuous administration of abrocitinib 200 mg QD. Following administration of once-daily abrocitinib 200 mg, the probabilities of thrombocytopaenia (<150 × 1000/μL) at the nadir were 8.6% and 95.5% for the typical patient with baseline platelet count of 270 × 1000/μL or 170 × 1000/μL, respectively. Adolescents had a lower probability of thrombocytopaenia compared with adults; platelet count distribution was similar in Asian and Western patients at the nadir and at week 12.

Conclusion: This analysis supports the safety of once-daily abrocitinib 200 mg and 100 mg dosing regimens, with low probability of thrombocytopaenia during treatment, except for higher risk of low-grade thrombocytopaenia that diminished after 4 weeks in patients with low baseline platelet counts.

Trial registration: ClinicalTrials.gov NCT03627767 NCT03575871 NCT03349060 NCT02780167 NCT02201524.

Keywords: dermatology; pharmacodynamics; pharmacokinetics; platelets.

Conflict of interest statement

All authors are employees and shareholders of Pfizer Inc.

© 2022 Pfizer Inc. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Figures

FIGURE 1

Visual predictive check stratified by treatment group. The observed data are represented by blue circles and the dashed black lines (median, 5th and 95th percentiles). Simulated platelet counts based on the analysis population (n = 1000 simulations) are represented by the red line and red shaded ribbon (median and 95% prediction intervals of the median, respectively), and the blue lines and blue shaded ribbons (median and 95% prediction intervals of the 5th and 95th percentiles, respectively). Yellow indicators in the x‐axis represent the time bins for summarizing the data (0, 7, 14, 28, 56 and 84 days). BID, twice daily; QD, once daily

FIGURE 2

Platelet time‐course for 1000 simulated typical individuals with baseline platelet counts 170, 200 or 270 × 1000/μL administered 100 mg (A) or 200 mg (B) for 12 weeks. Distribution of the nadir and platelet count at week 12 in typical individuals with baseline platelet counts 170, 200 or 270 × 1000/μL administered 100 mg (C) or 200 mg (D) for 12 weeks. Typical individual is White, 30‐year‐old male patient with atopic dermatitis weighing 70 kg. Horizontal lines (A, B) and vertical lines (C, D) represent thrombocytopaenia thresholds Grade 1 (<150 × 1000/μL; black dashed), Grade 2 (<75 × 1000/μL; black dotted) and Grade 3 (<50 × 1000/μL; red dotted), and platelet count of 100 × 1000/μL (red dashed). PI, prediction interval

FIGURE 3

Probability of thrombocytopaenia grades at the nadir and week 12 across different baseline platelet count scenarios administered abrocitinib 100 mg or 200 mg QD, once daily. Lines represent probabilities of developing thrombocytopaenia Grade 1 (75–150 × 1000/μL; blue), Grade 2 (50–75 × 1000/μL; red), Grade 3 (25–50 × 1000/μL; green) and Grade 4 (

FIGURE 4

Impact of missed consecutive doses on platelet time‐course for patients administered abrocitinib 200 mg. Black lines represent the population‐typical (White, 30‐year‐old male patient with atopic dermatitis weighing 70 kg) platelet 16‐week time‐course administered 200 mg QD for 12 weeks followed by 4‐week washout period. Each panel represents a scenario where seven consecutive doses are missed within a given week of the trial period. Blue shaded regions represent the time‐period where doses were not administered, and green shaded regions are the washout period for the trial. Red lines represent the scenario where no doses are missed. Times after the missed‐dosing period resume 200 mg QD dosing of abrocitinib

FIGURE 5

Evaluation of age on platelet nadir and week 12 platelet count in patients with atopic dermatitis administered abrocitinib 100 mg (A) or 200 mg (B). Red circles represent the distribution of the nadir or week 12 platelet count based on the empirical Bayes estimates for all atopic dermatitis patients in the analysis population randomized to 100 mg QD or 200 mg QD, and blue box‐and‐whisker plots depict newly simulated individuals (n = 200) based on the final population PK model. Horizontal lines represent Grade 1 (<150 × 1000/μL; black dashed) and Grade 2 (<75 × 1000/μL; black dotted) thrombocytopaenia thresholds, and platelet count of 100 × 1000/μL (red dashed). The model provides an appropriate depiction of the observed differences between the age categories

FIGURE 6

Evaluation of race on platelet nadir and week 12 platelet count in atopic dermatitis patients administered abrocitinib 100 mg (A) or 200 mg (B). Red circles represent the distribution of the nadir or week 12 platelet count based on the empirical Bayes estimates for all atopic dermatitis patients in the analysis population randomized to 100 mg QD or 200 mg QD, and blue box‐and‐whisker plots depict newly simulated individuals (n = 200) based on the final population PK model. Horizontal lines represent Grade 1 (<150 × 1000/μL; black dashed) and Grade 2 (<75 × 1000/μL; black dotted) thrombocytopaenia thresholds, and platelet count of 100 × 1000/μL (red dashed). The model provides an appropriate depiction of the observed differences between the race categories

FIGURE A1

Final model diagnostic plots stratified by treatment group. (A) Observed vs individual predicted platelet counts, (B) observed vs population predicted platelet counts, (C) conditional weighted residuals vs time after first dose, (D) conditional weighted residuals vs population predicted platelet counts. The black line is the line of identity, coloured lines are the linear regression stratified by treatment group, black dashed lines represent conditional weighted residuals ± 2 (fine) and ± 6 (bold) standard deviations from the mean