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

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 x 1000/mu L), 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 x 1000/mu L) at the nadir were 8.6% and 95.5% for the typical patient with baseline platelet count of 270 x 1000/mu L or 170 x 1000/mu L, 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.