Population Pharmacokinetic/Pharmacodynamic Modeling of the Effect of Abrocitinib on QT Intervals in Healthy Volunteers

Abrocitinib is a selective Janus kinase 1 inhibitor for the treatment of moderate to severe atopic dermatitis (AD). To assess the relationship between abrocitinib plasma concentrations and heart rate (HR)-corrected QT (QTc) and HR and calculate the effect of abrocitinib on these parameters at supratherapeutic concentrations, 36 healthy volunteers received single doses of abrocitinib 600 mg, placebo, and moxifloxacin 400 mg in a 3-period crossover study. The relationship between change from baseline in Fridericia-corrected QTc ( increment QTcF) values and abrocitinib plasma concentrations was modeled using a prespecified linear mixed-effects model. The 90%CIs for time-matched placebo-corrected increment QTcF ( increment increment QTcF) were calculated from model parameter estimates and assessed against the regulatory threshold (10 millisecond) at the predicted supratherapeutic concentration in patients with atopic dermatitis (2156 ng/mL). Mean (90%CI) time-matched placebo-corrected change from baseline in HR ( increment increment HR) was calculated similarly. At the supratherapeutic concentration, mean (90%CI) estimates for increment increment QTcF and increment increment HR were 6.00 (4.52-7.49) milliseconds and 6.51 (5.23-7.80) bpm, respectively. Despite a concentration-dependent effect on increment QTcF and increment HR, with statistically significant slopes (90%CI) of 0.0026 (0.0018-0.0035) milliseconds/(ng/mL) and 0.0031 (0.0024-0.0038) bpm/(ng/mL), respectively, abrocitinib does not have a clinically significant effect on QTc interval or HR at supratherapeutic exposures.