Population PK-PD Modeling of Danicopan Add-On Therapy in Participants With Paroxysmal Nocturnal Hemoglobinuria...

Danicopan is a first-in-class orally administered complement factor D inhibitor, approved as an add-on therapy to ravulizumab or eculizumab for the treatment of clinically significant extravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria (PNH). Population pharmacokinetics (PK) and pharmacodynamics (PK-PD) modeling was used to characterize danicopan PK and to evaluate the relationship between steady-state exposure and alternative pathway (AP) activity using data from healthy participants and patients with PNH treated with ravulizumab or eculizumab to support the danicopan dose regimens. Danicopan PK was described using a two-compartment model with linear elimination, with absorption characterized by a zero-order release followed by first-order absorption. Body weight, sex, renal impairment, formulation, and food status were identified as significant covariates affecting danicopan PK. Food status affected the absorption of danicopan but had a minimal effect on relative bioavailability. An inhibitory E_max model was used to describe the PK-PD relationship between danicopan exposure and AP activity; the IC50 and IC90 for AP inhibition were estimated to be 12 ng/mL and 108 ng/mL, respectively. PK-PD simulations support the approved danicopan dosing regimens of 150 mg or 200 mg three times daily (tid) and achieve the required exposure for 90% AP inhibition at trough. For both regimens, near-complete inhibition of AP activity (< 10%) was predicted regardless of food status. Overall, the effects of demographics, baseline, and food status variables were not considered clinically significant. These findings support the approved 150 mg and 200 mg tid dosing regimens for danicopan in patients with PNH.