Population Pharmacokinetics/Pharmacodynamics of 3,4‐Diaminopyridine Free Base in Patients With Lambert‐Eaton Myasthenia

Lambert‐Eaton myasthenia (LEM) is a rare autoimmune disorder associated with debilitating muscle weakness. There are limited treatment options and 3,4‐diaminopyridine (3,4‐DAP) free base is an investigational orphan drug used to treat LEM‐related weakness. We performed a population pharmacokinetic/pharmacodynamic (PK/PD) analysis using 3,4‐DAP and metabolite concentrations collected from a phase II study in patients with LEM. The Triple Timed Up & Go (3TUG) assessment, which measures lower extremity weakness, was the primary outcome measure. A total of 1,270 PK samples (49 patients) and 1,091 3TUG data points (32 randomized patients) were included in the PK/PD analysis. A two‐compartment and one‐compartment model for parent and metabolite, respectively, described the PK data well. Body weight and serum creatinine partially explained the variability in clearance for the final PK model. A fractional inhibitory maximum effect (E(max)) model characterized the exposure‐response relationship well. The PK/PD model was applied to identify a suggested dosing approach for 3,4‐DAP free base.