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

摘要

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.