PII-59Population pharmacokinetic analysis of AVP-923 (30 mg dextromethorphan and 30 mg quinidine)

Abstract

BACKGROUND AVP-923 is a combination product of 30 mg dextromethorphan (DM) and 30 mg quinidine (Q) for the treatment of pseudobulbar affect in patients with various neurological disorders. AIM To evaluate the population pharmacokinetics (PK) of AVP-923 in 170 subjects (53 healthy and 117 patients). METHODS Plasma samples were collected following oral administration of AVP-923 and concentrations of DM, dextrorphan (DX), and Q were assayed. Urine samples were collected for the determination of DM and DX. Compartmental analyses were performed using ADAPT-II®. Data for all analytes/matrices were modeled simultaneously and the impact of various covariates was investigated (age, gender, body weight, and phenotype). RESULTS The PK of Q was best described by a 1-compartment (CPT) model, while the PK of DM and DX were described by 2-CPT models. The model included a CYP2D6 inhibitory Emax effect driven by Q levels preventing biotransformation of DM to DX and reducing the renal clearances of DM and DX. Age had no effect on the PK of DM. For DX, there was an apparent increase in the central volume of distribution with increasing age. This was likely a reflection of a decrease in the terminal elimination rate constant since total clearance of both DM and DX was unaffected by age. Underlying diseases did not seem to affect the PK of DM or DX. CONCLUSIONS The effect of Q on DM and DX was adequately characterized using an inhibitory Emax function. Clinical Pharmacology & Therapeutics (2005) 79, P51–P51; doi: 10.1016/j.clpt.2005.12.184