Pharmacokinetics of a New Immediate-Release Methadone Tablet Formulation with Decreased In vitro Solubility

Abstract

A new tablet formulation of methadone was developed with unique physicochemical properties, allowing for decreased solubility in aqueous solutions in in vitro studies. It was unknown whether this newly developed formulation would affect its bioavailability compared with the currently available formulation of methadone. The objective of this study was to further examine the in vitro solubility of the new methadone formulation, and to evaluate and compare the relative bioavailability and pharmacokinetics to the previous reference formulation after a single oral dose administration under fasting conditions. In vitro comparative dissolution for the new methadone formulation and the previous reference formulation was conducted. A randomized, single-dose, blinded, two-period, two-sequence, crossover pharmacokinetic study was performed in 24 healthy volunteers under fasting conditions. The new methadone formulation demonstrated a 30-40% decrease in solubility over 30 minutes compared with the previous reference formulation at the highest dose; all other doses also showed decreased in vitro solubility. The pharmacokinetic parameters determined were: maximum plasma drug concentration (C(max)) of 38.1 ng/mL; time to reach C(max) (t(max)) of 2.80 hours; mean area under the plasma concentration-time curve (AUC) from time zero to 72 hours (AUC(72)) of 1043 ng · h/mL; mean AUC from time zero to infinity (AUC(∞)) of 1430 ng · h/mL; mean elimination rate constant (k(e)) of 0.0206 hours(-1); and mean elimination half-life (t(½)) of 36.7 hours. These values are statistically equivalent to the previous reference formulation of methadone. This study provides the first complete set of pharmacokinetic data on a novel methadone formulation. The formulation demonstrates decreased in vitro solubility while providing equivalent plasma methadone levels compared with the previous formulation.