A genetic-based population PK/PD modeling of methadone in Chinese opiate dependence patients

The full potential of methadone maintenance treatment (MMT) is often limited by the large inter-individual variability in both pharmacokinetics (PK) and pharmacodynamics (PD), and by the risk of torsade de pointes, a severe adverse effect caused by QTc prolongation. The current study aims to quantitate the contribution of genetic polymorphisms and other variables in PK/PD variability, and their contribution to the QTc interval prolongation in Chinese MMT patients.

Population PK models were developed to fit (R)- and (S)-methadone PK data. Hierarchical models were tested to characterize the PK profile, the concentration-QTc relationship, and concentration-urinalysis illicit drug testing relationship, with demographics and genetic variants being included as covariates. Simulation based on the developed PK/PD models was performed to assess the effect of methadone dose and genetic variants on QTc interval prolongation.

The PK data were best-fit by a one-compartment, first-order absorption model. Clearance of (R)- and (S)-methadone was both affected by the weighted activity score derived from genetic variants. A linear model was used to describe both the methadone concentration-urinalysis illicit drug testing relationship and the methadone concentration-QTc relationship. Concentration of (R)- and (S)-methadone exhibits a comparable effect on QTc prolongation. Simulation showed that the percentage of QTc higher than 450 ms was almost doubled in the lowest clearance group as compared the highest when methadone dose was greater than 120 mg.

The large variability in PK/PD profiles can be partially explained by the genetic variants in an extent different from other population, which confirmed the necessity to conduct such a study in the specific Chinese patients.