Population pharmacokinetics of methadone in opiate users: characterizationof time-dependent changes

Aims Although methadone is widely used to treat opiate dependence, guidelin es for its dosage are poorly defined. There is increasing evidence to sugge st that a strategy based on plasma drug monitoring may be useful to detect non-compliance. Therefore, we have developed a population-based pharmacokin etic (POP-PK) model that characterises adaptive changes in methadone kineti cs. Methods Sparse plasma rdc-methadone concentrations measured in 35 opiate-us ers were assessed using the P-Pharm software. The final structural model co mprised a biexponential function with first-order input and allowance for t ime-dependent change in both clearance (CL) and initial volume of distribut ion (V). Values of these parameters were allowed to increase or decrease ex ponentially to an asymptotic value. Results Increase in individual values of CL and increase or decrease in ind ividual values of V with time was observed in applying the model to the exp erimental data. Conclusions A time-dependent increase in the clearance of methadone is cons istent with auto-induction of CYP3A4, the enzyme responsible for much of th e metabolism of the drug. The changes in V with time might reflect both up- and downregulation of alpha(1)-acid glycoprotein, the major plasma binding site for methadone. By accounting for adaptive kinetic changes, the POP-PK model provides an improved basis for forecasting plasma methadone concentr ations to predict and adjust dosage of the drug and to monitor compliance i n opiate-users on maintenance treatment.