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

Br J Clin Pharmacol. 1999 Jul;48(1):43-52. doi: 10.1046/j.1365-2125.1999.00974.x.


Aims: Although methadone is widely used to treat opiate dependence, guidelines for its dosage are poorly defined. There is increasing evidence to suggest that a strategy based on plasma drug monitoring may be useful to detect non-compliance. Therefore, we have developed a population-based pharmacokinetic (POP-PK) model that characterises adaptive changes in methadone kinetics.

Methods: Sparse plasma rac-methadone concentrations measured in 35 opiate-users were assessed using the P-Pharm software. The final structural model comprised a biexponential function with first-order input and allowance for time-dependent change in both clearance (CL) and initial volume of distribution (V ). Values of these parameters were allowed to increase or decrease exponentially to an asymptotic value.

Results: Increase in individual values of CL and increase or decrease in individual values of V with time was observed in applying the model to the experimental data.

Conclusions: A time-dependent increase in the clearance of methadone is consistent with auto-induction of CYP3A4, the enzyme responsible for much of the metabolism of the drug. The changes in V with time might reflect both up- and down-regulation of alpha1-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 concentrations to predict and adjust dosage of the drug and to monitor compliance in opiate-users on maintenance treatment.

Publication types

  • Clinical Trial

MeSH terms

  • Adolescent
  • Adult
  • Analgesics, Opioid / administration & dosage
  • Analgesics, Opioid / pharmacokinetics*
  • Analgesics, Opioid / therapeutic use
  • Female
  • Humans
  • Male
  • Methadone / administration & dosage
  • Methadone / pharmacokinetics*
  • Methadone / therapeutic use
  • Models, Biological
  • Opioid-Related Disorders / drug therapy
  • Opioid-Related Disorders / metabolism*
  • Time Factors


  • Analgesics, Opioid
  • Methadone