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

Abstract

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 downregulation of a 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 concentrations to predict and adjust dosage of the drug and to monitor compliance in opiate-users on maintenance treatment.

Population pharmacokinetics of APOMINE™: A meta‐analysis in cancer patients and healthy males

“…Apomine has a molecular weight of 563 Da, and drugs with values greater than 500 Da tend to be cleared exclusively by metabolism and biliary secretion [8]. Many models have been developed to explain enterohepatic recycling, most using some form of caternary compartment model between the elimination compartment and absorption compartment [10][11][12].…”

“…Although induction in vivo has not been confirmed, an induction model was tested allowing apparent oral clearance to vary over time to determine whether induction improved the goodness of fit. Autoinduction has been modelled using both mechanistic [6], semimechanistic [7], and empirical models [8].…”

Alternative Sampling Strategies for Cytochrome P450 Phenotyping

“…A positive linear trend between this cumulative dose and EDDP/methadone ratios in hair was observed [64]. This could illustrate auto-induction of methadone metabolism, mainly mediated by CYP3A4 [65], or, again, elevated CYP450 activity during pregnancy [61][62][63]. These studies suggest that applying segmental hair analysis to retrospectively assess drug metabolism may hold promise as an alternative phenotyping approach.…”

Variability of Plasma Methadone Concentration in Opiate Dependent Receiving Methadone: A Personalised Approach Towards Optimizing Dose

“…These parameters are found to be higher in females and they are directly related to weight (Wolff et al, 2000). Furthermore, it has also been suggested that a time-dependent increase in methadone clearance may result from auto-induction of its own metabolism by CYP3A4, and the change in Vss may be due to up or down-regulation of AAG (Rostami-Hodjegan et al, 1999). Therefore, a time-dependent decrease in Vss may be associated with the observed timedependent increase in AAG.…”

“…It has been shown that at urinary pH of six and above, renal clearance accounts for four percent only. However, when urinary pH was lower than 6, the clearance of unchanged drug will be increased by 33 percent (Rostami-Hodjegan et al, 1999). It was concluded that, about 20-50 percent of the inter-individual variability can be explained by urinary excretion (KuKanich and Borum, 2008).…”