Desipramine, substrate for CYP2D6 activity: population pharmacokinetic model and design elements of drug–drug interaction trials

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Desipramine is extensively metabolized by CYP2D6 to its main metabolite 2-OH-desipramine.• Alternative metabolic pathways are 10-hydroxylation and further demethylation to didesipramine, but the concentration of these metabolites in plasma upon therapeutic oral doses are very low both in extensive and poor metabolizers of substrates of CYP2D6. • Desipramine has been used widely as a probe drug for CYP2D6 activity. WHAT THIS STUDY ADDS• The population pharmacokinetics of desipramine in healthy subjects were characterized.• The model allows performing simulations of trials which assess CYP2D6 interaction potential of novel compounds.• Study design elements, such as required sample size based on desipramine within and between-subject variance and optimal sampling schedules for the three subgroups, intermediate, extensive and ultrarapid metabolizers of CYP2D6 are suggested. AIMSTo develop a population pharmacokinetic model to describe the pharmacokinetics of desipramine in healthy subjects, after oral administration of a 50 mg dose. Additional objectives were to develop a semi-mechanistic population pharmacokinetic model for desipramine, which allowed simulation of CYP2D6-mediated inhibition, when using desipramine as a probe substrate, and to evaluate certain study design elements, such as duration of desipramine pharmacokinetic sampling, required sample size and optimal pharmacokinetic sampling schedule for intermediate, extensive and ultrarapid metabolizers of CYP2D6 substrates. RESULTSThe mean population estimates of the first order absorption rate constant (ka), apparent clearance (CL/F) and apparent volume of distribution at steady state (Vss/F) were 0.15 h -1, 111 l h -1 and 2950 l, respectively. Further, using the proposed semi-mechanistic hepatic intrinsic clearance model with Bayesian inference, mean population desipramine hepatic intrinsic clearance was estimated to be 262 l h -1 with between-subject variability of 84%. D-optimal PK sampling times for intermediate metabolizers were calculated to be approximately 0.25, 24, 75 and 200 h. Similar sampling times were found for ultrarapid and extensive metabolizers except that the second D-optimal sample was earlier at 14 and 19 h, respectively, compared with 24 h for intermediate metabolizers. This difference in sampling times between the three genotypes can be attributed to the different intrinsic clearances and elimination rates. CONCLUSIONSA two compartment population pharmacokinetic model best described desipramine disposition. The semi-mechanistic population model developed is suitable to describe the pharmacokinetic behaviour of desipramine for the dose routinely used in drug-drug interaction (DDI) studies. Based on this meta-analysis of seven trials, a sample size of 21 subjects in cross-over design is appropriate for assessing CYP2D6 interaction with novel compounds.

Discovery and In Vivo Evaluation of ACT-660602: A Potent and Selective Antagonist of the Chemokine Receptor CXCR3 for Autoimmune Diseases

“…Only 2D6 metabolized 9j leading to the formation of M1 and M2. 2D6 is highly polymorphic within the human population, and a compound being eliminated only via 2D6 metabolism is likely to produce highly variable plasma exposures in patients. , Consequently, the preclinical development of 9j was put on hold.…”

Human microsomal cyttrochrome P450-mediated reduction of oxysophocarpine, an active and highly toxic constituent derived from Sophora flavescens species, and its intestinal absorption and metabolism in rat

“…A life-threatening liver damage can occur when CYP3A inhibitors are co-administrated with terfenadine, astemizole, cisapride, or pimozide [5]. Furthermore, liver damage will happen when CYP2D6 inhibitors are co-administered with codeine and desipramine [8]. The phenotype of CYP2D6 poor metabolizer for CYP2D6 of a patient had major clinical importance in treatment with risperidone because the metabolic pathways are probably inhibited by haloperidol [17].…”

Investigation of the Differences in the Pharmacokinetics of CYP2D6 Substrates, Desipramine, and Dextromethorphan in Healthy African Subjects Carrying the Allelic Variants CYP2D6*17 and CYP2D6*29, When Compared with Normal Metabolizers

“…[9][10][11] The [9][10][11]13,14 All the reported PK parameters (except clearance) of dextromethorphan and desipramine followed a similar trend: (Nakashima D 2003, Chi 2013) and for desipramine (Harris 2007, Krutz 1997, Patroneva 2008) in human subjects exhibiting NM phenotype status (alleles are not specified in literature). 9,24,25,36,37 To qualify as comparable, the values in the literature were required to lie in the range of 90% confidence intervals of the PK parameters of the African-specific 2). The plasma drug/metabolite exposure (C max and AUC inf ) ratios of dextromethorphan were higher in the CYP2D6*17*17 and CYP2D6*29*29 cohorts when compared with the CYP2D6*1/*2 diplotype cohort, indicating the slower rate of formation of metabolites in these 2 cohorts.…”