Semi-Mechanistic Population Pharmacokinetic Drug-Drug Interaction Modelling of a Long Half-Life Substrate and Itraconazole

AbstractBackground: For compounds with a long elimination half-life, the evaluation of a drug-drug interaction (DDI) study can be challenging. The standard analytical approach of a non-compartmental analysis (NCA) might not be able to detect the full interaction potential and may lead to a significant underestimation of the interaction. The most appropriate method for data analysis might be a semi-mechanistic population pharmacokinetic modelling approach. Objectives: To accomplish a semi-mechanistic DDI model for a long-elimination-half-life drug substrate, tesofensine, and the cytochrome P450 (CYP) 3 A4 inhibitor itraconazole, and to compare the results of the semi-mechanistic model with the results obtained from the standard NCA approach. Additionally, the impact of different schedules of itraconazole on tesofensine pharmacokinetics and the general performance of the standard NCA approach were evaluated. Methods: Overall, 28 subjects received a single oral dose of tesofensine 2 mg; 14 of these subjects were coadministered an oral itraconazole 400 mg loading dose and a 200 mg maintenance dose for 6 days before and 5 days after administration of tesofensine. The dataset contained 465 plasma concentrations of tesofensine (full profiles) and 80 plasma concentrations of itraconazole (trough values). First, pharmacokinetic models of itraconazole and tesofensine were developed in parallel. Subsequently, a combined model was developed, taking into account CYP3A4 inhibition. The analyses were performed using NONMEM® software. Results: The plasma concentration-time profiles of itraconazole and tesofensine were best described by a one-compartment model for each drug, with first-order elimination rate constants that were both inhibited by itraconazole concentrations. Inhibition resulted in reduced clearances and prolonged elimination half-lives for tesofensine and itraconazole: using NCA, the actual study revealed an ∼9% increase in exposure for the timeframe of the coadministration with itraconazole (the area under the plasma concentration-time curve (AUC) from 0 to 144 hours [AUC144h]), and the impact on exposure estimated to infinity (AUC∞) was ∼26%. These results are in contrast to the model-predicted results, where the inhibitory effect of itraconazole caused a 38% reduction in the clearance of tesofensine, leading to a 63% increased exposure. Conclusions: This analysis presents a semi-mechanistic population pharmacokinetic approach that may be useful for the evaluation of DDI studies. The model can be an aid in evaluating DDI studies for compounds with a long elimination half-life, especially when the inhibitor cannot be administered over a sufficient period. Additionally, the population model-based approach may allow simplification of the design and the analysis and interpretation of safety and efficacy findings in DDI studies.