title: Pharmacokinetic Interactions for Drugs with a Long Half-Life—Evidence for the Need of Model-Based Analysis.
abstract: Pharmacokinetic drug-drug interactions (DDIs) can lead to undesired drug exposure, resulting in insufficient efficacy or aggravated toxicity. Accurate quantification of DDIs is therefore crucial but may be difficult when full concentration-time profiles are problematic to obtain. We have compared non-compartmental analysis (NCA) and model-based predictions of DDIs for long half-life drugs by conducting simulation studies and reviewing published trials, using antituberculosis drug bedaquiline (BDQ) as a model compound. Furthermore, different DDI study designs were evaluated. A sequential design mimicking conducted trials and a population pharmacokinetic (PK) model of BDQ and the M2 metabolite were utilized in the simulations where five interaction scenarios from strong inhibition (clearance fivefold decreased) to strong induction (clearance fivefold increased) were evaluated. In trial simulations, NCA systematically under-predicted the DDIs’ impact. The bias in average exposure was 29–96% for BDQ and 20–677% for M2. The model-based analysis generated unbiased predictions, and simultaneous fitting of metabolite data increased precision in DDI predictions. The discrepancy between the methods was also apparent for conducted trials, e.g., lopinavir/ritonavir was predicted to increased BDQ exposure 22% by NCA and 188% by model-based methods. In the design evaluation, studies with parallel designs were considered and shown to generally be inferior to sequential/cross-over designs. However, in the case of low inter-individual variability and no informative metabolite data, a prolonged parallel design could be favored. Model-based analysis for DDI assessments is preferable over NCA for victim drugs with a long half-life and should always be used when incomplete concentration-time profiles are part of the analysis.
authors.forename: Elin M
authors.initials: EM
authors.lastname: Svensson
authors.forename: Chayan
authors.initials: C
authors.lastname: Acharya
authors.forename: Björn
authors.initials: B
authors.lastname: Clauson
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Dooley
authors.forename: Mats O
authors.initials: MO
authors.lastname: Karlsson
mesh_terms: D000465:Algorithms; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000493:pharmacokinetics; D000995:Antitubercular Agents / Q000493:pharmacokinetics; D001711:Biotransformation; D003198:Computer Simulation; D065692:Cytochrome P-450 CYP3A Inhibitors; D064687:Diarylquinolines / Q000493:pharmacokinetics; D004347:Drug Interactions; D006207:Half-Life; D006801:Humans; D061466:Lopinavir / Q000009:adverse effects / Q000493:pharmacokinetics; D008954:Models, Biological; D010599:Pharmacokinetics; D019438:Ritonavir / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D064687:Diarylquinolines; D061466:Lopinavir; C493870:bedaquiline; D019438:Ritonavir