CYP3A4-based drug-drug interaction: CYP3A4 substrates' pharmacokinetic properties and ketoconazole dose regimen effect.
The aim of the study was to assess the magnitude of the CYP3A4 inhibitory effect of 2 dosing regimens of ketoconazole and the influence of the pharmacokinetic properties of the CYP3A4 substrate on the extent of the substrate exposure increase. For this purpose, a clinical study was conducted and PBPK modeling simulations were performed. A crossover study was conducted in healthy subjects. The study was designed to compare the effects of different regimens of reversible CYP3A4 inhibitors, i.e., ketoconazole 400 mg OD, ketoconazole 200 mg BID, on two CYP3A4 substrates, alprazolam and midazolam, reflecting different pharmacokinetic properties in terms of first-pass effect and elimination. In parallel, time-based simulations were performed using the Simcyp population-based Simulator to address the usefulness of modeling to assess interaction clinical study design with CYP3A4 substrates. Comparison of the OD versus BID regimens for ketoconazole showed an opposite trend for the 2 substrates: BID (200 mg) dosing regimen provided the maximal clearance inhibition for alprazolam, while it was OD (400 mg) dosing regimen for midazolam. However, these effects are moderate despite the well-known pharmacokinetic differences between these substrates, suggesting that these differences are not enough. In the other way round, these investigations show how two CYP3A4 substrates can be different without leading to a major impact of the ketoconazole dosing regimen. The clinical findings are consistent with the Simcyp predictions, in particular the opposite trend observed with midazolam and alprazolam and the ketoconazole dosing regimen. These clinical investigations showed the influence of the CYP3A4 substrates' pharmacokinetic properties and the relevance of ketoconazole dose regimen on the magnitude of the interaction ratios. In addition, PBPK Simcyp simulations demonstrated how they can be used to help clinical study design assessment to capture the maximum effect.
Drug Disposition Domain, Disposition Safety and Animal Research, Sanofi, 371 rue du Professeur J. Blayac, 34184, Montpellier Cedex 04, France. xavier.boulenc@sanofi.com.
Xavier
X
Boulenc
Drug Disposition Domain, Disposition Safety and Animal Research, Sanofi, 371 rue du Professeur J. Blayac, 34184, Montpellier Cedex 04, France.
Olivier
O
Nicolas
Clinical and Exploratory Pharmacology, Sanofi, Montpellier, France.
Stéphanie
S
Hermabessière
Clinical Documentation, Sanofi, Montpellier, France.
Isabelle
I
Zobouyan
Biostatistics, Sanofi, Chilly-Mazarin, France.
Valérie
V
Martin
Eurofins Optimed, Lyon, France.
Yves
Y
Donazzolo
Drug Disposition Domain, Disposition Safety and Animal Research, Sanofi, 371 rue du Professeur J. Blayac, 34184, Montpellier Cedex 04, France.
Céline
C
Ollier
D000293:Adolescent; D000328:Adult; D000525:Alprazolam / Q000008:administration & dosage / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000493:pharmacokinetics; D013379:Substrate Specificity / Q000187:drug effects / Q000502:physiology; D055815:Young Adult
D065692:Cytochrome P-450 CYP3A Inhibitors; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam; D007654:Ketoconazole; D000525:Alprazolam
Alprazolam; CYP3A4; Drug–drug interaction; Ketoconazole; Midazolam; PBPK simulation