Optimization of Drug-Drug Interaction Study Design: Comparison of Minimal Physiologically Based Pharmacokinetic Models on Prediction of CYP3A Inhibition by Ketoconazole

Abstract

Ketoconazole is a potent CYP3A inhibitor used to assess the contribution of CYP3A to drug clearance and quantify the increase in drug exposure due to a strong inhibitor. Physiologically based pharmacokinetic (PBPK) models have been used to evaluate treatment regimens resulting in maximal CYP3A inhibition by ketoconazole but have reached different conclusions. We compare two PBPK models of the ketoconazole-midazolam interaction, model 1 (Chien et al., 2006) and model 2 implemented in Simcyp (version 11), to predict 16 published treatment regimens. With use of model 2, 41% of the study point estimates of area under the curve (AUC) ratio and 71% of the 90% confidence intervals were predicted within 1.5-fold of the observed, but these increased to 82 and 100%, respectively, with model 1. For midazolam, model 2 predicted a maximal midazolam AUC ratio of 8 and a hepatic fraction metabolized by CYP3A (f m ) of 0.97, whereas model 1 predicted 17 and 0.90, respectively, which are more consistent with observed data. On the basis of model 1, ketoconazole (400 mg QD) for at least 3 days and substrate administration within 2 hours is required for maximal CYP3A inhibition. Ketoconazole treatment regimens that use 200 mg BID underestimate the systemic fraction metabolized by CYP3A (0.86 versus 0.90) for midazolam. The systematic underprediction also applies to CYP3A substrates with high bioavailability and long half-lives. The superior predictive performance of model 1 reflects the need for accumulation of ketoconazole at enzyme site and protracted inhibition. Model 2 is not recommended for inferring optimal study design and estimation of fraction metabolized by CYP3A.

Deciding on Success Criteria for Predictability of Pharmacokinetic Parameters from In Vitro Studies: An Analysis Based on In Vivo Observations

“…However, there is no specification for which fold should be used and thus there is no consistency across different publications. Published articles report their predictions within 1.5-fold (Han et al, 2013), 2-fold (Chen et al, 2012), 3-fold (Gibson et al, 2009), and 5-fold (Gombar and Hall, 2013) of the observed value. It is worth mentioning here that the term "observed values" in the bottom-up approach should be distinguished from that in the top-down approach.…”

Evaluation of drug–drug interactions for oncology therapies: in vitro–in vivo extrapolation model‐based risk assessment

“…Since then, investigators have been evaluating the potential options since ketoconazole was considered the strong inhibitor of choice and was used in the vast majority of DDI studies of strong CYP3A inhibition. It has been noted that both itraconazole (midazolam AUCR 6.16 – 10.8, at 200 mg once daily for 4 days) and clarithromycin (maximal midazolam AUCR 8.4 at 500 mg twice daily for 7 days) are clinically less potent than the standard high dose ketoconazole regimen (AUCR 9.5–16.7 at 400 mg once daily for 4–10 days) and are more comparable with lower dose ketoconazole (AUCR 5.2–9.2 at 200 mg once daily for 3–5 days) . That trend between itraconazole and ketoconazole is borne out in simulations using the mechanistic static model (Figure C) where a midazolam f m of 0.93 predicts an AUCR of 4.6 and 18.4 for itraconazole and ketoconazole, respectively.…”

Ibrutinib Dosing Strategies Based on Interaction Potential of CYP3A4 Perpetrators Using Physiologically Based Pharmacokinetic Modeling

“…Based on this potential prolonged ketoconazole inhibition, Han et al . validated two PBPK models (Simcyp v. 11 and a custom‐built model) for their predictions of in vivo DDIs and concluded that the Simcyp v. 11 model for ketoconazole resulted in underestimation of the inhibition of intestinal metabolism, as shown for compounds like midazolam and simvastatin . In addition, Seidegard et al .…”

“…18 Based on this potential prolonged ketoconazole inhibition, Han et al validated two PBPK models (Simcyp v. 11 and a custom-built model) for their predictions of in vivo DDIs and concluded that the Simcyp v. 11 model for ketoconazole resulted in underestimation of the inhibition of intestinal metabolism, as shown for compounds like midazolam and simvastatin. 19 In addition, Seidegard et al demonstrated that 16 mg ketoconazole was capable of inhibiting intestinal metabolism without affecting the liver, and at 200 mg, ketoconazole caused complete inhibition of CYP3A4 in the intestine. 20 To simulate complete inhibition of intestinal CYP3A4 while evaluating the DDI of 400 mg q.d.…”