Effect of Different Durations and Formulations of Diltiazem on the Single-Dose Pharmacokinetics of Midazolam: How Long Do We Go?

Abstract

Understanding how inhibition of cytochrome P4503A (CYP3A) affects the metabolism of a new drug is critical in determining if a clinically relevant drug interaction will occur. Diltiazem interaction studies assess a given compound's sensitivity to moderate CYP3A inhibition. The present study compared the effect different durations and formulations of diltiazem (extended release [XR] and conventional release [CR]) had on the single-dose pharmacokinetics of midazolam. The geometric mean ratio (GMR; midazolam + diltiazem(XR × 5 days)/midazolam + diltiazem(XR × 2 days)) for midazolam AUC(0-∞) was 0.98 (90% confidence interval [CI], 0.87, 1.10). The GMR (midazolam + diltiazem(XR × 2 days)/midazolam + diltiazem(CR × 2 days)) for midazolam AUC(0-∞) was 0.82 (90% CI, 0.73, 0.92). Simcyp simulations accurately predicted the observed clinical results only when a hepatic CYP3A degradation rate (k(deg)) different from that provided by the software was used. The data suggest that dosing diltiazem XR for 2 days predicts the change in midazolam AUC as reliably as 5 days of XR dosing and 2 days of CR dosing. In addition, the authors believe that a hepatic CYP3A kdeg of 0.03 h(-1) should be considered for future Simcyp studies.

Modeling of Rifampicin-Induced CYP3A4 Activation Dynamics for the Prediction of Clinical Drug-Drug Interactions from In Vitro Data

“…The parameters EC 50 , k inact , k rna,deg , k cyp,deg , p and q were estimated to be 1.18 µM, 0.0530 h –1 , 0.0282 h –1 , 0.313, and 4.34, respectively, in addition to the inter-donor variability of CYP 0 (ω 2 ) of 0.318. Interestingly, the k cyp,deg estimated was comparable to the one that was previously optimized for better in vitro / in vivo extrapolation (0.03 h –1 ) [51], [52]. Fig.…”

Determination of a Degradation Constant for CYP3A4 by Direct Suppression of mRNA in a Novel Human Hepatocyte Model, HepatoPac

“…(B) One-phase exponential decay equation using the mean and standard deviations generated from donors 1, 2, 3, 4, and 5. dmd.aspetjournals.org k deg for the enzyme as a key input parameter. As physiologically based pharmacokinetic modeling is more routinely applied to predict complex drug interactions, many researchers have noted improved prediction accuracy when using a CYP3A k deg of 0.03 hour 21 (Wang, 2010;Friedman et al, 2011;Yamashita et al, 2013), determined from the time course of CYP3A recovery following multiple-dose clarithromycin administration. The current approach, which resulted in an overall CYP3A k deg of 0.0240 hour…”

“…Additionally, improved prediction accuracy has been noted using ) (Quinney et al, 2010;Wang, 2010;Friedman et al, 2011;Yamashita et al, 2013). As discussed in detail by Yang et al (2008), a number of approaches have been applied to estimate half-life of P450 degradation.…”

Drug–Drug Interaction Studies: Regulatory Guidance and An Industry Perspective

“…In both cases, the predictions gave no false negatives (Table V). In this analysis, an enzyme turnover rate (k deg ) for CYP3A of 0.03 h −1 was used; this k deg value has recently been shown to yield more accurate predictions for time dependent inhibition of diltiazem and other TDIs on midazolam (74,79). Although limited, our data suggest that the results from the mechanistic static model may provide a more reasonable estimate for DDI risk if clinically observed unbound C max , instead of the agency's recommended unbound portal C max is used.…”

“…With the k deg value of 0.03 h −1 , the modeled GMR (95% CI) for the pioglitazone/midazolam DDI was 1.87 (1.78-1.97) versus the observed GMR of 0.74, and the corresponding value for the troglitazone/simvastatin DDI was 6.47 (6.10-6.86) versus the observed interaction of 0.59 (83). Interestingly, these predicted results are the best-case outcome, given that the prediction became worse using a k deg value of either 0.019 h −1 (predicted GMR02.1 and 7.0 for pioglitazone/simvastatin and troglitazone/simvastatin, respectively) or 0.008 h −1 (predicted GMR02.8 and 8.8 for pioglitazone/simvastatin and troglitazone/ simvastatin, respectively); both k deg values have also been commonly employed for CYP3A in many reportedly successful DDI predictions resulting from CYP3A inhibition (74,79,84). Furthermore, correction of the Ki and KI values of pioglitazone and troglitazone using the measured nonspecific binding (0.11 and 0.07, respectively-data not shown) caused the prediction to be even worse (i.e., predicted a greater magnitude of net inhibition).…”