Physiologically based mechanistic modelling to predict complex drug–drug interactions involving simultaneous competitive and time-dependent enzyme inhibition by parent compound and its metabolite in both liver and gut—The effect of diltiazem on the time-course of exposure to triazolam
Introduction
The calcium channel antagonist diltiazem undergoes extensive metabolism through multiple pathways including deacetylation by esterases and cytochrome P450 (CYP)-mediated N- and O-demethylation. N-demethylation to desmethyldiltiazem (MA) appears to be the major pathway of elimination in humans and is mediated primarily by CYP3A with minor contributions from CYP2C8 and CYP2C9 (Pichard et al., 1990, Sutton et al., 1997). MA is further N-demethylated, mainly by CYP3A, to N,N-didesmethyl diltiazem (MD) (Zhao et al., 2007). CYP2D6 is involved in the O-demethylation of diltiazem (Molden et al., 2002a) and the metabolism of desacetyl-diltiazem (Molden et al., 2002b).
Diltiazem causes clinically significant drug–drug interactions with compounds that are metabolised by CYP3A, including midazolam, triazolam, quinidine and simvastatin (Backman et al., 1994, Laganiere et al., 1996, Varhe et al., 1996, Mousa et al., 2000). Thus, inhibition of CYP3A has been attributed to the parent compound and its metabolites, consistent with the accumulation of MA and desacetyl-diltiazem after 2 weeks of administration (Montamat and Abernethy, 1987, Hoglund and Nilsson, 1989). This was supported by in vitro studies with human liver microsomes showing that MA and MD are potent competitive inhibitors of CYP3A (Ki values of 2 and 0.1 μM, respectively, for testosterone 6β-hydroxylation) (Sutton et al., 1997). Subsequently it was shown that both diltiazem and MA, but not MD, cause time-dependent inhibition through metabolite intermediate complex formation, with MA having a 4-fold greater kinact value than diltiazem (Jones et al., 1999, Mayhew et al., 2000; Rowland-Yeo and Yeo, 2001; Zhao et al., 2007, Zhang et al., 2009).
The application of a physiologically based pharmacokinetic model (PBPK) to predict in vivo drug–drug interactions involving mechanism (time)-based CYP3A inhibition from in vitro data has been described with respect to the coadministration of erythromycin and benzodiazepines (Ito et al., 2003) and the time-based auto-inhibition of CYP2D6 by methylenedioxymethamphetamine (MDMA, ‘ecstasy’) (Yang et al., 2006). However, only inhibition in the liver was considered in these simulations. More recently, a semi-PBPK model incorporating competitive and time-dependent inhibition at the gut wall for the interaction between diltiazem and midazolam was reported (Zhang et al., 2009). The inhibitory effect of the primary metabolite MA was also considered but only in the liver, and inhibition of the sequential CYP3A-mediated metabolism of MA by itself and by diltiazem was not incorporated. We now present the development and validation of a mechanistic PBPK model that considers both competitive and time-dependent inhibition in both gut and liver by both diltiazem and MA, as well as the complex interplay between the two moieties with respect to mutual inhibition of parent compound and its metabolite, using the interaction between diltiazem and triazolam as an example.
Section snippets
‘Victim’ drug kinetics
The kinetics of triazolam after oral administration were described by the model shown in Fig. 1A. This is essentially the same as that used by Ito et al., 1998, Ito et al., 2003, but with the incorporation of gut wall metabolism and a more physiological representation of the blood supply to the liver (Yang et al., 2003). The gut and the liver are represented as separate compartments and the other organs are lumped into a single systemic compartment. The following additional assumptions were
Concentration–time profiles following a single dose of diltiazem
Predicted and observed mean plasma concentration–time profiles of diltiazem and its inhibitory metabolite MA after a single oral dose of 60 mg diltiazem in solution are compared for 20 virtual trials in Fig. 2A. Mean predicted AUC(0,∞) values of diltiazem ranged from 0.39 to 0.58 mg/L h for the 20 simulated trials (median 0.50); the observed mean value was 0.44 mg/L h. Mean predicted AUC(0,∞) values of MA ranged from 0.19 to 0.34 mg/L h for the 20 simulated trials (median 0.25); the observed value
Discussion
N-desmethyl diltiazem (MA) is a much more potent competitive inhibitor and time-dependent inactivator of CYP3A than diltiazem (Zhao et al., 2007). Given that this metabolite is present in the systemic circulation at concentrations approaching half those of parent drug after diltiazem administration (Hoglund and Nilsson, 1989), predictions of drug–drug interactions based solely on inhibition by diltiazem should result in significant underestimation. Accordingly, we have incorporated competitive
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