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.
OBJECTIVE
To predict the magnitude of metabolic drug-drug interaction (mDDI) between triazolam and diltiazem and its primary metabolite N-desmethyldiltiazem (MA).


METHODS
Relevant in vitro metabolic and inhibitory data were incorporated into a mechanistic physiologically based pharmacokinetic model within Simcyp (Version 9.1) to simulate the time-course of changes in active CYP3A4 content in gut and liver and plasma concentrations of diltiazem, MA and triazolam in a virtual population with characteristics related to in vivo studies.


RESULTS
The predicted median increases in AUC(0,infinity) of triazolam, which ranged from 3.9 to 9.5 for 20 simulated trials (median 5.9), were within 1.5-fold of the observed median value (4.4) in 14 of the trials. Considering the effects of diltiazem only and not those of MA, and ignoring auto-inhibition of MA metabolism and inhibition of its metabolism by diltiazem, resulted in lower increases in triazolam exposure (AUC ratios of 1.5-2.0 (median 1.7) and 2.7-5.3 (median 3.4), respectively).


CONCLUSIONS
Prediction of mDDIs involving diltiazem requires consideration of both competitive and time-dependent inhibition in 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.
Rowland Yeo
Karen
K
Simcyp Limited, Blades Enterprise Centre, John Street, Sheffield S2 4SU, UK. k.r.yeo@simcyp.com
Jamei
Masoud
M
Yang
Jiansong
J
Tucker
Geoffrey T
GT
Rostami-Hodjegan
Amin
A
D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004110:Diltiazem / Q000493:pharmacokinetics / Q000494:pharmacology*; D004347:Drug Interactions; D007422:Intestines / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D014229:Triazolam / Q000493:pharmacokinetics / Q000494:pharmacology*
D014229:Triazolam; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D004110:Diltiazem