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Relationships of Changes in Pharmacokinetic Parameters of Substrate Drugs in Drug-Drug Interactions on Metabolizing Enzymes and Transporters.

Abstract：

:A general objective of drug-drug interaction (DDI) studies is to determine whether potential interactions of new molecular entities with concomitantly administered other drugs exist and, if DDIs occur, whether dosage adjustments are required. A typical end point for DDI evaluations is the ratio of area under the plasma concentration-time curve (AUC) of substrate drugs (AUCR), whereas the ratios of maximal plasma concentration (Cmax ) and terminal half-life (t1/2 ) are also important to understand DDI mechanisms (Cmax R and t1/2 R, respectively). Because changes in substrate AUC by precipitant drugs ultimately result from alterations of Cmax and t1/2 , AUCR can be considered a hybrid parameter of Cmax R and t1/2 R, for example, AUCR ≈ Cmax R × t1/2 R. The primary objective of this study was to investigate the relationships between AUCR, Cmax R, and t1/2 R in physiologically based pharmacokinetic model-predicted and clinically observed DDI results. First, the model-predicted results showed the excellent proportional relationship between AUCR and (Cmax R × t1/2 R) in DDI results of virtual substrates having a wide range of oral bioavailability with coadministration of ketoconazole, ritonavir, and rifampin. Second, the reasonable proportional relationships were also observed in the clinically observed DDI results of midazolam and statins (atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin) with various inhibitors and inducers. Finally, these results suggest that utilization of the proportional relationship between AUCR and (Cmax R × t1/2 R) can provide an additional framework to further interpret DDI results reasonably and clearly. Furthermore, the proportional relationship can be purposely used to assess study design and pharmacokinetic analyses in DDI studies.

journal_name

J Clin Pharmacol

journal_title

Journal of clinical pharmacology

authors

Yamazaki S

doi

10.1002/jcph.1104

subject

Has Abstract

pub_date

2018-08-01 00:00:00

pages

1053-1060

issue

eissn

0091-2700

issn

1552-4604

journal_volume

pub_type

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Relationships of Changes in Pharmacokinetic Parameters of Substrate Drugs in Drug-Drug Interactions on Metabolizing Enzymes and Transporters.