Risk Assessment for Drug-Drug Interaction Caused by Metabolism-Based Inhibition of CYP3A Using Automated in Vitro Assay Systems and Its Application in the Early Drug Discovery Process

104

ABSTRACT:Although reversible CYP3A inhibition testing is well established for predicting the drug-drug interaction potential of clinical candidates, time-dependent inhibition (TDI) has become the focus of drug designers only recently. Failure of several late-stage clinical candidates has been attributed to TDI, and this mechanism is also suspected to play a role in liver toxicities often observed in preclinical species. Measurement of enzyme inactivation rates (k inact and K I ) is technically challenging, and a great deal of variability can be found in the literature. In this article, we have evaluated the TDI potential for 400 registered drugs using a high-throughput assay format based on determination of the inactivation rate (k obs ) at a single concentration of test compound (10 M). The advantages of this new assay format are highlighted by comparison with data generated using the IC 50 shift assay, a current standard approach for preliminary assessment of TDI. With use of an empirically defined positive/negative k obs bin of 0.02 min ؊1, only 4% of registered drugs were found to be positive. This proportion increased to more than 20% when in-house lead optimization molecules were considered, emphasizing the importance of identifying this property in selection of promising drug candidates. Finally, it is suggested that the data and technology described here may be a good basis for building structure-activity relationships and in silico modeling.

“…Because TDI parameters obtained with the dilution method do not include the competition aspect, they are likely to be independent of the substrate used (Watanabe et al, 2007).…”

Section: Figmentioning

confidence: 99%

“…However, Obach et al, 2007 have recently proposed a risk ranking model based on the shifted IC 50 . As an alternative, single concentration, single time point assays were reported for which percentage activity remaining or apparent partition ratio was used for risk evaluation (Lim et al, 2005;Watanabe et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

CYP3A Time-Dependent Inhibition Risk Assessment Validated with 400 Reference Drugs

Zimmerlin

Trunzer²,

Faller³

2011

104

“…Alternatively, the MIC formed during preincubation can be dissociated from further incubation with potassium ferricyanide before another 5-fold or greater dilution for residual activity assessment using Ն4-fold K M probe substrate concentration in the presence of a minimum 50 mM potassium ferricyanide (Lim et al, 2005;Watanabe et al, 2007). Oxidation with potassium ferricyanide only dissociates nitrogen-based MICs (Franklin, 1991); therefore, oxidation with ferricyanide is not recommended for detection of other MIC-forming compounds.…”

Section: Experimental Approaches For Tdi Studies: Recommendationsmentioning

confidence: 99%

The Conduct of in Vitro Studies to Address Time-Dependent Inhibition of Drug-Metabolizing Enzymes: A Perspective of the Pharmaceutical Research and Manufacturers of America

Grimm

Einolf²,

Hall³

et al. 2009

278

246

ABSTRACT:Time-dependent inhibition (TDI) of cytochrome P450 (P450) enzymes caused by new molecular entities (NMEs) is of concern because such compounds can be responsible for clinically relevant drug-drug interactions (DDI). Although the biochemistry underlying mechanism-based inactivation (MBI) of P450 enzymes has been generally understood for several years, significant advances have been made only in the past few years regarding how in vitro time-dependent inhibition data can be used to understand and predict clinical DDI. In this article, a team of scientists from 16 pharmaceutical research organizations that are member companies of the Pharmaceutical Research and Manufacturers of America offer a discussion of the phenomenon of TDI with emphasis on the laboratory methods used in its measurement. Results of an anonymous survey regarding pharmaceutical industry practices and strategies around TDI are reported. Specific topics that still possess a high degree of uncertainty are raised, such as parameter estimates needed to make predictions of DDI magnitude from in vitro inactivation parameters. A description of follow-up mechanistic experiments that can be done to characterize TDI are described. A consensus recommendation regarding common practices to address TDI is included, the salient points of which include the use of a tiered approach wherein abbreviated assays are first used to determine whether NMEs demonstrate TDI or not, followed by more thorough inactivation studies for those that do to define the parameters needed for prediction of DDI.Pharmacokinetic drug-drug interactions (DDIs) can occur when one drug alters the metabolism of a coadministered drug. The outcome is an increase or decrease in the systemic clearance and/or bioavailability, and a corresponding change in the exposure to a coadministered drug. The clinical consequences of DDIs range from lack of therapeutic efficacy of a life saving drug to severe adverse drug reactions, including fatalities. Significant drug-drug interactions can lead to termination of development of otherwise promising new therapies, withdrawal of a drug from the market, or severe restrictions/limitations on its use (Wienkers and Heath, 2005). Because of the impact on patient health and safety, DDI was the subject of a position paper in 2003 by scientists from member companies of the Pharmaceutical Research and Manufacturers of America (PhRMA) that focused on Article, publication date, and citation information can be found at

“…Drugs that inhibit CYP3A4 such as ketoconazole, cisapride, ritonavir, and nefazodone have been found to cause deleterious side effects when coadministered with other drugs. Therefore, many drugs that strongly inhibit CYP3A4 such as mibefradil have been withdrawn from the market (SoRelle, 1998;Bohets et al, 2000;Watanabe et al, 2007; http://www.fda.gov/medwatch/SAFETY/1997/ posico.htm). Mibefradil was shown to strongly inhibit CYP3A4 via mechanism-based inactivation at its relevant therapeutic concentration.…”

Section: Downloaded Frommentioning

confidence: 99%

The Mibefradil Derivative NNC55-0396, a Specific T-Type Calcium Channel Antagonist, Exhibits Less CYP3A4 Inhibition than Mibefradil

Bui

Quesada²,

Handforth³

et al. 2008