The Conduct of In Vitro and In Vivo Drug-Drug Interaction Studies: A PhRMA Perspective

Abstract

Current regulatory guidances do not address specific study designs for in vitro and in vivo drug-drug interaction studies. There is a common desire by regulatory authorities and by industry sponsors to harmonize approaches to allow for a better assessment of the significance of findings across different studies and drugs. There is also a growing consensus for the standardization of cytochrome P450 (CYP) probe substrates, inhibitors, and inducers and for the development of classification systems to improve the communication of risk to health care providers and patients. While existing guidances cover mainly CYP-mediated drug interactions, the importance of other mechanisms, such as transporters, has been recognized more recently and should also be addressed. This paper was prepared by the Pharmaceutical Research and Manufacturers of America (PhRMA) Drug Metabolism and Clinical Pharmacology Technical Working Groups and represents the current industry position. The intent is to define a minimal best practice for in vitro and in vivo pharmacokinetic drug-drug interaction studies targeted to development (not discovery support) and to define a data package that can be expected by regulatory agencies in compound registration dossiers.

Limited Sampling Strategy of Partial Area Under the Concentration–Time Curves to Estimate Midazolam Systemic Clearance for Cytochrome P450 3A Phenotyping

“…In the current study, 1-hydroxymidazoam urine concentration data was not known and thus determining an observed metabolic CL and comparing these results to predicted metabolic CL would not be possible. Rather, the current study utilized systemic CL as this is an accepted parameter to estimate hepatic CYP3A activity with IV midazolam 2 . Lastly, this analysis included IV midazolam data, whereby results are applicable to estimation of hepatic CYP3A activity.…”

“…Phenotyping is used to determine real time, in vivo drug metabolizing enzyme activity and assess pharmacokinetic-mediated drug-drug interactions (DDIs) 1, 2 . Of the drug metabolizing enzymes, cytochrome P450 (CYP) 3A plays a substantial role in clinically significant DDIs as more than 50% of the drugs available on the market are subject to CYP3A4 and CYP3A5 pathways 3 .…”

“…Of the drug metabolizing enzymes, cytochrome P450 (CYP) 3A plays a substantial role in clinically significant DDIs as more than 50% of the drugs available on the market are subject to CYP3A4 and CYP3A5 pathways 3 . The preferred CYP3A probe for phenotyping is midazolam 2 with intravenous (IV) midazolam exclusively assessing hepatic CYP3A activity 1, 4 . Systemic (or total body) clearance (CL) of IV midazolam strongly correlates with hepatic CYP3A content (r = 0.93, p < 0.001) 5 and is commonly used as a surrogate for hepatic CYP3A activity.…”

In Vitro Evaluation of Reversible and Time-Dependent Inhibitory Effects of Kalanchoe crenata on CYP2C19 and CYP3A4 Activities

“…Recently, the Pharmaceutical Research and Manufacturers Association recommended the use of IC50-shift approach as the first step for TDI assays [24]. This method involves the application of HLMs or recombinant human CYPs to evaluate whether the potency of the NCE to inhibit CYP increases when the drug candidate is preincubated in the presence of NADPH.…”

Prediction of pharmacokinetics and drug-drug interaction potential using physiologically based pharmacokinetic (PBPK) modeling approach: A case study of caffeine and ciprofloxacin

“…Early prediction of DDIs has also become useful to support clinical candidate selection. DDI studies and their interpretation have been described in a white paper from the Pharmaceutical Research and Manufacturers of America (PhRMA) [3] and in a guidance document from the US FDA.…”