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.

Effect of danshen extract on the activity of CYP3A4 in healthy volunteers

“…Due to the fact that midazolam is predominantly metabolized to 1-hydroxymidazolam by CYP3A4 and/or CYP3A5, this drug is referred to as an in vivo marker of CYP3A activity [14]. In this study, administration of multiple doses of danshen tablets caused a significant increase (35.4%) in apparent oral clearance, a corresponding significant decline (31.1%) in Cmax from 113.98 ng ml following administration of four danshen tablets.…”

“…The purpose of this study was to investigate whether danshen tablets could induce CYP3A4 activity using midazolam, which is recognized as one of the preferred in vivo probes [14], in healthy volunteers. This finding could provide useful insight into the safe and effective use of danshen preparations in clinical practice.…”

“…Although these findings suggested that the lipophilic components of danshen extract might account for danshen-mediated CYP3A4 induction, no human studies have investigated the potential of danshen to alter drug metabolism of CYP3A substrates. The probable interaction between the lipophilic components of danshen tablets and substrates of CYP3A has not been investigated.The purpose of this study was to investigate whether danshen tablets could induce CYP3A4 activity using midazolam, which is recognized as one of the preferred in vivo probes [14], in healthy volunteers. This finding could provide useful insight into the safe and effective use of danshen preparations in clinical practice.…”

In vitro inhibition of cytochrome P-450 activities and quantification of constituents in a selection of commercial Rhodiola rosea products

“…The SupersomesV R CYP enzymes used in this study are not confounded by cellular uptake or other intracellular metabolic processes, and is the recommended approach to use for in vitro metabolic evaluation when looking at single enzymes (Bjornsson et al 2003;Parkinson et al 2010;FDA 2012;Goey et al 2013). However, the physiological hepatic environment and the influence on CYP metabolism will not be assessed with this approach (Bjornsson et al 2003).…”

“…However, the physiological hepatic environment and the influence on CYP metabolism will not be assessed with this approach (Bjornsson et al 2003). The extrapolation of in vitro data to in vivo conditions is thus difficult and among other factors dependent on the uptake, distribution and physiological parameters which are not known for R. rosea products.…”