Compelling Relationship of CYP3A Induction to Levels of the Putative Biomarker 4β‐Hydroxycholesterol and Changes in Midazolam Exposure

Abstract

Having reliable clinical CYP3A biomarkers is attractive to those engaged in drug development as well as to academic groups studying clinical variability resulting from differences or changes in basal individual metabolic status (eg, due to disease or genetics) or drug-drug interactions (DDI). Moreover, if biomarkers can be adequately qualified, it raises the possibility of their use to better anticipate the need, or lack thereof, for defined clinical studies to establish DDI potential. But qualification requires a comprehensive body of evidence that currently appears not to exist in the published literature.We have been following with interest the many reports on the use of plasma 4β-hydroxycholesterol (4βHC) as a potential clinical biomarker of cytochrome P450 3A (CYP3A) enzyme activity in humans. Although 4βHC has been explored for both inhibition and induction of CYP3A, we have been interested in studies of CYP3A induction. These have included results from our own studies 1 as well as several other industry and academic groups.2-4 CYP3A is a major enzyme involved in the metabolic clearance of many drug substances. It has become apparent due to factors described below that the 4βHC biomarker is most amenable to the investigation of increases in CYP3A activity, for example, as a result of enzyme induction or the reversal of repression (ie, by removal of mechanisms that may reduce CYP3A expression such as inflammation).A critical factor in 4βHC use is an understanding of how consistently 4βHC plasma levels change in response to weak, moderate, and strong CYP3A inducers.3 In this regard, results from 6 recent studies suggest an emerging trend. [1][2][3][4][5][6] In drug development, establishing DDI potential for a drug coadministered with CYP3A enzyme inducers commonly involves determining drug exposure before and after dosing with a known strong inducer such as rifampicin.Accordingly a typical clinical DDI study would use the inducer rifampicin (RIF, 600 mg, repeated daily dosing for 14 days) to establish a maximum induction response. The maximum fold change in 4βHC levels can be established under the same conditions, before and after induction.1,3 But understanding the effects of moderate or weak CYP3A induction is also needed. Such information exists in reports of changes in 4βHC plasma concentrations in response to RIF daily doses of 10, 20, 100, and 500 mg (14 days), with these lesser doses of RIF as surrogates for low to moderate inducers.2,4 Together, using available published data, 1-6 these 4βHC changes allow one to establish an empirical relationship of RIF dose to 4βHC (left Y-axis) as shown in Figure 1. This relationship seems well described using a simple E max model (eg, E = 1 + E max × Dose/[ED50 + Dose], with E max = 3.55 [fold increase over baseline] and ED50 = 127 mg, r 2 = 0.90; E max is the maximum effect, and ED50 is the dose producing 50% of this maximum effect).An additional benchmark of the consequence of CYP3A induction (or inhibition) in the clinic is the corresponding change produced in...

A Physiologically-Based Pharmacokinetic Modeling Approach To Predict Drug–Drug Interactions of Sonidegib (LDE225) with Perpetrators of CYP3A in Cancer Patients

“…The CYP3A activity biomarkers, plasma 4bHC and urinary 6bCR, were included as exploratory tools to further our understanding on what changes to expect in the presence of a strong inhibitor/inducer. The 3.6-fold increase in plasma 4bHC by rifampicin after 14 days of dosing in our study is consistent with the model-predicted increases for a strong CYP3A inducer, as described in an earlier publication (Mangold et al, 2016). Based on the biomarker measurement, minimal to no effect of single dose of sonidegib on CYP3A4 activity was observed.…”

Simultaneous Physiologically Based Pharmacokinetic (PBPK) Modeling of Parent and Active Metabolites to Investigate Complex CYP3A4 Drug-Drug Interaction Potential: A Case Example of Midostaurin

“…The net effect was an increase in observed 4bHC, suggesting CYP3A4 induction. Based on the relationships among midazolam AUC GMR, rifampicin dose, and plasma 4bHC level, a framework has been developed recently to classify the CYP3A4 inducer potencies of new chemical entities after 14 days of dosing (Mangold et al, 2016). Using this framework (although not accepted currently by regulatory authorities) and considering the observed increase in plasma 4bHC in our study (maximal 2-fold increase), midostaurin (100 mg twice daily for 28 days) could be viewed as a moderate CYP3A4 inducer in the worst-case scenario.…”

Drug‐Drug Interactions With the Hepatitis B Virus Capsid Assembly Modulator JNJ‐56136379 (Bersacapavir)

“…The increase in mean 4‐β‐OH‐cholesterol level was observed after repeated dosing of JNJ‐56136379 and confirmed the potential for CYP3A4 induction, as has been observed in nonclinical experiments. 10 , 11 The changes in exposure to midazolam appeared to be more consistent, confirming its value as an exogenous marker of CYP3A4 induction.…”