Evaluation of 4β‐Hydroxycholesterol as a Clinical Biomarker of CYP3A4 Drug Interactions Using a Bayesian Mechanism–Based Pharmacometric Model

Leil, Tarek A.; Kasichayanula, Sreeneeranj; Dw, Boulton; LaCreta, Frank

doi:10.1038/psp.2014.18

Cited by 28 publications

(34 citation statements)

References 24 publications

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“…It is sensitive to induction of both CYP3A4 and CYP3A5. These attributes make 4b-hydroxycholesterol suitable as a marker for CYP3A induction but not for single dose studies investigating CYP3A inhibition (Leil et al, 2014). Gut CYP3A is likely to have minimal impact on the circulating concentrations of 4b-hydroxycholesterol, and hence the large dynamic range observed with midazolam because significant first-pass metabolism will not be observed.…”

Section: B-hydroxycholesterol Clinical Biomarker Assessmentmentioning

confidence: 99%

Managing the Risk of CYP3A Induction in Drug Development: A Strategic Approach

et al. 2016

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Induction of cytochrome P450 (P450) can impact the efficacy and safety of drug molecules upon multiple dosing with coadministered drugs. This strategy is focused on CYP3A since the majority of clinically relevant cases of P450 induction are related to these enzymes. However, the in vitro evaluation of induction is applicable to other P450 enzymes; however, the in vivo relevance cannot be assessed because the scarcity of relevant clinical data. In the preclinical phase, compounds are screened using pregnane X receptor reporter gene assay, and if necessary structure-activity relationships (SAR) are developed. When projects progress toward the clinical phase, induction studies in a hepatocyte-derived model using HepaRG cells will generate enough robust data to assess the compound's induction liability in vivo. The sensitive CYP3A biomarker 4β-hydroxycholesterol is built into the early clinical phase I studies for all candidates since rare cases of in vivo induction have been found without any induction alerts from the currently used in vitro methods. Using this model, the AstraZeneca induction strategy integrates in vitro assays and in vivo studies to make a comprehensive assessment of the induction potential of new chemical entities. Convincing data that support the validity of both the in vitro models and the use of the biomarker can be found in the scientific literature. However, regulatory authorities recommend the use of primary human hepatocytes and do not advise the use of sensitive biomarkers. Therefore, primary human hepatocytes and midazolam studies will be conducted during the clinical program as required for regulatory submission.

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Section: B-hydroxycholesterol Clinical Biomarker Assessmentmentioning

confidence: 99%

Managing the Risk of CYP3A Induction in Drug Development: A Strategic Approach

et al. 2016

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“…Acknowledging the limited number of data points and use of mean data without interindividual variability, this composite (E max ‐I max ) model appears to form the basis for a reasonable induction potency‐biomarker correlation. This relationship has been noted by others and has been characterized using various modeling approaches, including Bayesian mechanism–based pharmacokinetic/pharmacodynamic (PK/PD) modeling and a population PK/PD model . For example, Jiang et al built a population PK/PD model using rifampicin concentrations (PK) and biomarker (PD) after 14 days of rifampicin dosing data and utilized it for predicting the increases in plasma 4βHC under the conditions of weak, moderate, and strong induction by using 10‐, 20‐, and 100‐mg rifampicin doses.…”

Section: Inducer Classification and Corresponding Model‐predicted 4βhmentioning

confidence: 99%

“…For example, Jiang et al built a population PK/PD model using rifampicin concentrations (PK) and biomarker (PD) after 14 days of rifampicin dosing data and utilized it for predicting the increases in plasma 4βHC under the conditions of weak, moderate, and strong induction by using 10‐, 20‐, and 100‐mg rifampicin doses. On the other hand, Leil et al developed a Bayesian mechanism–based PK/PD model based on a clinical study of the effects of ketoconazole and rifampicin on midazolam exposure and 4βHC concentrations. Interestingly, the basic classifications in terms of conclusions regarding inducer strength relative to the changes in plasma 4βHC derived from the current simple E max ‐I max model are very much in line with those obtained using far more elaborate and complex modeling approaches, as summarized in Table .…”

Section: Inducer Classification and Corresponding Model‐predicted 4βhmentioning

confidence: 99%

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

Mangold¹,

Wu²,

Rebello³

2016

Clinical Pharm in Drug Dev

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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...

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“…4βHC has been proposed as a potential endogenous biomarker for CYP3A activity in multiple species, including human [23][24][25]. For several reasons, developing bioanalytical assays for 4βHC is challenging.…”

Section: Key Termsmentioning

confidence: 99%

2017 White Paper on Recent Issues in Bioanalysis: Aren’t Bmv Guidance/Guidelines ‘ Scientific ’? (Part 1 – LCMS: Small Molecules, Peptides and Small Molecule Biomarkers)

Welink¹,

Yang

Hughes³

et al. 2017

Bioanalysis

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The 2017 11th Workshop on Recent Issues in Bioanalysis (11th WRIB) took place in Los Angeles/Universal City, California from 3 April 2017 to 7 April 2017 with participation of close to 750 professionals from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. WRIB was once again a 5-day, weeklong event – A Full Immersion Week of Bioanalysis, Biomarkers and Immunogenicity. As usual, it was specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small and large molecule analysis involving LCMS, hybrid LBA/LCMS and ligand-binding assay (LBA) approaches. This 2017 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2017 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 1) covers the recommendations for Small Molecules, Peptides and Small Molecule Biomarkers using LCMS. Part 2 (Biotherapeutics, Biomarkers and Immunogenicity Assays using Hybrid LBA/LCMS and Regulatory Agencies’ Inputs) and Part 3 (LBA: Immunogenicity, Biomarkers and PK Assays) are published in volume 9 of Bioanalysis, issues 23 and 24 (2017), respectively.

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Evaluation of 4β‐Hydroxycholesterol as a Clinical Biomarker of CYP3A4 Drug Interactions Using a Bayesian Mechanism–Based Pharmacometric Model

Cited by 28 publications

References 24 publications

Managing the Risk of CYP3A Induction in Drug Development: A Strategic Approach

Managing the Risk of CYP3A Induction in Drug Development: A Strategic Approach

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

2017 White Paper on Recent Issues in Bioanalysis: Aren’t Bmv Guidance/Guidelines ‘ Scientific ’? (Part 1 – LCMS: Small Molecules, Peptides and Small Molecule Biomarkers)

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