Identification of ω‐ or (ω‐1)‐Hydroxylated Medium‐Chain Acylcarnitines as Novel Urinary Biomarkers for CYP3A Activity

Kim, Bora; Lee, Jieon; Shin, Kye Chul; Lee, Seung Hwan; Yu, Kyung‐Sang; Jang, In Jin; Cho, Joo Youn

doi:10.1002/cpt.856

Cited by 12 publications

(13 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, could the addition of an orthogonal measure of CYP3A activity, such as a biomarker, provide additional insights into the magnitude of response or would that additional measurement of changes in CYP3A activity simply exhibit its own independent variability and complicate rather than deconvolute? There have been a number of endogenous and exogenous markers of CYP3A activity evaluated over the years, such as the erythromycin breath test (Watkins et al, 1989), 6b-hydroxycortisol (and the ratio to cortisol) (Ged et al, 1989), 4b-hydroxycholesterol (Mao et al, 2017), quinine (Wanwimolruk et al, 2002), and more recently v or v-1 hydroxylated medium chain acylcarnitines (Kim et al, 2018). All have had mixed success and limitations.…”

Section: Contributors To the Overall Variability Observed In Clinicalmentioning

confidence: 99%

Perspectives from the Innovation and Quality Consortium Induction Working Group on Factors Impacting Clinical Drug-Drug Interactions Resulting from Induction: Focus on Cytochrome 3A Substrates

et al. 2019

View full text Add to dashboard Cite

A recent publication from the Innovation and Quality Consortium Induction Working Group collated a large clinical data set with the goal of evaluating the accuracy of drug-drug interaction (DDI) prediction from in vitro data. Somewhat surprisingly, comparison across studies of the mean-or median-reported area under the curve ratio showed appreciable variability in the magnitude of outcome. This commentary explores the possible drivers of this range of outcomes observed in clinical induction studies. While recommendations on clinical study design are not being proposed, some key observations were informative during the aggregate analysis of clinical data. Although DDI data are often presented using median data, individual data would enable evaluation of how differences in study design, baseline expression, and the number of subjects contribute. Since variability in perpetrator pharmacokinetics (PK) could impact the overall DDI interpretation, should this be routinely captured? Maximal induction was typically observed after 5-7 days of dosing. Thus, when the half-life of the inducer is less than 30 hours, are there benefits to a more standardized study design? A large proportion of CYP3A4 inducers were also CYP3A4 inhibitors and/or inactivators based on in vitro data. In these cases, using CYP3A selective substrates has limitations. More intensive monitoring of changes in area under the curve over time is warranted. With selective CYP3A substrates, the net effect was often inhibition, whereas less selective substrates could discern induction through mechanisms not susceptible to inhibition. The latter included oral contraceptives, which raise concerns of reduced efficacy following induction. Alternative approaches for modeling induction, such as applying biomarkers and physiologically based pharmacokinetic modeling (PBPK), are also considered. SIGNIFICANCE STATEMENT The goal of this commentary is to stimulate discussion on whether there are opportunities to optimize clinical drug-drug interaction study design. The overall aim is to reduce, understand and contextualize the variability observed in the magnitude of induction across reported clinical studies. A large clinical CYP3A induction dataset was collected and further analyzed to identify trends and gaps. Reporting individual victim PK data, characterizing perpetrator PK and including additional PK assessments for mixed-mechanism perpetrators may provide insights into how these factors impact differences observed in clinical outcomes. The potential utility of biomarkers and PBPK modeling are discussed in considering future directions.

show abstract

Section: Contributors To the Overall Variability Observed In Clinicalmentioning

confidence: 99%

Perspectives from the Innovation and Quality Consortium Induction Working Group on Factors Impacting Clinical Drug-Drug Interactions Resulting from Induction: Focus on Cytochrome 3A Substrates

et al. 2019

View full text Add to dashboard Cite

show abstract

“…However, the long half-life of 4β-hydroxycholesterol resulted in limitations to assess the short-term CYP3A inhibition status (Diczfalusy et al, 2011;Kasichayanula et al, 2014). Due to the limited predictive capability of single biomarker, recent works tried to develop combinatory biomarkers based on bioinformatic tools (Shin et al, 2013;Kim et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Tertiary Oxidation of Deoxycholate Is Predictive of CYP3A Activity in Dogs

et al. 2021

View full text Add to dashboard Cite

Deoxycholate (DCA) is the major circulating secondary bile acid (BA), which is synthesized by gut flora in lower gut and selectively oxidized by CYP3A into tertiary metabolites including DCA-1β-ol and DCA-5β-ol in human. Since DCA has the similar "exogenous" nature and disposition mechanisms as xenobiotics, this work aimed to investigate whether the tertiary oxidations of DCA are predictive of in vivo CYP3A activities in beagle dogs. In vitro metabolism of midazolam (MDZ) and DCA in recombinant canine CYP1A1, 1A2, 2B11, 2C21, 2C41, 2D15, 3A12, 3A26 enzymes clarified that CYP3A12 was primarily responsible for either the oxidation elimination of MDZ or the regioselective oxidation metabolism of DCA into DCA-1β-ol and DCA-5β-ol in dog liver microsomes. Six male dogs completed the CYP3A intervention studies including phases of baseline, inhibition (ketoconazole treatments), recovery and induction (rifampicin treatments). The oral MDZ clearance after a single dose was determined on the last day of the baseline, inhibition and induction phases, and subjected to correlation analysis with the tertiary oxidation ratios of DCA detected in serum and urine samples. The results confirmed that the pre-dosing serum ratios of DCA oxidation, DCA-5β-ol/DCA and DCA-1β-ol/DCA, were significantly and positively correlated both intra-individually and inter-individually with oral MDZ clearance. It was therefore concluded that the tertiary oxidation of DCA is predictive of CYP3A activity in beagle dogs. Clinical transitional studies following the preclinical evidence are promising to provide novel biomarkers of the enterohepatic CYP3A activities.

show abstract

“…Pharmacogenomics is used in clinical trials to select appropriate patients and to further explain pharmacokinetics, pharmacodynamics, efficacy, and adverse drug reactions of new drug candidates [ 6 – 8 ]. Pharmacometabolomics can be used in clinical trials to identify drug targets, diagnosis disease, assess drug metabolic enzyme function in humans, and monitor the drug response and toxicity [ 9 – 13 ]. The importance of those evaluations is high in early phase clinical trials because it can help to simplify late phase clinical trials and increase the probability of success of clinical trials [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Utility of Integrated Analysis of Pharmacogenomics and Pharmacometabolomics in Early Phase Clinical Trial: A Case Study of a New Molecular Entity

et al. 2018

Genomics Inform

Self Cite

View full text Add to dashboard Cite

In this report, we present a case study of how pharmacogenomics and pharmacometabolomics can be useful to characterize safety and pharmacokinetic profiles in early phase new drug development clinical trials. During conducting a first-in-human trial for a new molecular entity, we were able to determine the mechanism of dichotomized variability in plasma drug concentrations, which appeared closely related to adverse drug reactions (ADRs) through integrated omics analysis. The pharmacogenomics screening was performed from whole blood samples using the Affymetrix DMET (Drug-Metabolizing Enzymes and Transporters) Plus microarray, and confirmation of genetic variants was performed using real-time polymerase chain reaction. Metabolomics profiling was performed from plasma samples using liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. A GSTM1 null polymorphism was identified in pharmacogenomics test and the drug concentrations was higher in GSTM1 null subjects than GSTM1 functional subjects. The apparent drug clearance was 13-fold lower in GSTM1 null subjects than GSTM1 functional subjects (p < 0.001). By metabolomics analysis, we identified that the study drug was metabolized by cysteinylglycine conjugation in GSTM functional subjects but those not in GSTM1 null subjects. The incidence rate and the severity of ADRs were higher in the GSTM1 null subjects than the GSTM1 functional subjects. Through the integrated omics analysis, we could understand the mechanism of inter-individual variability in drug exposure and in adverse response. In conclusion, integrated multi-omics analysis can be useful for elucidating the various characteristics of new drug candidates in early phase clinical trials.

show abstract

Identification of ω‐ or (ω‐1)‐Hydroxylated Medium‐Chain Acylcarnitines as Novel Urinary Biomarkers for CYP3A Activity

Cited by 12 publications

References 30 publications

Perspectives from the Innovation and Quality Consortium Induction Working Group on Factors Impacting Clinical Drug-Drug Interactions Resulting from Induction: Focus on Cytochrome 3A Substrates

Perspectives from the Innovation and Quality Consortium Induction Working Group on Factors Impacting Clinical Drug-Drug Interactions Resulting from Induction: Focus on Cytochrome 3A Substrates

Tertiary Oxidation of Deoxycholate Is Predictive of CYP3A Activity in Dogs

Utility of Integrated Analysis of Pharmacogenomics and Pharmacometabolomics in Early Phase Clinical Trial: A Case Study of a New Molecular Entity

Contact Info

Product

Resources

About