Physiologically‐based pharmacokinetic modelling of a CYP2C19 substrate, BMS‐823778, utilizing pharmacogenetic data

Gong, Jiachang; Iacono, Lisa; Iyer, Ramaswamy A.; Humphreys, W. Griffith; Zheng, Ming

doi:10.1111/bcp.13565

Cited by 11 publications

(7 citation statements)

References 35 publications

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“…49 ■ CASE SERIES 1: RENAL FILTRATION/EXCRETION AND RTR An example where there is a clear renal reabsorption process is with the disposition of BMS-823778 (Figure 2 and Table 2), an 11-β-hydroxysteriod dehydrogenase 1 inhibitor to treat diabetes. 68,69 BMS-823778 is directly conjugated by UGT1A4 and hydroxylated by CYP2C19. However, neither of those enzymes are expressed in kidney tissue, 70 so there is low probability for any renal metabolic clearance.…”

Section: ■ Drug Recycling Mechanismsmentioning

confidence: 99%

Intestinal Excretion, Intestinal Recirculation, and Renal Tubule Reabsorption Are Underappreciated Mechanisms That Drive the Distribution and Pharmacokinetic Behavior of Small Molecule Drugs

Zhang¹,

Wei

Hop³

et al. 2021

J. Med. Chem.

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Drug reabsorption following biliary excretion is well-known as enterohepatic recirculation (EHR). Renal tubular reabsorption (RTR) following renal excretion is also common but not easily assessed. Intestinal excretion (IE) and enteroenteric recirculation (EER) have not been recognized as common disposition mechanisms for metabolically stable and permeable drugs. IE and intestinal reabsorption (IR:EHR/EER), as well as RTR, are governed by dug concentration gradients, passive diffusion, active transport, and metabolism, and together they markedly impact disposition and pharmacokinetics (PK) of small molecule drugs. Disruption of IE, IR, or RTR through applications of active charcoal (AC), transporter knockout (KO), and transporter inhibitors can lead to changes in PK parameters. The impacts of intestinal and renal reabsorption on PK are under-appreciated. Although IE and EER/RTR can be an intrinsic drug property, there is no apparent strategy to optimize compounds based on this property. This review seeks to improve understanding and applications of IE, IR, and RTR mechanisms.

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Section: ■ Drug Recycling Mechanismsmentioning

confidence: 99%

Intestinal Excretion, Intestinal Recirculation, and Renal Tubule Reabsorption Are Underappreciated Mechanisms That Drive the Distribution and Pharmacokinetic Behavior of Small Molecule Drugs

Zhang¹,

Wei

Hop³

et al. 2021

J. Med. Chem.

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“…This approach has been reported by three other recent PBPK analyses of CYP2C19 substrates (lansoprazole, escitalopram, voriconazole, tofacitinib omeprazole 33‐35 ), which have also applied the European CYP2C19 liver abundance values to Japanese populations. Other PBPK models of CYP2C19 substrates have used different CYP2C19 liver abundance values (EMs, 4.7 pmol/mg protein, 4 8 pmol/mg protein 49 ) to obtain better pharmacokinetic predictions for the Japanese population. In Simcyp Version 18.2, the mean CYP2C19 liver abundance value for EMs in the Japanese population (4.1 pmol/mg protein) was based on data obtained from a small sample of livers ( n = 29) of unspecified CYP2C19 genotype 50 …”

Section: Discussionmentioning

confidence: 99%

A physiologically based pharmacokinetic model of clopidogrel in populations of European and Japanese ancestry: An evaluation of CYP2C19 activity

Duong

Nand

Patel

et al. 2022

Pharmacology Res & Perspec

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Treatment response to clopidogrel is associated with CYP2C19 activity through the formation of the active H4 metabolite. The aims of this study were to develop a physiologically based pharmacokinetic (PBPK) model of clopidogrel and its metabolites for populations of European ancestry, to predict the pharmacokinetics in the Japanese population by CYP2C19 phenotype, and to investigate the effect of clinical and demographic factors. A PBPK model was developed and verified to describe the two metabolic pathways of clopidogrel (H4 metabolite, acyl glucuronide metabolite) for a population of European ancestry using plasma data from published studies. Subsequently, model predictions in the Japanese population were evaluated. The effects of CYP2C19 activity, fluvoxamine coadministration (CYP2C19 inhibitor), and population‐specific factors (age, sex, BMI, body weight, cancer, hepatic, and renal dysfunction) on the pharmacokinetics of clopidogrel and its metabolites were then characterized. The predicted/observed ratios for clopidogrel and metabolite exposure parameters were acceptable (twofold acceptance criteria). For all CYP2C19 phenotypes, steady‐state AUC0‐τ of the H4 metabolite was lower for the Japanese (e.g., EM, 7.69 [6.26–9.45] ng·h/ml; geometric mean [95% CI]) than European (EM, 24.8 [20.4–30.1] ng·h/ml, p < .001) population. In addition to CYP2C19‐poor metabolizer phenotype, fluvoxamine coadministration, hepatic, and renal dysfunction were found to reduce H4 metabolite but not acyl glucuronide metabolite concentrations. This is the first PBPK model describing the two major metabolic pathways of clopidogrel, which can be applied to populations of European and Japanese ancestry by CYP2C19 phenotype. The differences between the two populations appear to be determined primarily by the effect of varying CYP2C19 liver activity.

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“…Similarly, Gong et al addressed, with a hybrid bottom-up and top-down full PBPK model, the case of BMS-823778, a potent and selective inhibitor of a microsomal enzyme regulating the tissue concentration of biologically active cortisol (Gong et al, 2018). In vitro permeability of BMS-823778 was determined in a Caco-2 cell bi-directional permeability assay and effective permeability was predicted with a Simcyp built-in algorithm based on in vitro Caco-2 permeability results.…”

Section: Discussionmentioning

confidence: 99%

Reviewing Data Integrated for PBPK Model Development to Predict Metabolic Drug-Drug Interactions: Shifting Perspectives and Emerging Trends

et al. 2021

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Physiologically-based pharmacokinetics (PBPK) modeling is a robust tool that supports drug development and the pharmaceutical industry and regulatory authorities. Implementation of predictive systems in the clinics is more than ever a reality, resulting in a surge of interest for PBPK models by clinicians. We aimed to establish a repository of available PBPK models developed to date to predict drug-drug interactions (DDIs) in the different therapeutic areas by integrating intrinsic and extrinsic factors such as genetic polymorphisms of the cytochromes or environmental clues. This work includes peer-reviewed publications and models developed in the literature from October 2017 to January 2021. Information about the software, type of model, size, and population model was extracted for each article. In general, modeling was mainly done for DDI prediction via Simcyp® software and Full PBPK. Overall, the necessary physiological and physio-pathological parameters, such as weight, BMI, liver or kidney function, relative to the drug absorption, distribution, metabolism, and elimination and to the population studied for model construction was publicly available. Of the 46 articles, 32 sensibly predicted DDI potentials, but only 23% integrated the genetic aspect to the developed models. Marked differences in concentration time profiles and maximum plasma concentration could be explained by the significant precision of the input parameters such as Tissue: plasma partition coefficients, protein abundance, or Ki values. In conclusion, the models show a good correlation between the predicted and observed plasma concentration values. These correlations are all the more pronounced as the model is rich in data representative of the population and the molecule in question. PBPK for DDI prediction is a promising approach in clinical, and harmonization of clearance prediction may be helped by a consensus on selecting the best data to use for PBPK model development.

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Physiologically‐based pharmacokinetic modelling of a CYP2C19 substrate, BMS‐823778, utilizing pharmacogenetic data

Cited by 11 publications

References 35 publications

Intestinal Excretion, Intestinal Recirculation, and Renal Tubule Reabsorption Are Underappreciated Mechanisms That Drive the Distribution and Pharmacokinetic Behavior of Small Molecule Drugs

Intestinal Excretion, Intestinal Recirculation, and Renal Tubule Reabsorption Are Underappreciated Mechanisms That Drive the Distribution and Pharmacokinetic Behavior of Small Molecule Drugs

A physiologically based pharmacokinetic model of clopidogrel in populations of European and Japanese ancestry: An evaluation of CYP2C19 activity

Reviewing Data Integrated for PBPK Model Development to Predict Metabolic Drug-Drug Interactions: Shifting Perspectives and Emerging Trends

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