Performance Verification of CYP2C19 Enzyme Abundance Polymorphism Settings within the Simcyp Simulator v21

Sychterz, Caroline; Gardner, Iain; Chiang, Manting; Rachumallu, Ramakrishna; Perera, Vidya; Garonzik, Samira M.; Schmidt, Benjamin; Gaohua, Lu

doi:10.3390/metabo12101001

Cited by 7 publications

(2 citation statements)

References 54 publications

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“…PBPK studies on antineoplastic and immunomodulatory drugs were the most important topics of concern in this area, followed by studies on cardiovascular and anti-infective drugs [ 59 ]. Models for specific products such as herbal products, therapeutic protein drugs, and antibody–drug conjugates were also described [ 60 ]. Most PBPK research focused on simulating cytochrome P450 (CYP)-mediated DDIs [ 61 ], whereas some were used on transporter-mediated DDIs or a combination of CYP and transporter-mediated DDIs [ 62 ].…”

Section: Application In Medical Fieldmentioning

confidence: 99%

Recent Progress on Physiologically Based Pharmacokinetic (PBPK) Model: A Review Based on Bibliometrics

Huang,

Zhao,

Qin

et al. 2024

Toxics

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Physiologically based pharmacokinetic/toxicokinetic (PBPK/PBTK) models are designed to elucidate the mechanism of chemical compound action in organisms based on the physiological, biochemical, anatomical, and thermodynamic properties of organisms. After nearly a century of research and practice, good results have been achieved in the fields of medicine, environmental science, and ecology. However, there is currently a lack of a more systematic review of progress in the main research directions of PBPK models, especially a more comprehensive understanding of the application in aquatic environmental research. In this review, a total of 3974 articles related to PBPK models from 1996 to 24 March 2024 were collected. Then, the main research areas of the PBPK model were categorized based on the keyword co-occurrence maps and cluster maps obtained by CiteSpace. The results showed that research related to medicine is the main application area of PBPK. Four major research directions included in the medical field were “drug assessment”, “cross-species prediction”, “drug–drug interactions”, and “pediatrics and pregnancy drug development”, in which “drug assessment” accounted for 55% of the total publication volume. In addition, bibliometric analyses indicated a rapid growth trend in the application in the field of environmental research, especially in predicting the residual levels in organisms and revealing the relationship between internal and external exposure. Despite facing the limitation of insufficient species-specific parameters, the PBPK model is still an effective tool for improving the understanding of chemical–biological effectiveness and will provide a theoretical basis for accurately assessing potential risks to ecosystems and human health. The combination with the quantitative structure–activity relationship model, Bayesian method, and machine learning technology are potential solutions to the previous research gaps.

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Section: Application In Medical Fieldmentioning

confidence: 99%

Recent Progress on Physiologically Based Pharmacokinetic (PBPK) Model: A Review Based on Bibliometrics

Huang,

Zhao,

Qin

et al. 2024

Toxics

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“…Omeprazole has been combined with antibiotics such as amoxicillin and clarithromycin to eradicate helicobacter pylori 8 . The main metabolizing enzyme of omeprazole is CYP2C19 9 , and the factors affecting the activity of CYP2C19 include age 9 , medications 10 , etc., which may also influence the metabolism of omeprazole, causing changes in area under curve (AUC) and its activity. The abnormality of the CYP2C19 coding gene is the most crucial and researched pharmacogenetic factor affecting the clearance of omeprazole and its efficacy 10 , 11 .…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and bioequivalence evaluation of omeprazole and sodium bicarbonate dry suspensions in healthy Chinese volunteers

Zhang

Guo

Zhou

et al. 2023

Sci Rep

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Omeprazole and sodium bicarbonate dry suspension are effective treatments for acid-related disorders. This study compared the bioequivalence and safety of the two formulations of omeprazole and sodium bicarbonate powder and assessed how CYP2C19 gene polymorphisms affect pharmacokinetics (PK). A single-center, randomized, single-dose, 2-sequence and 2-period crossover method was performed in forty healthy Chinese subjects. Blood samples were collected after a single dose for PK (AUC0–∞, AUC0–t, and Cmax) analysis. The concentrations of Omeprazole in human plasma were determined by HPLC–MS/MS. Besides, the gene polymorphisms of CYP2C19 were assessed by Sanger sequencing. The geometric mean ratios (90% confidence interval) [GMR (95% CI)] of Test/Reference preparation for Cmax: 95.2% (88.48%, 102.43%), AUC0–t: 97.47% (94.4%, 101.02%), AUC0–∞: 97.68% (94.27%, 101.21%) were within the range of 80.00–125.00%. The non-parametric test showed no statistical difference in Tmax between the two groups (p > 0.05). All drugs were well tolerated, no severe adverse reactions occurred, and no significant differences in adverse events between the two drugs. For CYP2C19 gene polymorphisms, the results showed that of 40 subjects, 12 subjects were extensive metabolizers, 24 were intermediate metabolizers, and 4 were poor metabolizers, the frequency of metabolic genotypes were 30%, 60%, and 10%. And the allele distributions for CYP2C19 were *1, *2, and *3 at 60%, 38.75%, and 1.25%. Both the CYP2C19 alleles and metabolic genotypes were consistent with other studies in Chinese. The results of PK parameters showed that different genotypes of CYP2C19 lead to significant differences in t1/2, AUC0–t, AUC0–∞ and Cmax, but no significant differences in Tmax in each group. At the same time, we confirmed that the PK parameters of the test and reference had no differences between the males and females. This study has shown that the pharmacokinetic parameters of the two formulations are not significantly different, which showed bioequivalence and exemplary safety. CYP2C19 gene polymorphism significantly differed in the PK parameters of omeprazole sodium bicarbonate powder.

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Drug–Drug Interaction Potential of Mavacamten with Midazolam: Combined Results from Clinical and Model‐Based Studies

Merali,

Sychterz,

Perera

et al. 2024

The Journal of Clinical Pharma

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Mavacamten is a potential inducer of cytochrome P450 (CYP) 3A4 and could reduce the effectiveness of concomitant drugs that are metabolized by CYP3A4, such as midazolam. This study aimed to determine if repeat doses of mavacamten achieving clinically relevant exposures affected midazolam exposure. This was a single‐center, open‐label study in healthy participants. Participants received: on day 1, midazolam 5 mg; on days 2–3, mavacamten 25 mg; on days 4–16, mavacamten 15 mg; and on day 17, mavacamten 15 mg and midazolam 5 mg. Plasma concentrations of mavacamten, midazolam, and the midazolam metabolite 1′‐hydroxymidazolam were measured. A physiologically based pharmacokinetic (PBPK) model was used to simulate the effect of mavacamten‐mediated CYP3A4 induction on midazolam exposure by CYP2C19 phenotype. Thirteen adult participants were enrolled (46.2% were female; mean [SD] age: 34.0 [9.0] years). Compared with midazolam alone, midazolam coadministered with mavacamten decreased the maximum observed plasma concentration (Cmax), area under the drug concentration‐time curve (AUC) from time zero to infinity (AUC0‐inf), and AUC from time zero to last measurable concentration (AUC0‐last) for midazolam by 7%, 13%, and 24%, respectively; for 1′‐hydroxymidazolam, AUC0–inf and AUC0–last increased by 20% and 11%, respectively. Ten participants experienced adverse events and the majority were mild in severity. The PBPK model predicted the clinical trial data well. The PBPK simulation assessed that the overall impact of mavacamten on midazolam Cmax and AUC was predicted to be weak regardless of CYP2C19 phenotype. At clinically relevant exposures, mavacamten had a negligible effect on midazolam exposure.

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Performance Verification of CYP2C19 Enzyme Abundance Polymorphism Settings within the Simcyp Simulator v21

Cited by 7 publications

References 54 publications

Recent Progress on Physiologically Based Pharmacokinetic (PBPK) Model: A Review Based on Bibliometrics

Recent Progress on Physiologically Based Pharmacokinetic (PBPK) Model: A Review Based on Bibliometrics

Pharmacokinetics and bioequivalence evaluation of omeprazole and sodium bicarbonate dry suspensions in healthy Chinese volunteers

Drug–Drug Interaction Potential of Mavacamten with Midazolam: Combined Results from Clinical and Model‐Based Studies

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