Physiologically Based Pharmacokinetic Modeling Approach to Identify the Drug–Drug Interaction Mechanism of Nifedipine and a Proton Pump Inhibitor, Omeprazole

Merdy, Maxime Le; Tan, Ming‐Liang; Sun, Dajun; Ni, Zhanglin; Lee, Sue‐Chih; Babiskin, Andrew; Zhao, Liang

doi:10.1007/s13318-020-00649-x

Cited by 9 publications

(28 citation statements)

References 26 publications

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“…24 We adapted an existing model by changing the Cl R as it was assumed that 5-OH-omeprazole Cl R was the same as that of omeprazole. 25 This new 5-OH-omeprazole plasma concentration is consistent with data observed in the literature. 19 Esomeprazole is a well-known CYP2C19 inhibitor that was systematically prescribed in our cohort study to prevent the occurrence of stress ulcer, although we would have liked to exclude all CYP modulators.…”

Section: Discussionsupporting

confidence: 91%

“…24 We used a previously published and validated model as the basis for implementing this metabolite in our PBPK model. 25 However, the renal clearance (Cl R ) was changed from 0.037 to 0 L/h to be consistent with that of the built-in library model of omeprazole (Table 1).…”

Section: Modeling Of Omeprazole Metabolitementioning

confidence: 56%

“…A previously developed and validated PBPK model was used for esomeprazole, the S-isomer of omeprazole (Table 2). 25 This published model considered that T A B L E 1 Parameters for omeprazole and 5-OH-OMPZ esomeprazole was both a reversible and irreversible inhibitor of CYP2C19 and CYP3A4, even though its effect on CYP3A4 is not usually considered relevant in clinical practice. 8,26,27 Published data indeed suggest a short-term effect of esomeprazole on midazolam concentration but no irreversible CYP3A inhibition, even with twice the dose used for the current simulation.…”

Section: Modeling Of Esomeprazolementioning

confidence: 99%

“…19 The esomeprazole model also needed to be validated as a previously validated model was modified. 25 We extracted the concentration-time profile of esomeprazole from one study with the same dose used in the cohort study to obtain observational data. 34 PK parameters were estimated by standard noncompartmental methods using WinNonlin Version 6.2.1 (Pharsight) and by Simcyp TM .…”

Section: Development and Validation Of Pbpk Model To Simulate The Interaction Between Inflammation (Il-6) And Cyp3a And Cyp2c19 Substratementioning

confidence: 99%

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Prediction of cytochromes P450 3A and 2C19 modulation by both inflammation and drug interactions using physiologically based pharmacokinetics

Lenoir

Niederer

Rollason

et al. 2021

CPT Pharmacom & Syst Pharma

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Xenobiotics can interact with cytochromes P450 (CYPs), resulting in drug-drug interactions, but CYPs can also contribute to drug-disease interactions, especially in the case of inflammation, which downregulates CYP activities through pretranscriptional and posttranscriptional mechanisms. Interleukin-6 (IL-6), a key proinflammatory cytokine, is mainly responsible for this effect. The aim of our study was to develop a physiologically based pharmacokinetic (PBPK) model to foresee the impact of elevated IL-6 levels in combination with drug interactions with esomeprazole on CYP3A and CYP2C19. Data from a cohort of elective hip surgery patients whose CYP3A and CYP2C19 activities were measured before and after surgery were used to validate the accurate prediction of the developed models. Successive steps were to fit models for IL-6, esomeprazole, and omeprazole and its metabolite from the literature and to validate them. The models for midazolam and its metabolite were obtained from the literature. When appropriate, a correction factor was applied to convert drug concentrations from whole blood to plasma. Mean ratios between simulated and observed areas under the curve for omeprazole/5-hydroxy omeprazole, esomeprazole, and IL-6 were 1.53, 1.06, and 0.69, respectively, indicating an accurate prediction of the developed models. The impact of IL-6 and esomeprazole on the exposure to CYP3A and CYP2C19 probe substrates and respective metabolites were correctly predicted. Indeed, the ratio between predicted and observed mean concentrations were <2 for all observations (ranging from 0.51 to 1.7).The impact of IL-6 and esomeprazole on CYP3A and CYP2C19 activities after a hip surgery were correctly predicted with the developed PBPK models. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?There is high interindividual variability in cytochrome P450 (CYP) activities due to genetic, environmental, and physiological factors, including drug-drug and | 31

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Section: Discussionsupporting

confidence: 91%

Section: Modeling Of Omeprazole Metabolitementioning

confidence: 56%

Section: Modeling Of Esomeprazolementioning

confidence: 99%

Section: Development and Validation Of Pbpk Model To Simulate The Interaction Between Inflammation (Il-6) And Cyp3a And Cyp2c19 Substratementioning

confidence: 99%

See 2 more Smart Citations

Prediction of cytochromes P450 3A and 2C19 modulation by both inflammation and drug interactions using physiologically based pharmacokinetics

Lenoir

Niederer

Rollason

et al. 2021

CPT Pharmacom & Syst Pharma

View full text Add to dashboard Cite

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“…NSAID-induced ulcers are a side effect of NSAIDs that cannot be ignored. Proton pump inhibitors (PPIs) and prostaglandin (PG) analogs are often used to treat NSAID-induced ulcers [3], but their side effects [4][5][6][7][8][9] and drug interactions with other medications [10][11][12][13][14] are a concern.…”

Section: Introductionmentioning

confidence: 99%

Gastroprotective Effect of Enteral Nutrition Formula in Mice Injected Subcutaneously with Indomethacin

et al. 2021

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We have previously shown that two enteral nutrition formulas suppressed gastric lesions induced by the oral administration of indomethacin (IND) in mice. However, the mechanism of their protective effect is unknown. In this study, the effect of the two enteral nutrition formulas on gastric lesions induced by subcutaneous IND injection was investigated, with the objective of exploring the possibility that they may interact directly with IND in the gastrointestinal tract. Ten-week-old, male, ICR mice were fasted, then orally given either purified water, Mermed® One, or 2-fold diluted Terumeal® 2.0α as enteral nutrition formula (25 mL/kg). IND was injected subcutaneously at 20 mg/kg after 30 min, and the stomach was removed 6 h later and fixed in formalin. The number and area of lesions in the stomachs of mice given enteral nutrition formula was reduced to 56–89% and 34–61%, respectively, compared with the mice given purified water. The time courses of plasma IND concentrations were comparable among the three groups. These results suggested that the effect of these enteral nutrition formulas on gastric lesions did not originate from their direct interaction with IND in the gastrointestinal tract or their effect on the disposition of IND.

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Use of Modeling and Simulation to Predict the Influence of Triazole Antifungal Agents on the Pharmacokinetics of Crizotinib

Chen

2022

Clinical Pharm in Drug Dev

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Crizotinib is used for the treatment of c-ros oncogene 1-positive advanced non-small-cell lung cancer. Triazole antifungal agents are widely used for invasive fungal infections in clinical practice. To predict the potential influence of different triazoles (voriconazole, fluconazole, and itraconazole) on the pharmacokinetics of crizotinib by modeling and simulation the physiologically based pharmacokinetic models were established and validated in virtual cancer subjects through Simcyp software based on the essential physicochemical properties and pharmacokinetic data collected. The validated physiologically based pharmacokinetic models were applied to predict the drug-drug interactions between crizotinib and different triazoles (voriconazole, fluconazole, or itraconazole) in patients with cancer. Crizotinib and triazole antifungal agents were administered orally. The predicted plasma concentration vs time profiles of crizotinib, voriconazole, fluconazole, and itraconazole showed good agreement with observed, respectively. The geometric mean area under the plasma concentration-time curve (AUC) of crizotinib was increased by 84%, 58%, and 79% when coadministered with voriconazole, fluconazole, or itraconazole at multiple doses, respectively. The drug-drug interaction results showed increased pharmacokinetic exposure (maximum plasma concentration and area under the plasma concentration-time curve) of crizotinib when coadministrated with different triazoles (voriconazole > itraconazole > fluconazole). Among the 3 triazoles, voriconazole exhibited the most significant influence on the pharmacokinetic exposure of crizotinib. In clinic, adverse drug reactions and toxicity related to crizotinib should be carefully monitored, and therapeutic drug monitoring for crizotinib is recommended to guide dosing and optimize treatment when coadministered with voriconazole, fluconazole, or itraconazole.

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Physiologically Based Pharmacokinetic Modeling Approach to Identify the Drug–Drug Interaction Mechanism of Nifedipine and a Proton Pump Inhibitor, Omeprazole

Cited by 9 publications

References 26 publications

Prediction of cytochromes P450 3A and 2C19 modulation by both inflammation and drug interactions using physiologically based pharmacokinetics

Prediction of cytochromes P450 3A and 2C19 modulation by both inflammation and drug interactions using physiologically based pharmacokinetics

Gastroprotective Effect of Enteral Nutrition Formula in Mice Injected Subcutaneously with Indomethacin

Use of Modeling and Simulation to Predict the Influence of Triazole Antifungal Agents on the Pharmacokinetics of Crizotinib

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