Evidence map›Paper›PMID 33064292›Full record

ArticleEuropean journal of drug metabolism and pharmacokinetics2021

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

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

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Article in European journal of drug metabolism and pharmacokinetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing papers in PubMed
0.6field-weighted citation impact, top 30% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

5 citing papers in PubMed, 10 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

7 authors at 1 institution in 1 country.

Maxime Le MerdyDivision of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA.
Ming-Liang TanDivision of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA.
Dajun SunDivision of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA.
Zhanglin NiDivision of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA.
Sue-Chih LeeDivision of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA.
Andrew BabiskinDivision of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA. Andrew.Babiskin@fda.hhs.gov.ORCID http://orcid.org/0000-0001-9968-0197
Liang ZhaoDivision of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA.
Center for Drug Evaluation and Research · US

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

BACKGROUND AND

objectivesProton pump inhibitors (PPIs) can affect the intragastric release of other drugs from their dosage forms by elevating the gastric pH. They may also influence drug absorption and metabolism by interacting with P-glycoprotein or with the cytochrome P450 (CYP) enzyme system. Nifedipine is a Biopharmaceutics Classification System (BCS) class II drug with low solubility across physiologic pH and high permeability. Previous studies have demonstrated that drug-drug interaction (DDI) existed between omeprazole and nifedipine with significantly increased systemic exposure of nifedipine in subjects after pre-treatment for 7 days with omeprazole compared to the subjects without omeprazole treatment. It was shown that omeprazole not only induced an increase in intragastric pH, but also inhibited the CYP3A4 activity, while CYP3A4-mediated oxidation is the main metabolic pathway of nifedipine. The purpose of this study is to apply a physiologically based pharmacokinetic (PBPK) modeling approach to investigate the DDI mechanism for an immediate release formulation of nifedipine with omeprazole.

methodsA previously published model for omeprazole was modified to integrate metabolites and to update CYP inhibition based on the most updated published in vitro data. We simulated the nifedipine pharmacokinetics in healthy subjects with or without the multiple-dose pretreatment of omeprazole (20 mg) following oral administrations of immediate-release (IR) (10 mg) nifedipine. Nifedipine solubility at different pHs was used to simulate the nifedipine pharmacokinetics for both clinical arms. Multiple sensitivity analyses were performed to understand the impact of gastric pH and the CYP3A4-mediated gut and liver first pass metabolism on the overall nifedipine pharmacokinetics.

resultsThe developed PBPK model properly described the pharmacokinetics of nifedipine and predicted the inhibitory effect of multiple-dose omeprazole on CYP3A4 activity. With the incorporation of the physiologic effect of omeprazole on both gastric pH and CYP3A4 to the PBPK model, the verified PBPK model allows evaluating the impact of the increase in gastric pH and/or CYP3A4 inhibition. The simulated results show that the nifedipine metabolic inhibition by omeprazole may play an important role in the DDI between nifedipine and omeprazole for IR nifedipine formulation.

conclusionThe developed full PBPK model with the capability to simulate DDI by considering gastric pH change and metabolic inhibition provides a mechanistic understanding of the observed DDI of nifedipine with a PPI, omeprazole.

Indexed as

Models, BiologicalCalcium Channel BlockersCytochrome P-450 CYP3A InhibitorsDrug InteractionsHumansNifedipineOmeprazoleProton Pump InhibitorsCalcium Channel BlockersCytochrome P-450 CYP3A InhibitorsNifedipineOmeprazoleProton Pump Inhibitors

Identifiers

PMID33064292
OpenAlexW3093028580

What OpenQuestion holds

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Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.