ArticleClinical pharmacokinetics2016
Evaluation of Cytochrome P450 3A4-Mediated Drug-Drug Interaction Potential for Cobimetinib Using Physiologically Based Pharmacokinetic Modeling and Simulation.
Article in Clinical pharmacokinetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT05216614 (Fluvoxamine to Augment Olfactory Recovery For Long COVID-19 Parosmia), which is not on this map. Cited by 22 papers, 2 of them syntheses that pooled it.
What it found
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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.
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.
Fluvoxamine to Augment Olfactory Recovery For Long COVID-19 Parosmia (FluCOP Trial)
Who cites it
22 citing papers in PubMed, 2 syntheses or guidelines pooled it, 37 citations in OpenAlex.
- A systematic review on disease-drug-drug interactions with immunomodulating drugs: A critical appraisal of risk assessment and drug labelling.British journal of clinical pharmacology · 2022Pooled it
- Utility of physiologically based pharmacokinetic (PBPK) modeling in oncology drug development and its accuracy: a systematic review.European journal of clinical pharmacology · 2018Pooled it
- Targeted Therapies Modulating Mesenchymal-Epithelial Transition-Linked Oncogenic Signaling in the Tumor Microenvironment: Comparative Profiling of Capmatinib, Bemcentinib, and Galunisertib.Journal of clinical medicine · 2025Review
- Impact of Drug-Drug Interactions on Clinical Outcomes in Metastatic Melanoma Patients Treated With Combined BRAF/MEK Inhibitors: A Real-World Study.Pigment cell & melanoma research · 2025Observational
- Clinical impact of drug-drug interactions on abemaciclib in the real-world experience of AB-ITALY study.NPJ breast cancer · 2024Article
- Application of physiologically based pharmacokinetics modeling in the research of small-molecule targeted anti-cancer drugs.Cancer chemotherapy and pharmacology · 2023Review
- Article
- Repurposing antifungal drugs for cancer therapy.Journal of advanced research · 2023Review
- Involvement of Transporters in Intestinal Drug-Drug Interactions of Oral Targeted Anticancer Drugs Assessed by Changes in Drug Absorption Time.Pharmaceutics · 2022Article
- Evaluation of drug-drug interaction potential for pemigatinib using physiologically based pharmacokinetic modeling.CPT: pharmacometrics & systems pharmacology · 2022Article
- Drug-Drug Interaction Between Oxycodone and Diazepam by a CombinedACS chemical neuroscience · 2021Article
- Effect of Hepatic Impairment on Cobimetinib Pharmacokinetics: The Complex Interplay Between Physiological Changes and Drug Characteristics.Clinical pharmacology in drug development · 2021Article
- A Review of CYP3A Drug-Drug Interaction Studies: Practical Guidelines for Patients Using Targeted Oral Anticancer Drugs.Frontiers in pharmacology · 2021Review
- Article
- Utilization of Physiologically Based Pharmacokinetic Modeling in Clinical Pharmacology and Therapeutics: an Overview.Current pharmacology reports · 2020Review
- Clinical Pharmacokinetic and Pharmacodynamic Considerations in the (Modern) Treatment of Melanoma.Clinical pharmacokinetics · 2019Review
- Interaction between phytotherapy and oral anticancer agents: prospective study and literature review.Medical oncology (Northwood, London, England) · 2019Review
- Improved predictions of time-dependent drug-drug interactions by determination of cytosolic drug concentrations.Scientific reports · 2019Article
- Oral oncolytic and antiretroviral therapy administration: dose adjustments, drug interactions, and other considerations for clinical use.Drugs in context · 2019Review
- Clinically relevant drug interactions with multikinase inhibitors: a review.Therapeutic advances in medical oncology · 2019Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
BACKGROUND AND
objectivesCobimetinib is eliminated mainly through cytochrome P450 (CYP) 3A4-mediated hepatic metabolism in humans. A clinical drug-drug interaction (DDI) study with the potent CYP3A4 inhibitor itraconazole resulted in an approximately sevenfold increase in cobimetinib exposure. The DDI risk for cobimetinib with other CYP3A4 inhibitors and inducers needs to be assessed in order to provide dosing instructions.
methodsA physiologically based pharmacokinetic (PBPK) model was developed for cobimetinib using in vitro data. It was then optimized and verified using clinical pharmacokinetic data and itraconazole-cobimetinib DDI data. The contribution of CYP3A4 to the clearance of cobimetinib in humans was confirmed using sensitivity analysis in a retrospective simulation of itraconazole-cobimetinib DDI data. The verified PBPK model was then used to predict the effect of other CYP3A4 inhibitors and inducers on cobimetinib pharmacokinetics.
resultsThe PBPK model described cobimetinib pharmacokinetic profiles after both intravenous and oral administration of cobimetinib well and accurately simulated the itraconazole-cobimetinib DDI. Sensitivity analysis suggested that CYP3A4 contributes ~78 % of the total clearance of cobimetinib. The PBPK model predicted no change in cobimetinib exposure (area under the plasma concentration-time curve, AUC) with the weak CYP3A inhibitor fluvoxamine and a three to fourfold increase with the moderate CYP3A inhibitors, erythromycin and diltiazem. Similarly, cobimetinib exposure in the presence of strong (rifampicin) and moderate (efavirenz) CYP3A inducers was predicted to decrease by 83 and 72 %, respectively.
conclusionThis study demonstrates the value of using PBPK simulation to assess the clinical DDI risk inorder to provide dosing instructions with other CYP3A4 perpetrators.
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Registered trials
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.