Evaluation of modafinil as a perpetrator of metabolic drug–drug interactions using a model informed cocktail reaction phenotyping trial protocol

Rowland, Angela; Dyk, Madelé van; Warncken, David; Mangoni, Arduino A.; Sorich, Michael J.

doi:10.1111/bcp.13478

Cited by 16 publications

(15 citation statements)

References 27 publications

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“…The models of the strong CYP3A4 inducer, rifampin, qualified by Simcyp . The modafinil PBPK model was qualified by comparing the predicted PK parameters after a single and multiple dose with the observed values . Furthermore, the observed AUC and C max ratios of palbociclib, triazolam, and midazolam in the presence and absence of modafinil are within 0.78‐ to 1.14‐fold of the observed values (Table S7).…”

Section: Resultsmentioning

confidence: 99%

“…The prediction of the effect of efavirenz (600 mg QD) was performed using the Simcyp v16 library file, implemented in Simcyp v14. The inducers were dosed orally for 12 days, and on day 7, a 200‐mg dose of abemaciclib was given concurrently with the dose of the inducer, except for the interaction with modafinil, where modafinil was dosed QD for 40 days, and abemaciclib was given on day 27 to reproduce dosing schedules from several published clinical trials …”

Section: Methodsmentioning

confidence: 99%

“…Because the model was able to accurately predict the autoinduction of bosentan with regard to CYP3A4 metabolism in both the gut and liver, no induction of OATPs by bosentan was necessary in the model. The modafinil induction file was built based on a published model, with minor changes to the input parameters . The input parameters for bosentan and modafinil are shown in Table S3.…”

Section: Methodsmentioning

confidence: 99%

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Predicting Clinical Effects of CYP3A4 Modulators on Abemaciclib and Active Metabolites Exposure Using Physiologically Based Pharmacokinetic Modeling

Posada

Morse

Turner

et al. 2020

The Journal of Clinical Pharma

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Abemaciclib, a selective inhibitor of cyclin‐dependent kinases 4 and 6, is metabolized mainly by cytochrome P450 (CYP)3A4. Clinical studies were performed to assess the impact of strong inhibitor (clarithromycin) and inducer (rifampin) on the exposure of abemaciclib and active metabolites. A physiologically based pharmacokinetic (PBPK) model incorporating the metabolites was developed to predict the effect of other strong and moderate CYP3A4 inhibitors and inducers. Clarithromycin increased the area under the plasma concentration‐time curve (AUC) of abemaciclib and potency‐adjusted unbound active species 3.4‐fold and 2.5‐fold, respectively. Rifampin decreased corresponding exposures 95% and 77%, respectively. These changes influenced the fraction metabolized via CYP3A4 in the model. An absolute bioavailability study informed the hepatic and gastric availability. In vitro data and a human radiolabel study determined the fraction and rate of formation of the active metabolites as well as absorption‐related parameters. The predicted AUC ratios of potency‐adjusted unbound active species with rifampin and clarithromycin were within 0.7‐ and 1.25‐fold of those observed. The PBPK model predicted 3.78‐ and 7.15‐fold increases in the AUC of the potency‐adjusted unbound active species with strong CYP3A4 inhibitors itraconazole and ketoconazole, respectively; and 1.62‐ and 2.37‐fold increases with the concomitant use of moderate CYP3A4 inhibitors verapamil and diltiazem, respectively. The model predicted modafinil, bosentan, and efavirenz would decrease the AUC of the potency‐adjusted unbound active species by 29%, 42%, and 52%, respectively. The current PBPK model, which considers changes in unbound potency‐adjusted active species, can be used to inform dosing recommendations when abemaciclib is coadministered with CYP3A4 perpetrators.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Predicting Clinical Effects of CYP3A4 Modulators on Abemaciclib and Active Metabolites Exposure Using Physiologically Based Pharmacokinetic Modeling

Posada

Morse

Turner

et al. 2020

The Journal of Clinical Pharma

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“…Cocktail approaches for phenotyping involving the administration of multiple CYP‐specific or P‐gp‐specific probe drugs were used to simultaneously assess the activities of these enzymes and the transporter P‐gp. Many phenotyping cocktails have been developed and used in recent years . For this study, the compilation of the probe drugs was selected according to a validated phenotyping cocktail (Geneva cocktail), which also included a probe drug for P‐gp (fexofenadine).…”

mentioning

confidence: 99%

“…Many phenotyping cocktails have been developed and used in recent years. [20][21][22][23][24][25] For this study, the compilation of the probe drugs was selected according to a validated phenotyping cocktail (Geneva cocktail 26,27 ), which also included a probe drug for P-gp (fexofenadine). To our knowledge, this is the first seven-probe drug cocktail interaction study investigating St. John's wort.…”

mentioning

confidence: 99%

No Clinically Relevant Interactions of St. John's Wort Extract Ze 117 Low in Hyperforin With Cytochrome P450 Enzymes and P‐glycoprotein

Zahner

Kruttschnitt

Uricher

et al. 2019

Clin Pharma and Therapeutics

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Hypericum perforatum L. (St. John's wort) is used to treat mild‐to‐moderate depression. Its potential safety risks are pharmacokinetic drug interactions via cytochrome P450 (CYP) enzymes and P‐glycoprotein, presumably caused by hyperforin. In a phase I, open‐label, nonrandomized, single‐sequence study, the low‐hyperforin Hypericum extract Ze 117 was investigated using a drug cocktail in 20 healthy volunteers. No pharmacokinetic interactions of Ze 117 were observed for CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP3A4, and P‐glycoprotein. Area under the curve (AUC) and peak plasma concentration (Cmax) of the used probe drugs showed 90% confidence intervals (CIs) of the geometric mean ratios of the drugs taken together with Ze 117 vs. probe drug alone, well within the predefined bioequivalence range of 80–125%. Though Ze 117 did not induce dextromethorphan metabolism by CYP2D6, it weakly increased dextromethorphan AUC ratio (mean 147.99, 95% CI 126.32–173.39) but not the corresponding metabolic ratio. Ze 117 does not show clinically relevant pharmacokinetic interactions with important CYPs and P‐glycoprotein.

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Leveraging Human Plasma‐Derived Small Extracellular Vesicles as Liquid Biopsy to Study the Induction of Cytochrome P450 3A4 by Modafinil

Rodrigues

Wood

Vourvahis

et al. 2021

Clin Pharma and Therapeutics

Self Cite

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Study HighlightsWHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Drug interactions involving CYP3A4 induction are well documented, and the differentiation of none, weak, moderate, and strong inducers usually requires the use of probe drugs (e.g., midazolam) and biomarkers (e.g., plasma 4β-hydroxycholesterol/ cholesterol ratio). However, such tools are not always able to differentiate the induction of gut vs. liver CYP3A4. WHAT QUESTION DID THIS STUDY ADDRESS? Is it possible to leverage plasma-derived sEVs as liquid biopsy, to facilitate liver and nonliver CYP3A4 expression profiling, following the 14-day administration of a weak to moderate inducer like modafinil?WHAT DOES THIS STUDY ADD TO OUR KNOW-LEDGE? One can profile plasma-derived sEVs and differentiate liver vs. nonliver CYP3A4 induction following modafinil. HOW MIGHT THIS CHANGE CLINICAL PHARMA-COLOGY OR TRANSLATIONAL SCIENCE? Plasma-derived sEVs can facilitate the study of CYP3A4 induction, as it is possible to use sEVs proteomic data to predict plasma area under the plasma concentration-time curve ratios (AUCRs) for different victim drugs. Importantly, weak to moderate CYP3A4 inducers (e.g., modafinil) can be differentiated from strong inducers (e.g., rifampicin) using the approach.

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Evaluation of modafinil as a perpetrator of metabolic drug–drug interactions using a model informed cocktail reaction phenotyping trial protocol

Cited by 16 publications

References 27 publications

Predicting Clinical Effects of CYP3A4 Modulators on Abemaciclib and Active Metabolites Exposure Using Physiologically Based Pharmacokinetic Modeling

Predicting Clinical Effects of CYP3A4 Modulators on Abemaciclib and Active Metabolites Exposure Using Physiologically Based Pharmacokinetic Modeling

No Clinically Relevant Interactions of St. John's Wort Extract Ze 117 Low in Hyperforin With Cytochrome P450 Enzymes and P‐glycoprotein

Leveraging Human Plasma‐Derived Small Extracellular Vesicles as Liquid Biopsy to Study the Induction of Cytochrome P450 3A4 by Modafinil

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