The Overview on the Pharmacokinetic and Pharmacodynamic Interactions of Triazoles

Czyrski, Andrzej; Resztak, Matylda; Świderski, Paweł; Brylak, Jan; Główka, Franciszek

doi:10.3390/pharmaceutics13111961

Cited by 34 publications

(22 citation statements)

References 132 publications

(218 reference statements)

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“…azoles, quinolones) in virtually all countries. 9,10 In principle, this approach could be applied to other drugs such as ibrutinib, bendamustine, ruxolitinib, imatinib, dasatinib, and ponatinib. 11,12 Venetoclax is metabolized by cytochrome P450, specifically by the CYP3A4 isoenzyme.…”

Section: Discussionmentioning

confidence: 99%

Orbital myeloid sarcoma treated with low-dose venetoclax and a potent cytochrome P450 inhibitor

Garza-Salazar

Peña-Lozano

Gómez‐Almaguer

et al. 2022

J Oncol Pharm Pract

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Case report We report the first case of orbital myeloid sarcoma that was successfully treated with a standard venetoclax dose of 25%. A 38-year-old man with acute myeloid leukemia (AML) post-haplo-hematopoietic stem cell transplantation (HSCT) presented with a nine-month history of progressive right proptosis and a visual acuity deficit. The patient was treated with venetoclax (100 mg orally on days 1–28), cytarabine (40 mg subcutaneously, days 1–10), and itraconazole (100 mg twice daily orally on days 1–28). Management and outcome The present case report shows that using cytochrome P450 (CYP) inhibitors is a helpful strategy to reduce the cost of expensive treatments. Discussion There are limited data on the use of CYP inhibitors as a strategy to reduce the costs of expensive drugs (i.e. venetoclax). This approach has some advantages over standard dose venetoclax (400 mg/day) such as significantly reduced costs (which is relevant for patients in low-income countries). In this case, we used itraconazole—a potent CYP3A4 inhibitor—which can theoretically reduce the dose to 100 mg/day without losing serum therapeutic concentrations.

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Section: Discussionmentioning

confidence: 99%

Orbital myeloid sarcoma treated with low-dose venetoclax and a potent cytochrome P450 inhibitor

Garza-Salazar

Peña-Lozano

Gómez‐Almaguer

et al. 2022

J Oncol Pharm Pract

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“…Itraconazole has been extensively explored for its CYP3A4 inhibitory properties and is frequently used as a standard CYP3A inhibitor in DDI-directed studies. Although itraconazole is a known inhibitor of ABCB1 (P-glycoprotein)-mediated efflux [ 34 , 35 , 36 ], there is a relative paucity of data pertaining to its interaction with other xenobiotic transporters. Previous studies have shown that itraconazole metabolites, keto-itraconazole and hydroxy-itraconazole, potently inhibit OATP1B-type transport [ 11 , 13 ], and this prior knowledge is consistent with our present in vitro studies.…”

Section: Discussionmentioning

confidence: 99%

Itraconazole-Induced Increases in Gilteritinib Exposure Are Mediated by CYP3A and OATP1B

et al. 2022

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Gilteritinib, an FDA-approved tyrosine kinase inhibitor approved for the treatment of relapsed/refractory FLT3-mutated acute myeloid leukemia, is primarily eliminated via CYP3A4-mediated metabolism, a pathway that is sensitive to the co-administration of known CYP3A4 inhibitors, such as itraconazole. However, the precise mechanism by which itraconazole and other CYP3A-modulating drugs affect the absorption and disposition of gilteritinib remains unclear. In the present investigation, we demonstrate that pretreatment with itraconazole is associated with a significant increase in the systemic exposure to gilteritinib in mice, recapitulating the observed clinical drug–drug interaction. However, the plasma levels of gilteritinib were only modestly increased in CYP3A-deficient mice and not further influenced by itraconazole. Ensuing in vitro and in vivo studies revealed that gilteritinib is a transported substrate of OATP1B-type transporters, that gilteritinib exposure is increased in mice with OATP1B2 deficiency, and that the ability of itraconazole to inhibit OATP1B-type transport in vivo is contingent on its metabolism by CYP3A isoforms. These findings provide new insight into the pharmacokinetic properties of gilteritinib and into the molecular mechanisms underlying drug–drug interactions with itraconazole.

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“…The objective of this clinical study was to characterize the cilofexor drug-drug interaction (DDI) profile both as a victim and as a perpetrator in order to inform dosing recommendations for administering cilofexor with other medications that are either perpetrators or substrates of CYP enzymes and drug transporters. As a victim, the effects of cyclosporine (a mixed OATP/P-gp/multidrug resistance-associated protein 2 [MRP2]/CYP3A inhibitor) [ 6 ], rifampin (a selective OATP1B1/1B3 inhibitor [single dose] [ 7 ] and OATP/CYP3A/CYP2C8/P-gp inducer [multiple doses]) [ 8 ], voriconazole (strong CYP3A inhibitor) [ 9 ], gemfibrozil (strong CYP2C8 inhibitor/OATP1B1 inhibitor) [ 7 ], and grapefruit juice (intestinal uptake transport and CYP3A inhibitor) [ 10 ] on the exposure of cilofexor were evaluated. As a perpetrator, the effects of cilofexor on the exposure of midazolam (CYP3A substrate), atorvastatin (mixed OATP/CYP3A substrate), dabigatran etexilate (P-gp substrate), pravastatin (OATP substrate), and rosuvastatin (OATP/BCRP substrate) were evaluated [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the Potential for Cytochrome P450 and Transporter-Mediated Drug-Drug Interactions for Cilofexor, a Selective Nonsteroidal Farnesoid X Receptor (FXR) Agonist

et al. 2023

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Background and objective Cilofexor is a selective farnesoid X receptor (FXR) agonist in development for the treatment of nonalcoholic steatohepatitis and primary sclerosing cholangitis. Our objective was to evaluate potential drug-drug interactions of cilofexor as a victim and as a perpetrator. Methods In this Phase 1 study, healthy adult participants ( n = 18–24 per each of the 6 cohorts) were administered cilofexor in combination with either perpetrators or substrates of cytochrome P-450 (CYP) enzymes and drug transporters. Results In total, 131 participants completed the study. As a victim, cilofexor area under the curve (AUC) was 651%, 795%, and 175% when administered following single-dose cyclosporine (600 mg; organic anion transporting polypeptide [OATP]/P-glycoprotein [P-gp]/CYP3A inhibitor), single-dose rifampin (600 mg; OATP1B1/1B3 inhibitor), and multiple-dose gemfibrozil (600 mg twice daily [BID]; CYP2C8 inhibitor), respectively, compared with the administration of cilofexor alone. Cilofexor AUC was 33% when administered following multiple-dose rifampin (600 mg; OATP/CYP/P-gp inducer). Multiple-dose voriconazole (200 mg BID; CYP3A4 inhibitor) and grapefruit juice (16 ounces; intestinal OATP inhibitor) did not affect cilofexor exposure. As a perpetrator, multiple-dose cilofexor did not affect the exposure of midazolam (2 mg; CYP3A substrate), pravastatin (40 mg; OATP substrate), or dabigatran etexilate (75 mg; intestinal P-gp substrate), but atorvastatin (10 mg; OATP/CYP3A4 substrate) AUC was 139% compared with atorvastatin administered alone. Conclusion Cilofexor may be coadministered with inhibitors of P-gp, CYP3A4, or CYP2C8 without the need for dose modification. Cilofexor may be coadministered with OATP, BCRP, P-gp, and/or CYP3A4 substrates—including statins—without dose modification. However, coadministration of cilofexor with strong hepatic OATP inhibitors, or with strong or moderate inducers of OATP/CYP2C8, is not recommended.

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The Overview on the Pharmacokinetic and Pharmacodynamic Interactions of Triazoles

Cited by 34 publications

References 132 publications

Orbital myeloid sarcoma treated with low-dose venetoclax and a potent cytochrome P450 inhibitor

Orbital myeloid sarcoma treated with low-dose venetoclax and a potent cytochrome P450 inhibitor

Itraconazole-Induced Increases in Gilteritinib Exposure Are Mediated by CYP3A and OATP1B

Evaluation of the Potential for Cytochrome P450 and Transporter-Mediated Drug-Drug Interactions for Cilofexor, a Selective Nonsteroidal Farnesoid X Receptor (FXR) Agonist

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