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Lack of clinically relevant drug-drug interactions when dalcetrapib is co-administered with ezetimibe.

ABSTRACT: Dalcetrapib, which targets cholesteryl ester transfer protein activity, is in development for prevention of cardiovascular events. Because dalcetrapib will likely be prescribed with other lipid-modifying therapies such as ezetimibe, a study was performed to investigate potential pharmacokinetic interactions between dalcetrapib and ezetimibe. Lipids changes and tolerability were secondary endpoints.Co-administration of dalcetrapib 900 mg (higher than the phase III dose) with ezetimibe was investigated in a three period, three treatment crossover study in healthy males: 7 days of dalcetrapib, 7 days of dalcetrapib plus ezetimibe, 7 days of ezetimibe alone. A full pharmacokinetic profile was performed on day 7 of each treatment.Co-administration of dalcetrapib with ezetimibe was associated with minimal changes in dalcetrapib exposure compared with dalcetrapib alone. Least squares mean ratio (LSMR) (90% confidence interval) was 93.6 (87.1, 100.7) for AUC(0,24 h) and 99.0 (85.2, 115.0) for C(max) . Ezetimibe exposure was reduced with co-administration of ezetimibe with dalcetrapib compared with ezetimibe alone: LSMR 80.3 (74.6, 86.4) for AUC(0,24 h) and 88.9 (80.9, 99.9) for C(max) for total ezetimibe. High-density lipoprotein cholesterol increases associated with co-administration of dalcetrapib with ezetimibe (+29.8%) were comparable with those with dalcetrapib alone (+25.6%), while the reduction in low-density lipoprotein cholesterol with co-administration (-35.9%) was greater than with ezetimibe alone (-20.9%). Dalcetrapib was generally well tolerated when administered alone and when co-administered with ezetimibe.Co-administration of dalcetrapib with ezetimibe was not associated with clinically significant changes in pharmacokinetic parameters or tolerability and did not diminish the lipid effects of either drug.

SUBMITTER: Derks M

PROVIDER: S-EPMC3014066 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Lack of clinically relevant drug-drug interactions when dalcetrapib is co-administered with ezetimibe.

Derks Michael M Abt Markus M Phelan Mary M

British journal of clinical pharmacology 20101201 6

<h4>Aims</h4>Dalcetrapib, which targets cholesteryl ester transfer protein activity, is in development for prevention of cardiovascular events. Because dalcetrapib will likely be prescribed with other lipid-modifying therapies such as ezetimibe, a study was performed to investigate potential pharmacokinetic interactions between dalcetrapib and ezetimibe. Lipids changes and tolerability were secondary endpoints.<h4>Methods</h4>Co-administration of dalcetrapib 900 mg (higher than the phase III dos ...[more]

PMID: 21175438

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Project description:Background and objectiveTucatinib is approved for treatment of human epidermal growth factor receptor 2-positive metastatic breast cancer. Understanding potential drug-drug interactions (DDIs) informs proper dosing when co-administering tucatinib with other therapies. The aim of this study was to evaluate DDIs between tucatinib and metabolizing enzymes and transporters in healthy volunteers.MethodsParts A-C assessed the impact of itraconazole (cytochrome P450 [CYP] 3A4 inhibitor), rifampin (CYP3A4/CYP2C8 inducer), or gemfibrozil (CYP2C8 inhibitor) on the pharmacokinetics of a single 300 mg dose of tucatinib administered orally and its primary metabolite, ONT-993. Parts D and E assessed the effect of steady-state tucatinib on the pharmacokinetics of repaglinide (CYP2C8 substrate), tolbutamide (CYP2C9 substrate), midazolam (CYP3A4 substrate), and digoxin (P-glycoprotein substrate).ResultsTucatinib area under the concentration-time curve from time 0 extrapolated to infinity (AUC0-inf) increased by ~ 1.3- and 3.0-fold with itraconazole and gemfibrozil, respectively, and decreased by 48% with rifampin, indicating that tucatinib is metabolized primarily by CYP2C8, and to a lesser extent via CYP3A. Tucatinib was a strong inhibitor of CYP3A (midazolam AUC0-inf increased 5.7-fold), a weak inhibitor of CYP2C8 and P-glycoprotein, and had no impact on CYP2C9-mediated metabolism in humans. Tucatinib was well tolerated, alone and with co-administered drugs.ConclusionThe potential DDIs identified here may be mitigated by avoiding concomitant use of tucatinib with strong CYP3A inducers, moderate CYP2C8 inducers, CYP3A substrates with a narrow therapeutic window (modifying substrate dose where concomitant use is unavoidable), and strong CYP2C8 inhibitors (decreasing tucatinib dose where concomitant use is unavoidable), or by reducing the dose of P-glycoprotein substrates with a narrow therapeutic window.Trial registrationThis trial (NCT03723395) was registered on October 29, 2018.

Dataset Information

Lack of clinically relevant drug-drug interactions when dalcetrapib is co-administered with ezetimibe.

Publications

Lack of clinically relevant drug-drug interactions when dalcetrapib is co-administered with ezetimibe.

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