Elimination of tucatinib, a small molecule kinase inhibitor of HER2, is primarily governed by CYP2C8 enantioselective oxidation of gem-dimethyl

Sun, Hao; Cardinal, Kristen A.; Wienkers, Larry C.; Chin, Alice; Kumar, Vineet; Neace, Calvin; Henderson, Clark M.; Endres, Christopher J.; Topletz‐Erickson, Ariel R.; Regal, Kelly; Vo, Alex C. H.; Alley, Stephen C.; Lee, Anthony J.

doi:10.1007/s00280-022-04429-z

Cited by 9 publications

(18 citation statements)

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“…In that study, ONT-993 was the most abundant radioactive component in urine and feces, accounting for 1.5% and 37% of the dose, respectively [16]. This, and findings from in vitro studies, indicated the primary role of CYP2C8 in the metabolism of tucatinib [5,16]. The effect of inducers and inhibitors of metabolizing enzymes on tucatinib pharmacokinetics, as observed in Parts A-C of this DDI study, confirmed that CYP2C8 is the main metabolizing enzyme by which DDIs may affect tucatinib plasma levels, with CYP3A4 playing a lesser role.…”

Section: Discussionmentioning

confidence: 86%

“…An absorption, metabolism, and excretion study determined that oxidative metabolism was the predominant clearance route for tucatinib in humans (NCT03758339). In that study, ONT-993 was the most abundant radioactive component in urine and feces, accounting for 1.5% and 37% of the dose, respectively [16]. This, and findings from in vitro studies, indicated the primary role of CYP2C8 in the metabolism of tucatinib [5,16].…”

Section: Discussionmentioning

confidence: 95%

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Evaluation of Safety and Clinically Relevant Drug–Drug Interactions with Tucatinib in Healthy Volunteers

et al. 2022

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Background and Objective Tucatinib 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. Methods Parts 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). Results Tucatinib area under the concentration-time curve from time 0 extrapolated to infinity (AUC 0-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 AUC 0-inf increased 5.7-fold), a weak inhibitor of CYP2C8 and P-glycoprotein, and had no impact on CYP2C9mediated 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 Registration This trial (NCT03723395) was registered on October 29, 2018.

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 95%

Evaluation of Safety and Clinically Relevant Drug–Drug Interactions with Tucatinib in Healthy Volunteers

et al. 2022

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Section: Introductionmentioning

confidence: 99%

“…In vitro metabolism studies in human liver microsomes suggest tucatinib is predominantly cleared by the drug metabolizing enzyme cytochrome P450 (CYP) 2C8, to a lesser extent by CYP3A4 and CYP3A5, and subsequent biliary excretion [ 16 ]. The predominant metabolite of tucatinib, ONT-993, is formed via hydroxylation by CYP2C8 [ 16 ]. The cytotoxic potency of ONT-993 is two- to three-fold less than that of tucatinib and the potency adjusted exposure of ONT-993 is < 10% of the total pharmacological activity [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

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The Pharmacokinetics and Safety of Tucatinib in Volunteers with Hepatic Impairment

et al. 2022

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Background and Objective Tucatinib, a highly selective tyrosine kinase inhibitor of the human epidermal growth factor receptor 2 (HER2) approved for HER2-positive metastatic breast cancer, is cleared by hepatic metabolism and subsequent biliary excretion. Liver disease can alter drug disposition and pharmacokinetics (PK). The objective of this study is to characterize PK and safety of tucatinib in volunteers with hepatic impairment. Methods This Phase 1 study compared the PK and safety of a single 300-mg oral dose of tucatinib in volunteers with mild, moderate, and severe hepatic impairment (Child-Pugh A/B/C) to healthy volunteers matched for sex, age, and body mass index. Pharmacokinetic parameters were determined for tucatinib and its predominant metabolite ONT-993. Results Compared with healthy volunteers, tucatinib exposure was similar in volunteers with mild impairment and increased in those with moderate or severe impairment without reaching statistical significance. Respective fold increases in geometric mean ratios for AUC 0-t and AUC 0-∞ were 1.13 and 1.15 in moderate impairment, and 1.43 and 1.61 in severe impairment compared with healthy volunteers. Three treatment-emergent adverse events (nausea, dermatitis, and increased transaminases) were reported in three volunteers and showed no obvious association with hepatic impairment status. Conclusion The 1.61-fold geometric mean ratio AUC 0-∞ increase in volunteers with severe hepatic impairment supports the recommendation in the tucatinib prescribing information to reduce the dose from 300 mg twice daily to 200 mg twice daily in patients with severe impairment; no dose adjustment is recommended for patients with mild or moderate hepatic impairment. This trial (NCT03722823) was registered on October 29, 2018. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-022-01183-6 .

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Creation of Novel Sensitive Probe Substrate and Moderate Inhibitor Models for a Comprehensive Prediction of CYP2C8 Interactions for Tucatinib

Templeton,

Rowland‐Yeo,

Jones

et al. 2023

Clin Pharma and Therapeutics

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A physiologically based pharmacokinetic (PBPK) model was developed to simulate plasma concentrations of tucatinib (Tukysa®) after single‐dose or multiple‐dose administration of 300 mg BID orally. This PBPK model was subsequently applied to support evaluation of DDI risk as a perpetrator resulting from tucatinib inhibition of CYP3A4, CYP2C8, CYP2C9, P‐gp, or MATE1/2‐K. The PBPK model was also applied to support evaluation of DDI risk as a victim resulting from co‐administration with CYP3A4 or CYP2C8 inhibitors, or a CYP3A4 inducer. After refinement with clinical DDI data, the final PBPK model was able to recover the clinically observed single and multiple‐dose plasma concentrations for tucatinib when tucatinib was administered as a single agent in healthy subjects. In addition, the final model was able to recover clinically observed plasma concentrations of tucatinib when administered in combination with itraconazole, rifampin, or gemfibrozil as well as clinically observed plasma concentrations of probe substrates of CYP3A4, CYP2C8, CYP2C9, P‐gp, or MATE1/2‐K. The PBPK model was then applied to prospectively predict the potential perpetrator or victim DDIs with other substrates, inducers, or inhibitors. To simulate a potential interaction with a moderate CYP2C8 inhibitor, two novel PBPK models representing a moderate CYP2C8 inhibitor and a sensitive CYP2C8 substrate were developed based on the existing PBPK models for gemfibrozil and rosiglitazone, respectively. The simulated population GMRAUC of tucatinib with a moderate CYP2C8 inhibitor ranged from 1.98‐ to 3.08‐fold, and based on these results, no dose modifications were proposed for moderate CYP2C8 inhibitors for the tucatinib label.

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Elimination of tucatinib, a small molecule kinase inhibitor of HER2, is primarily governed by CYP2C8 enantioselective oxidation of gem-dimethyl

Cited by 9 publications

References 25 publications

Evaluation of Safety and Clinically Relevant Drug–Drug Interactions with Tucatinib in Healthy Volunteers

Evaluation of Safety and Clinically Relevant Drug–Drug Interactions with Tucatinib in Healthy Volunteers

The Pharmacokinetics and Safety of Tucatinib in Volunteers with Hepatic Impairment

Creation of Novel Sensitive Probe Substrate and Moderate Inhibitor Models for a Comprehensive Prediction of CYP2C8 Interactions for Tucatinib

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Elimination of tucatinib, a small molecule kinase inhibitor of HER2, is primarily governed by CYP2C8 enantioselective oxidation of gem-dimethyl

Cited by 9 publications

References 25 publications

Evaluation of Safety and Clinically Relevant Drug–Drug Interactions with Tucatinib in Healthy Volunteer﻿s

Evaluation of Safety and Clinically Relevant Drug–Drug Interactions with Tucatinib in Healthy Volunteer﻿s

The Pharmacokinetics and Safety of Tucatinib in Volunteers with Hepatic Impairment

Creation of Novel Sensitive Probe Substrate and Moderate Inhibitor Models for a Comprehensive Prediction of CYP2C8 Interactions for Tucatinib

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Evaluation of Safety and Clinically Relevant Drug–Drug Interactions with Tucatinib in Healthy Volunteers

Evaluation of Safety and Clinically Relevant Drug–Drug Interactions with Tucatinib in Healthy Volunteers