Association between clinically relevant toxicities of pazopanib and sunitinib and the use of weak CYP3A4 and P-gp inhibitors
Sunitinib and pazopanib, two tyrosine kinase inhibitors (TKI), may be targets of potential pharmacokinetic drug-drug interactions (P-PK-DDIs). While strong cytochrome P4503A (CYP3A4) inhibitors or inducers should cause a clinically relevant modification in plasma TKI concentrations, the effect of weak inhibitors is unknown. The objective of this study was to evaluate the association between weak P-PK-DDI and clinically relevant toxicity in real life.
Patients and methods
This was a single-center retrospective study including patients treated with sunitinib or pazopanib for any malignancies, for whom a PK-DDI analysis was performed before starting TKI. The primary endpoint was the correlation between P-PK-DDIs and a dose decrease after 1 month of treatment. The secondary endpoint was the correlation between PK-DDIs and drug withdrawal due to toxicity.
Seventy-six patients were assessed. A P-PK-DDI with weak CYP3A4 or P-gp inhibition was found in 14 patients. In patients with P-PK-DDI or without, the dose was reduced during the first month in 57.1% and 17.7% (p = 0.003) and the drug withdrawn in 42.8% and 11.3% (p = 0.011), respectively. In multivariate analysis, a significant correlation was found between P-PK-DDI (CYP3A4 and P-gp inhibitors) and dose reduction, and between drug withdrawal and PK-DDI (CYP3A4 inhibitors).
P-PK-DDI was correlated with dose reduction and drug withdrawal due to toxicity. The causality of this relationship warrants to be assessed; therefore, therapeutic drug monitoring is necessary in patients treated with TKI.
KeywordsPazopanib Sunitinib Drug-drug interaction CYP3A4 P-gp
Compliance with ethical standards
The study was performed in compliance with ethical standards.
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval for retrospective study
As a retrospective study, no informed consent was required but patients were informed that their data could be used for clinical evaluation. None refused.
- 2.van der Graaf WTA, Blay J-Y, Chawla SP, Kim D-W, Bui-Nguyen B, Casali PG, Schöffski P, Aglietta M, Staddon AP, Beppu Y, le Cesne A, Gelderblom H, Judson IR, Araki N, Ouali M, Marreaud S, Hodge R, Dewji MR, Coens C, Demetri GD, Fletcher CD, Dei Tos AP, Hohenberger P, EORTC Soft Tissue and Bone Sarcoma Group, PALETTE study group (2012) Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 379:1879–1886. https://doi.org/10.1016/S0140-6736(12)60651-5 CrossRefPubMedGoogle Scholar
- 3.Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J et al (2006) Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 368:1329–1338. https://doi.org/10.1016/S0140-6736(06)69446-4 CrossRefPubMedGoogle Scholar
- 4.Raymond E, Dahan L, Raoul J-L, Bang Y-J, Borbath I, Lombard-Bohas C, Valle J, Metrakos P, Smith D, Vinik A, Chen JS, Hörsch D, Hammel P, Wiedenmann B, van Cutsem E, Patyna S, Lu DR, Blanckmeister C, Chao R, Ruszniewski P (2011) Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 364:501–513. https://doi.org/10.1056/NEJMoa1003825 CrossRefPubMedGoogle Scholar
- 6.Boudou-Rouquette P, Tlemsani C, Blanchet B, Huillard O, Jouinot A, Arrondeau J, Thomas-Schoemann A, Vidal M, Alexandre J, Goldwasser F (2016) Clinical pharmacology, drug-drug interactions and safety of pazopanib: a review. Expert Opin Drug Metab Toxicol 12:1433–1444. https://doi.org/10.1080/17425255.2016.1225038 CrossRefPubMedGoogle Scholar
- 8.Tang SC, Lagas JS, Lankheet NAG, Poller B, Hillebrand MJ, Rosing H, Beijnen JH, Schinkel AH (2012) Brain accumulation of sunitinib is restricted by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) and can be enhanced by oral elacridar and sunitinib coadministration. Int J Cancer 130:223–233. https://doi.org/10.1002/ijc.26000 CrossRefPubMedGoogle Scholar
- 9.Tan AR, Gibbon DG, Stein MN, Lindquist D, Edenfield JW, Martin JC, Gregory C, Suttle AB, Tada H, Botbyl J, Stephenson JJ (2013) Effects of ketoconazole and esomeprazole on the pharmacokinetics of pazopanib in patients with solid tumors. Cancer Chemother Pharmacol 71:1635–1643. https://doi.org/10.1007/s00280-013-2164-3 CrossRefPubMedGoogle Scholar
- 11.US Food and Drug Administration, Center for Drug Evaluation and Research. Pazopanib clinical pharmacology and biopharmaceutics review 2008Google Scholar
- 12.Sun L, Liang C, Shirazian S, Zhou Y, Miller T, Cui J, Fukuda JY, Chu JY, Nematalla A, Wang X, Chen H, Sistla A, Luu TC, Tang F, Wei J, Tang C (2003) Discovery of 5-[5-fluoro-2-oxo-1,2- dihydroindol-(3Z)-ylidenemethyl]-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase. J Med Chem 46:1116–1119. https://doi.org/10.1021/jm0204183 CrossRefPubMedGoogle Scholar
- 16.Mickey RM, Greenland S (1989) The impact of confounder selection criteria on effect estimation. Am J Epidemiol 129:125–137. https://doi.org/10.1093/oxfordjournals.aje.a115101 CrossRefPubMedGoogle Scholar
- 17.Escudier B, Porta C, Bono P, Powles T, Eisen T, Sternberg CN, Gschwend JE, de Giorgi U, Parikh O, Hawkins R, Sevin E, Négrier S, Khan S, Diaz J, Redhu S, Mehmud F, Cella D (2014) Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES study. J Clin Oncol 32:1412–1418. https://doi.org/10.1200/JCO.2013.50.8267 CrossRefPubMedGoogle Scholar
- 18.Bowlin SJ, Xia F, Wang W, Robinson KD, Stanek EJ (2013) Twelve-month frequency of drug-metabolizing enzyme and transporter-based drug-drug interaction potential in patients receiving oral enzyme-targeted kinase inhibitor antineoplastic agents. Mayo Clin Proc 88:139–148. https://doi.org/10.1016/j.mayocp.2012.10.020 CrossRefPubMedGoogle Scholar
- 20.van Leeuwen RWF, Brundel DHS, Neef C, van Gelder T, Mathijssen RHJ, Burger DM, Jansman FG (2013) Prevalence of potential drug-drug interactions in cancer patients treated with oral anticancer drugs. Br J Cancer 108:1071–1078. https://doi.org/10.1038/bjc.2013.48 CrossRefPubMedPubMedCentralGoogle Scholar
- 24.Suttle AB, Ball HA, Molimard M, Hutson TE, Carpenter C, Rajagopalan D, Lin Y, Swann S, Amado R, Pandite L (2014) Relationships between pazopanib exposure and clinical safety and efficacy in patients with advanced renal cell carcinoma. Br J Cancer 111:1909–1916. https://doi.org/10.1038/bjc.2014.503 CrossRefPubMedPubMedCentralGoogle Scholar
- 25.Cabel L, Blanchet B, Thomas-Schoemann A, Huillard O, Bellesoeur A, Cessot A, Giroux J, Boudou-Rouquette P, Coriat R, Vidal M, Saidu NEB, Golmard L, Alexandre J, Goldwasser F (2018) Drug monitoring of sunitinib in patients with advanced solid tumors: a monocentric observational French study. Fundam Clin Pharmacol 32:98–107. https://doi.org/10.1111/fcp.12327 CrossRefPubMedGoogle Scholar
- 28.Zhou S-F, Xue CC, Yu X-Q, Li C, Wang G (2007) Clinically important drug interactions potentially involving mechanism-based inhibition of cytochrome P450 3A4 and the role of therapeutic drug monitoring. Ther Drug Monit 29:687–710. https://doi.org/10.1097/FTD.0b013e31815c16f5 CrossRefPubMedGoogle Scholar
- 30.Verheijen RB, Swart LE, Beijnen JH, Schellens JHM, Huitema ADR, Steeghs N (2017) Exposure-survival analyses of pazopanib in renal cell carcinoma and soft tissue sarcoma patients: opportunities for dose optimization. Cancer Chemother Pharmacol 80:1171–1178. https://doi.org/10.1007/s00280-017-3463-x CrossRefPubMedPubMedCentralGoogle Scholar
- 31.Lankheet NAG, Kloth JSL, Gadellaa-van Hooijdonk CGM, Cirkel GA, Mathijssen RHJ, Lolkema MPJK et al (2014) Pharmacokinetically guided sunitinib dosing: a feasibility study in patients with advanced solid tumours. Br J Cancer 110:2441–2449. https://doi.org/10.1038/bjc.2014.194 CrossRefPubMedPubMedCentralGoogle Scholar
- 35.Puts MTE, Costa-Lima B, Monette J, Girre V, Wolfson C, Batist G, Bergman H (2009) Medication problems in older, newly diagnosed cancer patients in Canada: how common are they? A prospective pilot study. Drugs Aging 26:519–536. https://doi.org/10.2165/00002512-200926060-00008 CrossRefPubMedGoogle Scholar
- 41.de Jonge MJA, Hamberg P, Verweij J, Savage S, Suttle AB, Hodge J, Arumugham T, Pandite LN, Hurwitz HI (2013) Phase I and pharmacokinetic study of pazopanib and lapatinib combination therapy in patients with advanced solid tumors. Investig New Drugs 31:751–759. https://doi.org/10.1007/s10637-012-9885-8 CrossRefGoogle Scholar
- 44.McAlister RK, Aston J, Pollack M, Du L, Koyama T, Chism DD (2018) Effect of concomitant pH-elevating medications with pazopanib on progression-free survival and overall survival in patients with metastatic renal cell carcinoma. Oncologist 23:686–692. https://doi.org/10.1634/theoncologist.2017-0578 CrossRefPubMedPubMedCentralGoogle Scholar
- 45.Mir O, Touati N, Lia M, Litière S, Le Cesne A, Sleijfer S et al (2019) Impact of concomitant administration of gastric acid-suppressive agents and pazopanib on outcomes in soft-tissue sarcoma patients treated within the EORTC 62043/62072 trials. Clin Cancer Res 25:1479–1485. https://doi.org/10.1158/1078-0432.CCR-18-2748 CrossRefPubMedGoogle Scholar
- 46.van Leeuwen RWF, Jansman FGA, Hunfeld NG, Peric R, Reyners AKL, Imholz ALT, Brouwers JRBJ, Aerts JG, van Gelder T, Mathijssen RHJ (2017) Tyrosine kinase inhibitors and proton pump inhibitors: An evaluation of treatment options. Clin Pharmacokinet 56:683–688. https://doi.org/10.1007/s40262-016-0503-3 CrossRefPubMedPubMedCentralGoogle Scholar