Abstract
Purpose
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.
Results
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with P-PK-DDI or without, the dose was reduced during the first month in 57.1% and 17.7% (p = 0.003) and the drug withdrawn in 42.8% and 11.3% (p = 0.011), respectively.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).
Conclusion
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.
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Data availability
The dataset analyzed during the present study is available from the corresponding author on request.
References
Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J et al (2013) Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 369:722–731. https://doi.org/10.1056/NEJMoa1303989
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
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
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
Shao J, Markowitz JS, Bei D, An G (2014) Enzyme- and transporter-mediated drug interactions with small molecule tyrosine kinase inhibitors. J Pharm Sci 103:3810–3833. https://doi.org/10.1002/jps.24113
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
Thomas-Schoemann A, Blanchet B, Bardin C, Noé G, Boudou-Rouquette P, Vidal M et al (2014) Drug interactions with solid tumour-targeted therapies. Crit Rev Oncol Hematol 89:179–196. https://doi.org/10.1016/j.critrevonc.2013.08.007
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
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
Kollmannsberger C, Soulieres D, Wong R, Scalera A, Gaspo R, Bjarnason G (2007) Sunitinib therapy for metastatic renal cell carcinoma: recommendations for management of side effects. Can Urol Assoc J 1:S41–S54
US Food and Drug Administration, Center for Drug Evaluation and Research. Pazopanib clinical pharmacology and biopharmaceutics review 2008
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
Bilbao-Meseguer I, Jose BS, Lopez-Gimenez LR, Gil MA, Serrano L, Castaño M, Sautua S, Basagoiti AD, Belaustegui A, Baza B, Baskaran Z, Bustinza A (2015) Drug interactions with sunitinib. J Oncol Pharm Pract 21:52–66. https://doi.org/10.1177/1078155213516158
Despiau F, Bombail M, Leches C, Montastruc M, Gladieff L, Delord J-P (2015) Nurse telephone support at home during chemotherapy. Rev Infirm:37–39. https://doi.org/10.1016/j.revinf.2015.06.011
Loue C, Tod M (2014) Reliability and extension of quantitative prediction of CYP3A4-mediated drug interactions based on clinical data. AAPS J 16:1309–1320. https://doi.org/10.1208/s12248-014-9663-y
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
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
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
Voll ML, Yap KD, Terpstra WE, Crul M (2010) Potential drug-drug interactions between anti-cancer agents and community pharmacy dispensed drugs. Pharm World Sci 32:575–580. https://doi.org/10.1007/s11096-010-9410-0
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
Frampton JE (2017) Pazopanib: a review in advanced renal cell carcinoma. Target Oncol 12:543–554. https://doi.org/10.1007/s11523-017-0511-8
Heinze G, Dunkler D (2017) Five myths about variable selection. Transpl Int 30:6–10. https://doi.org/10.1111/tri.12895
Sperandei S (2014) Understanding logistic regression analysis. Biochem Med (Zagreb) 24:12–18. https://doi.org/10.11613/BM.2014.003
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
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
Krasulova K, Holas O, Anzenbacher P (2017) Influence of amlodipine enantiomers on human microsomal cytochromes P450: stereoselective time-dependent inhibition of CYP3A enzyme activity. Molecules 22. https://doi.org/10.3390/molecules22111879
Ohyama K, Nakajima M, Suzuki M, Shimada N, Yamazaki H, Yokoi T (2000) Inhibitory effects of amiodarone and its N-deethylated metabolite on human cytochrome P450 activities: prediction of in vivo drug interactions. Br J Clin Pharmacol 49:244–253
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
Ito K, Brown HS, Houston JB (2004) Database analyses for the prediction of in vivo drug-drug interactions from in vitro data. Br J Clin Pharmacol 57:473–486. https://doi.org/10.1111/j.1365-2125.2003.02041.x
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
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
Widmer N, Bardin C, Chatelut E, Paci A, Beijnen J, Levêque D, Veal G, Astier A (2014) Review of therapeutic drug monitoring of anticancer drugs part two--targeted therapies. Eur J Cancer 50:2020–2036. https://doi.org/10.1016/j.ejca.2014.04.015
Verheijen RB, Yu H, Schellens JHM, Beijnen JH, Steeghs N, Huitema ADR (2017) Practical recommendations for therapeutic drug monitoring of kinase inhibitors in oncology. Clin Pharmacol Ther 102:765–776. https://doi.org/10.1002/cpt.787
Riechelmann RP, Moreira F, Smaletz O, Saad ED (2005) Potential for drug interactions in hospitalized cancer patients. Cancer Chemother Pharmacol 56:286–290. https://doi.org/10.1007/s00280-004-0998-4
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
Lalani A-KA, Li H, Heng DYC, Wood L, Kalirai A, Bjarnason GA et al (2017) First-line sunitinib or pazopanib in metastatic renal cell carcinoma: the Canadian experience. Can Urol Assoc J 11:112–117. https://doi.org/10.5489/cuaj.4398
Lee C-K, Choi J-S, Choi D-H (2015) Effects of HMG-CoA reductase inhibitors on the pharmacokinetics of nifedipine in rats: possible role of P-gp and CYP3A4 inhibition by HMG-CoA reductase inhibitors. Pharmacol Rep 67:44–51. https://doi.org/10.1016/j.pharep.2014.08.005
Kamiyama E, Nakai D, Mikkaichi T, Okudaira N, Okazaki O (2010) Interaction of angiotensin II type 1 receptor blockers with P-gp substrates in Caco-2 cells and hMDR1-expressing membranes. Life Sci 86:52–58. https://doi.org/10.1016/j.lfs.2009.11.006
Weiss J, Dormann S-MG, Martin-Facklam M, Kerpen CJ, Ketabi-Kiyanvash N, Haefeli WE (2003) Inhibition of P-glycoprotein by newer antidepressants. J Pharmacol Exp Ther 305:197–204. https://doi.org/10.1124/jpet.102.046532
Klotz U (2002) Interaction potential of lercanidipine, a new vasoselective dihydropyridine calcium antagonist. Arzneimittelforschung 52:155–161. https://doi.org/10.1055/s-0031-1299873
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
Ha VH, Ngo M, Chu MP, Ghosh S, Sawyer MB, Chambers CR (2015) Does gastric acid suppression affect sunitinib efficacy in patients with advanced or metastatic renal cell cancer? J Oncol Pharm Pract 21:194–200. https://doi.org/10.1177/1078155214527145
Lalani A-KA, McKay RR, Lin X, Simantov R, Kaymakcalan MD, Choueiri TK (2017) Proton pump inhibitors and survival outcomes in patients with metastatic renal cell carcinoma. Clin Genitourin Cancer 15:724–732. https://doi.org/10.1016/j.clgc.2017.05.019
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
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
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
Agarwal M, Thareja N, Benjamin M, Akhondi A, Mitchell GD (2018) Tyrosine kinase inhibitor-induced hypertension. Curr Oncol Rep 20:65–10. https://doi.org/10.1007/s11912-018-0708-8
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Azam, C., Claraz, P., Chevreau, C. et al. Association between clinically relevant toxicities of pazopanib and sunitinib and the use of weak CYP3A4 and P-gp inhibitors. Eur J Clin Pharmacol 76, 579–587 (2020). https://doi.org/10.1007/s00228-020-02828-w
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DOI: https://doi.org/10.1007/s00228-020-02828-w