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Review

Evaluating the utility of therapeutic drug monitoring in the clinical use of small molecule kinase inhibitors: a review of the literature

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Pages 803-821 | Received 09 Feb 2021, Accepted 11 Jun 2021, Published online: 19 Jul 2021

References

  • Mueller-Schoell A, Groenland SL, Scherf-Clavel O, et al. Therapeutic drug monitoring of oral targeted antineoplastic drugs. Eur J Clin Pharmacol. 2020;77:441–464.
  • Centanni M, Friberg LE. Model-based biomarker selection for dose individualization of tyrosine-kinase inhibitors. Front Pharmacol. 2020;11:316.
  • Escudier B, Gore M. Axitinib for the management of metastatic renal cell carcinoma. Drugs R & D. 2011;11(2):113–126.
  • Takahashi N, Miura M, Kuroki J, et al. Multicenter phase II clinical trial of nilotinib for patients with imatinib-resistant or -intolerant chronic myeloid leukemia from the East Japan CML study group evaluation of molecular response and the efficacy and safety of nilotinib. Biomark Res. 2014;2(1):6.
  • Kichenadasse G, Hughes JH, Miners JO, et al. Relationship between vemurafenib plasma concentrations and survival outcomes in patients with advanced melanoma. Cancer Chemother Pharmacol. 2020;85(3):615–620.
  • Kluwe F, Michelet R, Mueller-Schoell A, et al. Perspectives on model-informed precision dosing in the digital health era: challenges, opportunities, and recommendations. Clin Pharmacol Ther. 2020;109(1):29–36.
  • Rowland A, van Dyk M, Mangoni AA, et al. Kinase inhibitor pharmacokinetics: comprehensive summary and roadmap for addressing inter-individual variability in exposure. Expert Opin Drug Metab Toxicol. 2017;13(1):31–49.
  • De Wit D, Guchelaar HJ, Den Hartigh J, et al. Individualized dosing of tyrosine kinase inhibitors: are we there yet? Drug Discov Today. 2015;20(1):18–36.
  • Klumpen HJ, Samer CF, Mathijssen RH, et al. Moving towards dose individualization of tyrosine kinase inhibitors. Cancer Treat Rev. 2011;37(4):251–260.
  • Hopkins AM, Menz BD, Wiese MD, et al. Nuances to precision dosing strategies of targeted cancer medicines. Pharmacol Res Perspect. 2020;8(4):e00625.
  • Bardin C, Veal G, Paci A, et al. Therapeutic drug monitoring in cancer--are we missing a trick? Eur J Cancer. 2014;50(12):2005–2009.
  • Bouchet S, Royer B, Le Guellec C, et al. Suivi Therapeutique Pharmacologique de la Societe Francaise de Pharmacologie et de T [Therapeutic drug monitoring of tyrosine-kinase inhibitors in the treatment of chronic myelogenous leukaemia: interests and limits]. Therapie 2010;65(3):213–218.
  • Haouala A, Zanolari B, Rochat B, et al. Therapeutic Drug Monitoring of the new targeted anticancer agents imatinib, nilotinib, dasatinib, sunitinib, sorafenib and lapatinib by LC tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2009;877(22):1982–1996.
  • Widmer N, Bardin C, Chatelut E, et al. Review of therapeutic drug monitoring of anticancer drugs part two--targeted therapies. Eur J Cancer. 2014;50(12):2020–2036.
  • Yu H, Steeghs N, Nijenhuis CM, et al. Practical guidelines for therapeutic drug monitoring of anticancer tyrosine kinase inhibitors: focus on the pharmacokinetic targets. Clin Pharmacokinet. 2014;53(4):305–325.
  • Kang JS, Lee MH. Overview of therapeutic drug monitoring. Korean J Intern Med. 2009;24(1):1–10.
  • van Dyk M, Miners J, Kichenadasse G, et al. A novel approach for the simultaneous quantification of 18 small molecule kinase inhibitors in human plasma. J Chromatogr B. 2016;1033-1034:17–26.
  • Gross AS. Best practice in therapeutic drug monitoring. Br J Clin Pharmacol. 2001;52(Suppl1):5S–10S.
  • Holford NH, Buclin T. Safe and effective variability-a criterion for dose individualization. Ther Drug Monit. 2012;34(5):565–568.
  • Spector R, Park GD, Johnson GF, et al. Therapeutic drug monitoring. Clin Pharmacol Ther. 1988;43(4):345–353.
  • Williams HD, Ford L, Han S, et al. Enhancing the oral absorption of kinase inhibitors using lipophilic salts and lipid-based formulations. Mol Pharm. 2018;15(12):5678–5696.
  • van Dyk M, Rowland A. PBPK modeling as an approach to evaluate the effect of covariates and drug-drug interactions on variability in EGFR kinase inhibitor exposure. Transl Cancer Res. 2017;6(S10):S1600–15.
  • Rowland A, van Dyk M, Hopkins A, et al. Physiologically based pharmacokinetic modeling to identify physiological and molecular characteristics driving variability in drug exposure. Clin Pharmacol Ther. 2018;104(6):1219–1228.
  • Sorich M, Mulflib F, van Dyk M, et al. Use of Physiologically Based Pharmacokinetic Modeling to Identify Physiological and Molecular Characteristics Driving Variability in Axitinib Exposure: A Fresh Approach to Precision Dosing in Oncology. J Clin Pharmacol. 2019;59(6):872–879.
  • Mikus G, Foerster K. Role of CYP3A4 in kinase inhibitor metabolism and assessment of CYP3A4 activity. Transl Cancer Res. 2017;6(S10):S1592–9.
  • Kiser JJ, Burton JR Jr, Everson GT. Drug-drug interactions during antiviral therapy for chronic hepatitis C. Nat Rev Gastroenterol Hepatol. 2013;10(10):596–606.
  • Ulvestad M, Skottheim IB, Jakobsen GS, et al. Impact of OATP1B1, MDR1, and CYP3A4 expression in liver and intestine on interpatient pharmacokinetic variability of atorvastatin in obese subjects. Clin Pharmacol Ther. 2013;93(3):275–282.
  • Kapetas A, Sorich M, Rodrigues A, et al. Guidance for rifampin and midazolam dosing protocols to study intestinal and hepatic Cyotchrome P450 (CYP) 3A4 induction and de-induction. AAPS J. 2019;21(5):78.
  • Eckstein N, Roper L, Haas B, et al. Clinical pharmacology of tyrosine kinase inhibitors becoming generic drugs: the regulatory perspective. J Exp Clin Cancer Res. 2014;33(1):15.
  • Rowland A, Sorich MJ. Preface to precision dosing of targeted anti-cancer drugs. Transl Cancer Res. 2017;6(S10):S1498–9.
  • Fallahi P, Ferrari SM, Elia G, et al. THERAPY OF ENDOCRINE DISEASE: endocrine-metabolic effects of treatment with multikinase inhibitors. Eur J Endocrinol. 2021;184(1):R29–r40.
  • Zhao S, Zhang Z, Fang W, et al. Efficacy and tolerability of erlotinib 100 mg/d vs. gefitinib 250 mg/d in EGFR-mutated advanced non-small cell lung cancer (E100VG250): an open-label, randomized, phase 2 study. Front Oncol. 2020;10:587849.
  • Ornstein MC, Pal SK, Wood LS, et al. Individualised axitinib regimen for patients with metastatic renal cell carcinoma after treatment with checkpoint inhibitors: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2019;20(10):1386–1394.
  • European medicines agency inlyta CHMP assessment report 2012 05/24/12. Report No.
  • Sorich MJ, Mutlib F, van Dyk M, et al. Use of physiologically based pharmacokinetic modeling to identify physiological and molecular characteristics driving variability in axitinib exposure: a fresh approach to precision dosing in oncology. J Clin Pharmacol. 2019;59(6):872–879.
  • Pithavala YK, Tortorici M, Toh M, et al. Effect of rifampin on the pharmacokinetics of Axitinib (AG-013736) in Japanese and Caucasian healthy volunteers. Cancer Chemother Pharmacol. 2010;65(3):563–570.
  • Rini BI, Garrett M, Poland B, et al. Axitinib in metastatic renal cell carcinoma: results of a pharmacokinetic and pharmacodynamic analysis. J Clin Pharmacol. 2013;53(5):491–504.
  • Liu G, Rugo HS, Wilding G, et al. Dynamic contrast-enhanced magnetic resonance imaging as a pharmacodynamic measure of response after acute dosing of AG-013736, an oral angiogenesis inhibitor, in patients with advanced solid tumors: results from a phase I study. J Clin Oncol. 2005;23(24):5464–5473.
  • Rini BI, Melichar B, Fishman MN, et al. Axitinib dose titration: analyses of exposure, blood pressure and clinical response from a randomized phase II study in metastatic renal cell carcinoma. Ann Oncol. 2015;26(7):1372–1377.
  • Miura Y, Imamura CK, Uchino K, et al. Individualized dosing of axitinib based on first-dose area under the concentration–time curve for metastatic renal-cell carcinoma. Clin Genitourin Cancer. 2019;17(1):e1–e11.
  • Tsuchiya N, Igarashi R, Suzuki-Honma N, et al. Association of pharmacokinetics of axitinib with treatment outcome and adverse events in advanced renal cell carcinoma patients. J clin oncol. 2015;33(7_suppl):506.
  • Yamamoto Y, Tsunedomi R, Fujita Y, et al. Pharmacogenetics-based area-under-curve model can predict efficacy and adverse events from axitinib in individual patients with advanced renal cell carcinoma. Oncotarget. 2018;9(24):17160–17170.
  • Rini BI, Melichar B, Ueda T, et al. Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma: a randomised double-blind phase 2 trial. Lancet Oncol. 2013;14(12):1233–1242.
  • Yu H, van Erp N, Bins S, et al. Development of a pharmacokinetic model to describe the complex pharmacokinetics of pazopanib in cancer patients. Clin Pharmacokinet. 2017;56(3):293–303.
  • Heath EI, Chiorean EG, Sweeney CJ, et al. A phase I study of the pharmacokinetic and safety profiles of oral pazopanib with a high-fat or low-fat meal in patients with advanced solid tumors. Clin Pharmacol Ther. 2010;88(6):818–823.
  • Tan AR, Gibbon DG, Stein MN, et al. Effects of ketoconazole and esomeprazole on the pharmacokinetics of pazopanib in patients with solid tumors. Cancer Chemother Pharmacol. 2013;71(6):1635–1643.
  • 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. 2020;76(4):579–587.
  • Sternberg CN, Donskov F, Haas NB, et al. Pazopanib exposure relationship with clinical efficacy and safety in the adjuvant treatment of advanced renal cell carcinoma. Clin Cancer Res. 2018;24(13):3005.
  • Suttle AB, Ball HA, Molimard M, et al. Relationships between pazopanib exposure and clinical safety and efficacy in patients with advanced renal cell carcinoma. Br J Cancer. 2014;111(10):1909–1916.
  • Verheijen RB, Swart LE, Beijnen JH, et al. Exposure-survival analyses of pazopanib in renal cell carcinoma and soft tissue sarcoma patients: opportunities for dose optimization. Cancer Chemother Pharmacol. 2017;80(6):1171–1178.
  • Verheijen RB, Bins S, Mathijssen RHJ, et al. Individualized pazopanib dosing: a prospective feasibility study in cancer patients. Clin Cancer Res. 2016;22(23):5738.
  • Teo YL, Chue XP, Chau NM, et al. Association of drug exposure with toxicity and clinical response in metastatic renal cell carcinoma patients receiving an attenuated dosing regimen of sunitinib. Target Oncol. 2015;10(3):429–437.
  • Sabanathan D, Zhang A, Fox P, et al. Dose individualization of sunitinib in metastatic renal cell cancer: toxicity-adjusted dose or therapeutic drug monitoring. Cancer Chemother Pharmacol. 2017;80(2):385–393.
  • Houk BE, Bello CL, Kang D, et al. A population pharmacokinetic meta-analysis of sunitinib malate (SU11248) and its primary metabolite (SU12662) in healthy volunteers and oncology patients. Clin Cancer Res. 2009;15(7):2497.
  • Houk BE, Bello CL, Poland B, et al. Relationship between exposure to sunitinib and efficacy and tolerability endpoints in patients with cancer: results of a pharmacokinetic/pharmacodynamic meta-analysis. Cancer Chemother Pharmacol. 2010;66(2):357–371.
  • Noda S, Otsuji T, Baba M, et al. Assessment of sunitinib-induced toxicities and clinical outcomes based on therapeutic drug monitoring of sunitinib for patients with renal cell carcinoma. Clin Genitourin Cancer. 2015;13(4):350–358.
  • Abrams TJ, Murray LJ, Pesenti E, et al. Preclinical evaluation of the tyrosine kinase inhibitor SU11248 as a single agent and in combination with “standard of care” therapeutic agents for the treatment of breast cancer. Mol Cancer Ther. 2003;2(10):1011–1021.
  • Mendel DB, Laird AD, Xin X, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res off J Am Assoc Cancer Res. 2003;9(1):327–337.
  • Abrams TJ, Lee LB, Murray LJ, et al. SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther. 2003;2(5):471–478.
  • Faivre S, Delbaldo C, Vera K, et al. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J clin oncol. 2006;24(1):25–35.
  • Lankheet NAG, Kloth JSL, Gadellaa-van Hooijdonk CGM, et al. Pharmacokinetically guided sunitinib dosing: a feasibility study in patients with advanced solid tumours. Br J Cancer. 2014;110(10):2441–2449.
  • Takasaki S, Kawasaki Y, Kikuchi M, et al. Relationships between sunitinib plasma concentration and clinical outcomes in Japanese patients with metastatic renal cell carcinoma. Int J Clin Oncol. 2018;23(5):936–943.
  • De Wit D, Gelderblom H, Sparreboom A, et al. Midazolam as a phenotyping probe to predict sunitinib exposure in patients with cancer. Cancer Chemother Pharmacol. 2014;73(1):87–96.
  • Rini BI, Cohen DP, Lu DR, et al. Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst. 2011;103(9):763–773.
  • Jain L, Woo S, Gardner ER, et al. Population pharmacokinetic analysis of sorafenib in patients with solid tumours. Br J Clin Pharmacol. 2011;72(2):294–305.
  • Boudou-Rouquette P, Narjoz C, Golmard JL, et al. Early sorafenib-induced toxicity is associated with drug exposure and UGTIA9 genetic polymorphism in patients with solid tumors: a preliminary study. PloS One. 2012;7(8):e42875–e.
  • Kobayashi K, Higai K, Matsuo K, et al. Quantitative measurements of sorafenib in patients with advanced hepatocellular carcinoma. Int J Res Stud Med Health Sci. 2018;3(2):14–19.
  • Labeur TA, Hofsink Q, Takkenberg RB, et al. The value of sorafenib trough levels in patients with advanced hepatocellular carcinoma – a substudy of the SORAMIC trial. Acta Oncologica. 2020;59(9):1028–1035.
  • Fukudo M, Ito T, Mizuno T, et al. Exposure–toxicity relationship of sorafenib in japanese patients with renal cell carcinoma and hepatocellular carcinoma. Clin Pharmacokinet. 2014;53(2):185–196.
  • Shimada M, Okawa H, Kondo Y, et al. Monitoring serum levels of sorafenib and its n-oxide is essential for long-term sorafenib treatment of patients with hepatocellular carcinoma. Tohoku J Exp Med. 2015;237(3):173–182.
  • Ruanglertboon W, Sorich MJ, Rowland A, et al. Effect of early adverse events resulting in sorafenib dose adjustments on survival outcomes of advanced hepatocellular carcinoma patients. Int J Clin Oncol. 2020;25(9):1672–1677.
  • Ruanglertboon W, Sorich MJ, Logan JM, et al. The effect of proton pump inhibitors on survival outcomes in advanced hepatocellular carcinoma treated with sorafenib. J Cancer Res Clin Oncol. 2020;146(10):2693–2697.
  • Estfan B, Byrne M, Kim R. Sorafenib in advanced hepatocellular carcinoma: hypertension as a potential surrogate marker for efficacy. Am J Clin Oncol. 2013;36(4):319–324.
  • Akutsu N, Sasaki S, Takagi H, et al. Development of hypertension within 2 weeks of initiation of sorafenib for advanced hepatocellular carcinoma is a predictor of efficacy. Int J Clin Oncol. 2015;20(1):105–110.
  • Szmit S, Zaborowska M, Waśko-Grabowska A, et al. Cardiovascular comorbidities for prediction of progression-free survival in patients with metastatic renal cell carcinoma treated with sorafenib. Kidney Blood Press Res. 2012;35(6):468–476.
  • Lankheet NA, Knapen LM, Schellens JH, et al. Plasma concentrations of tyrosine kinase inhibitors imatinib, erlotinib, and sunitinib in routine clinical outpatient cancer care. Ther Drug Monit. 2014;36(3):326–334.
  • Hidalgo M, Siu LL, Nemunaitis J, et al. Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J clin oncol. 2001;19(13):3267–3279.
  • EMA tarceva EPAR scientific discussion european medicines agency, 2005.
  • Mita AC, Papadopoulos K, de Jonge MJA, et al. Erlotinib ‘dosing-to-rash’: a phase II intrapatient dose escalation and pharmacologic study of erlotinib in previously treated advanced non-small cell lung cancer. Br J Cancer. 2011;105(7):938–944.
  • Hamilton M, Wolf JL, Rusk J, et al. Effects of Smoking on the Pharmacokinetics of Erlotinib. Clin Cancer Res. 2006;12(7):2166.
  • Rakhit A, Pantze MP, Fettner S, et al. The effects of CYP3A4 inhibition on erlotinib pharmacokinetics: computer-based simulation (SimCYP) predicts in vivo metabolic inhibition. Eur J Clin Pharmacol. 2008;64(1):31–41.
  • Tiseo M, Andreoli R, Gelsomino F, et al. Correlation between erlotinib pharmacokinetics, cutaneous toxicity and clinical outcomes in patients with advanced non-small cell lung cancer (NSCLC). Lung Cancer. 2014;83(2):265–271.
  • Yeo WL, Riely GJ, Yeap BY, et al. Erlotinib at a dose of 25 mg daily for non-small cell lung cancers with EGFR mutations. J Thorac Oncol. 2010;5(7):1048–1053.
  • Binder D, Buckendahl AC, Hübner RH, et al. Erlotinib in patients with advanced non-small-cell lung cancer: impact of dose reductions and a novel surrogate marker. Med Oncol. 2012;29(1):193–198.
  • Lampson BL, Nishino M, Dahlberg SE, et al. Activity of erlotinib when dosed below the maximum tolerated dose for EGFR-mutant lung cancer: implications for targeted therapy development. Cancer. 2016;122(22):3456–3463.
  • Miyamoto S, Azuma K, Ishii H, et al. Low-dose erlotinib treatment in elderly or frail patients with EGFR mutation-positive non-small cell lung cancer: a multicenter phase 2 trial. JAMA Oncol. 2020;6(7):e201250.
  • Yamada K, Aono H, Hosomi Y, et al. A prospective, multicentre phase II trial of low-dose erlotinib in non-small cell lung cancer patients with EGFR mutations pretreated with chemotherapy: thoracic oncology research group 0911. Eur J Cancer. 2015;51(14):1904–1910.
  • Lu JF, Eppler SM, Wolf J, et al. Clinical pharmacokinetics of erlotinib in patients with solid tumors and exposure-safety relationship in patients with non-small cell lung cancer. Clin Pharmacol Ther. 2006;80(2):136–145.
  • Wacker B, Nagrani T, Weinberg J, et al. Correlation between development of rash and efficacy in patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in two large phase III studies. Clin Cancer Res off J Am Assoc Cancer Res. 2007;13(13):3913–3921.
  • Steffens M, Paul T, Hichert V, et al. Dosing to rash?--The role of erlotinib metabolic ratio from patient serum in the search of predictive biomarkers for EGFR inhibitor-mediated skin rash. Eur J Cancer. 2016;55:131–139.
  • FDA Iressa clinical pharmacology review 2014.
  • Swaisland HC, Smith RP, Laight A, et al. Single-dose clinical pharmacokinetic studies of gefitinib. Clin Pharmacokinet. 2005;44(11):1165–1177.
  • Li J, Karlsson MO, Brahmer J, et al. CYP3A phenotyping approach to predict systemic exposure to EGFR tyrosine kinase inhibitors. JNCI. 2006;98(23):1714–1723.
  • Wan Z, Guo L, Li P, et al. Determinants of gefitinib pharmacokinetics in healthy Chinese male subjects: a pharmacogenomic study of cytochrome p450 enzymes and transporters. J Clin Pharm Ther. 2020;45(5):1159–1167.
  • Swaisland H, Laight A, Stafford L, et al. Pharmacokinetics and tolerability of the orally active selective epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 in healthy volunteers. Clin Pharmacokinet. 2001;40(4):297–306.
  • Zhao -Y-Y, Li S, Zhang Y, et al. The relationship between drug exposure and clinical outcomes of non-small cell lung cancer patients treated with gefitinib. Med Oncol. 2011;28(3):697–702.
  • Guan S, Chen X, Xin S, et al. Establishment and application of a predictive model for gefitinib-induced severe rash based on pharmacometabolomic profiling and polymorphisms of transporters in non-small cell lung cancer. Transl Oncol. 2021;14(1):100951.
  • Xin S, Zhao Y, Wang X, et al. The dissociation of gefitinib trough concentration and clinical outcome in NSCLC patients with EGFR sensitive mutations. Sci Rep. 2015;5(1):12675.
  • Wang X, Hochhaus A, Kantarjian HM, et al. Dasatinib pharmacokinetics and exposure-response (E-R): relationship to safety and efficacy in patients (pts) with chronic myeloid leukemia (CML). J clin oncol. 2008;26(15_suppl):3590.
  • Takahashi N, Miura M, Niioka T, et al. Influence of H2-receptor antagonists and proton pump inhibitors on dasatinib pharmacokinetics in Japanese leukemia patients. Cancer Chemother Pharmacol. 2012;69(4):999–1004.
  • Rousselot P, Mollica L, Guerci-Bresler A, et al. Dasatinib daily dose optimization based on residual drug levels resulted in reduced risk of pleural effusions and high molecular response rates: final results of the randomized optim dasatinib trial. Haematologica. 2014;99:237‐8.
  • Larson RA, Yin OQP, Hochhaus A, et al. Population pharmacokinetic and exposure-response analysis of nilotinib in patients with newly diagnosed Ph+ chronic myeloid leukemia in chronic phase. Eur J Clin Pharmacol. 2012;68(5):723–733.
  • Abumiya M, Takahashi N, Niioka T, et al. Influence of UGT1A1 *6, *27, and *28 polymorphisms on nilotinib-induced hyperbilirubinemia in Japanese patients with chronic myeloid leukemia. Drug Metab Pharmacokinet. 2014;29(6):449–454.
  • Tanaka C, Yin OQ, Sethuraman V, et al. Clinical pharmacokinetics of the BCR-ABL tyrosine kinase inhibitor nilotinib. Clin Pharmacol Ther. 2010;87(2):197–203.
  • Tanaka C, Yin OQ, Smith T, et al. Effects of rifampin and ketoconazole on the pharmacokinetics of nilotinib in healthy participants. J Clin Pharmacol. 2011;51(1):75–83.
  • Yin OQ, Gallagher N, Li A, et al. Effect of grapefruit juice on the pharmacokinetics of nilotinib in healthy participants. J Clin Pharmacol. 2010;50(2):188–194.
  • Giles FJ, Yin OQP, Sallas WM, et al. Nilotinib population pharmacokinetics and exposure-response analysis in patients with imatinib-resistant or -intolerant chronic myeloid leukemia. Eur J Clin Pharmacol. 2013;69(4):813–823.
  • Miners JO, Chau N, Rowland A, et al. Inhibition of human UDP-glucuronosyltransferase enzymes by lapatinib, pazopanib, regorafenib and sorafenib: implications for hyperbilirubinemia. Biochem Pharmacol. 2017;129:85–95.
  • Singer JB, Shou Y, Giles F, et al. UGT1A1 promoter polymorphism increases risk of nilotinib-induced hyperbilirubinemia. Leukemia. 2007;21(11):2311–2315.
  • Yoo C, Ryu M-H, Kang BW, et al. Cross-sectional study of imatinib plasma trough levels in patients with advanced gastrointestinal stromal tumors: impact of gastrointestinal resection on exposure to imatinib. J clin oncol. 2010;28(9):1554–1559.
  • Bouchet S, Poulette S, Titier K, et al. Relationship between imatinib trough concentration and outcomes in the treatment of advanced gastrointestinal stromal tumours in a real-life setting. Eur J Cancer. 2016;57:31–38.
  • Demetri GD, Wang Y, Wehrle E, et al. Imatinib plasma levels are correlated with clinical benefit in patients with unresectable/metastatic gastrointestinal stromal tumors. J clin oncol. 2009;27(19):3141–3147.
  • Delbaldo C, Chatelut E, Ré M, et al. Pharmacokinetic-pharmacodynamic relationships of imatinib and its main metabolite in patients with advanced gastrointestinal stromal tumors. Clin Cancer Res. 2006;12(20):6073.
  • Widmer N, Decosterd LA, Leyvraz S, et al. Relationship of imatinib-free plasma levels and target genotype with efficacy and tolerability. Br J Cancer. 2008;98(10):1633–1640.
  • Peng B, Hayes M, Resta D, et al. Pharmacokinetics and pharmacodynamics of imatinib in a phase i trial with chronic myeloid leukemia patients. J clin oncol. 2004;22(5):935–942.
  • Takahashi N, Miura M, Scott SA, et al. Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia. J Hum Genet. 2010;55(11):731–737.
  • Singh O, Chan JY, Lin K, et al. SLC22A1-ABCB1 haplotype profiles predict imatinib pharmacokinetics in Asian patients with chronic myeloid leukemia. PLoS One. 2012;7(12):e51771.
  • Larson RA, Druker BJ, Guilhot F, et al. Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood. 2008;111(8):4022–4028.
  • Picard S, Titier K, Etienne G, et al. Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood. 2006;109(8):3496–3499.
  • François G, Timothy PH, Jorge C, et al. Plasma exposure of imatinib and its correlation with clinical response in the tyrosine kinase inhibitor optimization and selectivity trial. Haematologica. 2012;97(5):731–738.
  • Gotta V, Widmer N, Decosterd LA, et al. Clinical usefulness of therapeutic concentration monitoring for imatinib dosage individualization: results from a randomized controlled trial. Cancer Chemother Pharmacol. 2014;74(6):1307–1319.
  • Alecensa product information. 2017.
  • Groenland SL, Geel DR, Janssen JM, et al. Exposure–response analyses of anaplastic lymphoma kinase inhibitors crizotinib and alectinib in non-small cell lung cancer patients. Clin Pharmacol Ther. 2021;109(2):394–402.
  • Hsu JC, Carnac R, Henschel V, et al. Population pharmacokinetics (popPK) and exposure-response (ER) analyses to confirm alectinib 600 mg BID dose selection in a crizotinib-progressed or intolerant population. J clin oncol. 2016;34(15_suppl):e20598–e.
  • Morcos PN, Nueesch E, Jaminion F, et al. Exposure-response analysis of alectinib in crizotinib-resistant ALK-positive non-small cell lung cancer. Cancer Chemother Pharmacol. 2018;82(1):129–138.
  • Alecensa assessment report. EMA, 2016.
  • Xu H, O’Gorman M, Tan W, et al. The effects of ketoconazole and rifampin on the single-dose pharmacokinetics of crizotinib in healthy subjects. Eur J Clin Pharmacol. 2015;71(12):1441–1449.
  • Crizotinib clinical pharmacology and biopharmaceutics review 2011.
  • Kurata Y, Miyauchi N, Suno M, et al. Correlation of plasma crizotinib trough concentration with adverse events in patients with anaplastic lymphoma kinase positive non-small-cell lung cancer. J Pharm Health Care Sci. 2015;1(1):8.
  • AusPAR attachment 2, extract from the clinical evaluation report for dabrafenibn mesilate. 2013.
  • Groenland SL, Janssen JM, Nijenhuis C, et al. 567P exposure-response analyses of dabrafenib and trametinib in melanoma patients. Ann Oncol. 2020;31:S486–S7.
  • Balakirouchenane D, Guégan S, Csajka C, et al. Population pharmacokinetics/pharmacodynamics of dabrafenib plus trametinib in patients with BRAF-mutated metastatic melanoma. Cancers (Basel). 2020;12(4):4.
  • Ouellet D, Grossmann KF, Limentani G, et al. Effects of particle size, food, and capsule shell composition on the oral bioavailability of dabrafenib, a BRAF inhibitor, in patients with BRAF mutation-positive tumors. J Pharm Sci. 2013;102(9):3100–3109.
  • Lawrence SK, Nguyen D, Bowen C, et al. The metabolic drug-drug interaction profile of Dabrafenib: in vitro investigations and quantitative extrapolation of the P450-mediated DDI risk. Drug Metab Dispos. 2014;42(7):1180–1190.
  • Suttle AB, Grossmann KF, Ouellet D, et al. Assessment of the drug interaction potential and single- and repeat-dose pharmacokinetics of the BRAF inhibitor dabrafenib. J Clin Pharmacol. 2015;55(4):392–400.
  • Funck-Brentano E, Raynal M, Alvarez J-C, et al. Plasma concentrations of dabrafenib and trametinib (PCD/T) monitoring in advanced BRAFV600mut melanoma patients. J clin oncol. 2019;37(15_suppl):9541.
  • Rousset M, Dutriaux C, Bosco-Lévy P, et al. Trough dabrafenib plasma concentrations can predict occurrence of adverse events requiring dose reduction in metastatic melanoma. Clin Chim Acta. 2017;472:26–29.
  • Menzies AM, Ashworth MT, Swann S, et al. Characteristics of pyrexia in BRAFV600E/K metastatic melanoma patients treated with combined dabrafenib and trametinib in a phase I/II clinical trial. Ann Oncol. 2015;26(2):415–421.
  • Ouellet D, Kassir N, Chiu J, et al. Population pharmacokinetics and exposure–response of trametinib, a MEK inhibitor, in patients with BRAF V600 mutation-positive melanoma. Cancer Chemother Pharmacol. 2016;77(4):807–817.
  • Cox DS, Papadopoulos K, Fang L, et al. Evaluation of the effects of food on the single-dose pharmacokinetics of trametinib, a first-in-class MEK inhibitor, in patients with cancer. J Clin Pharmacol. 2013;53(9):946–954.
  • Zhang W, Heinzmann D, Grippo JF. Clinical Pharmacokinetics of Vemurafenib. Clin Pharmacokinet. 2017;56(9):1033–1043.
  • Goldwirt L, Chami I, Feugeas JP, et al. Reply to ‘Plasma vemurafenib concentrations in advanced BRAFV600mut melanoma patients: impact on tumour response and tolerance’ by Funck-Brentano et al. Ann Oncol. 2016;27(2):363–364.
  • Funck-Brentano E, Alvarez JC, Longvert C, et al. Plasma vemurafenib concentrations in advanced BRAFV600mut melanoma patients: impact on tumour response and tolerance†. Ann Oncol. 2015;26(7):1470–1475.
  • Funck-Brentano E, Alvarez JC, Longvert C, et al. Reply to the letter to the editor ‘Plasma vemurafenib concentrations in advanced BRAFV600mut melanoma patients: impact on tumor response and tolerance’ by Funck-Brentano et al. Ann Oncol. 2016;27(2):364–365.
  • Kramkimel N, Thomas-Schoemann A, Sakji L, et al. Vemurafenib pharmacokinetics and its correlation with efficacy and safety in outpatients with advanced BRAF-mutated melanoma. Target Oncol. 2016;11(1):59–69.
  • Goulooze S, Martin J, Smith A Therapeutic drug monitoring trials for gastrointestinal stromal tumors treated with sunitinib cannot be expected to detect clinical outcome improvement ASCEPT-APSA JSM; Hobart; 2015. p. p524.
  • Goulooze SC, Galettis P, Boddy AV, et al. Monte Carlo simulations of the clinical benefits from therapeutic drug monitoring of sunitinib Cancer Chemo Pharmacol. Cancer Chemotherapy and Pharmacology. 2016;78(1):209–216.
  • Rodrigues A, Rowland A. From endogenous compounds as biomarkers to plasma-derived nanovesicles as liquid biopsy; has the golden age of translational PK-ADME-DDI science finally arrived? Clin Pharmacol Ther. 2019;105:1407–1420.
  • Rowland A, Ruanglertboon W, van Dyk M, et al. Plasma extracellular nanovesicle (exosome) derived biomarkers for ADME pathways: a novel approach to characterise variability in drug exposure. Br J Clin Pharmacol. 2019;85(1):216–226.
  • Ruanglertboon W, Sorich MJ, Hopkins AM, et al. Mechanistic modelling identifies and addresses the risks of empiric concentration-guided sorafenib dosing. Pharmaceuticals. 2021;14(5):389.

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