The metabolic drug-drug interaction profile of dabrafenib: In vitro investigations and quantitative extrapolation of the P450-mediated DDI risks

Drug Metabolism and Disposition

Volumn 42, Issue 7, 2014, Pages 1180-1190

  Lawrence, Sarah K ^a   Nguyen, Dung ^a   Bowen, Chet ^a   Richards Peterson, Lauren ^a   Skordos, Konstantine W ^a  

^a GLAXOSMITHKLINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ATORVASTATIN; CYTOCHROME P450; CYTOCHROME P450 2B6; CYTOCHROME P450 2C19; CYTOCHROME P450 2C8; CYTOCHROME P450 2C9; CYTOCHROME P450 3A4; DABRAFENIB; DRUG METABOLITE; MESSENGER RNA; MIDAZOLAM; NIFEDIPINE; IMIDAZOLE DERIVATIVE; OXIME; PROTEIN KINASE INHIBITOR;

AEROBIC METABOLISM; AREA UNDER THE CURVE; ARTICLE; CONCENTRATION RESPONSE; CONTROLLED STUDY; DRUG ANTAGONISM; DRUG METABOLISM; DRUG STRUCTURE; ENZYME ACTIVITY; ENZYME INHIBITION; HUMAN; HUMAN CELL; IC 50; IN VITRO STUDY; LIVER CELL; PRIORITY JOURNAL; RISK ASSESSMENT; DRUG INTERACTION; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY;

CHROMATOGRAPHY, HIGH PRESSURE LIQUID; DRUG INTERACTIONS; HUMANS; IMIDAZOLES; IN VITRO TECHNIQUES; OXIMES; PROTEIN KINASE INHIBITORS;

EID: 84903204194     PISSN: 00909556     EISSN: 1521009X     Source Type: Journal    
DOI: 10.1124/dmd.114.057778     Document Type: Article

References (56)

1. American Cancer Society (2013) Cancer Facts & Figures 2013, American Cancer Society, Atlanta.
2. Bachmann KA and Lewis JD (2005) Predicting inhibitory drug-drug interactions and evaluating drug interaction reports using inhibition constants. Ann Pharmacother 39 :1064-1072.
3. Baer BR, DeLisle RK, and Allen A (2009) Benzylic oxidation of gemfibrozil-1-O-beta-glucuronide by P450 2C8 leads to heme alkylation and irreversible inhibition. Chem Res Toxicol 22:1298-1309.
4. Baldwin SJ, Bloomer JC, Smith GJ, Ayrton AD, Clarke SE, and Chenery RJ (1995) Ketoconazole and sulphaphenazole as the respective selective inhibitors of P4503A and 2C9. Xenobiotica 25: 261-270.
5. Baldwin SJ, Clarke SE, and Chenery RJ (1999) Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of rosiglitazone. Br J Clin Pharmacol 48: 424-432.
6. Bershas DA, Ouellet D, Mamaril-Fishman DB, Nebot N, Carson SW, Blackman SC, Morrison RA, Adams JL, Jurusik KE, and Knecht DM, et al. (2013) Metabolism and disposition of oral dabrafenib in cancer patients: proposed participation of aryl nitrogen in carbon-carbon bond cleavage via decarboxylation following enzymatic oxidation. Drug Metab Dispos 41: 2215-2224.
7. Borges S, Li L, Hamman MA, Jones DR, Hall SD, and Gorski JC (2005) Dextromethorphan to dextrorphan urinary metabolic ratio does not reflect dextromethorphan oral clearance. Drug Metab Dispos 33:1052-1055.
8. Chen M, Nafziger AN, and Bertino JS, Jr (2006) Drug-metabolizing enzyme inhibition by ketoconazole does not reduce interindividual variability of CYP3A activity as measured by oral midazolam. Drug Metab Dispos 34:2079-2082.
9. Cheng Y and Prusoff WH (1973) Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol 22:3099-3108.
10. Eggermont AMM and Robert C (2011) New drugs in melanoma: it's a whole new world. Eur J Cancer 47:2150-2157.
11. Einolf HJ (2007) Comparison of different approaches to predict metabolic drug-drug interactions. Xenobiotica 37:1257-1294.
12. Fahmi OA, Maurer TS, Kish M, Cardenas E, Boldt S, and Nettleton D (2008) A combined model for predicting CYP3A4 clinical net drug-drug interaction based on CYP3A4 inhibition, inactivation, and induction determined in vitro. Drug Metab Dispos 36:1698-1708.
13. Falchook GS, Long GV, Kurzrock R, Kim KB, Arkenau TH, Brown MP, Hamid O, Infante JR, Millward M, and Pavlick AC, et al. (2012) Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet 379: 1893-1901.
14. Flaherty KT and McArthur G (2010) BRAF, a target in melanoma: implications for solid tumor drug development. Cancer 116:4902-4913.
15. Galetin A, Gertz M, and Houston JB (2008) Potential role of intestinal first-pass metabolism in the prediction of drug-drug interactions. Expert Opin Drug Metab Toxicol 4:909-922.
16. Grimm SW, Einolf HJ, Hall SD, He K, Lim HK, Ling KH, Lu C, Nomeir AA, Seibert E, and Skordos KW, et al. (2009) The conduct of in vitro studies to address time-dependent inhibition of drug-metabolizing enzymes: a perspective of the pharmaceutical research and manufacturers of America. Drug Metab Dispos 37:1355-1370.
17. Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P, Blank CU, Miller WH Jr, Kaempgen E, Martín-Algarra S, Karaszewska B, Mauch C, Chiarion-Sileni V, Martin AM, Swann S, Haney P, Mirakhur B, Guckert ME, Goodman V, and Chapman PB. (2012) Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet; 380(9839):358-65.
18. Heakal Y, Kester M, and Savage S (2011) Vemurafenib (PLX4032): an orally available inhibitor of mutated BRAF for the treatment of metastatic melanoma. Ann Pharmacother 45:1399-1405.
19. Honkalammi J, Niemi M, Neuvonen PJ, and Backman JT (2011) Mechanism-based inactivation of CYP2C8 by gemfibrozil occurs rapidly in humans. Clin Pharmacol Ther 89:579-586.
20. Kenny JR, Mukadam S, Zhang C, Tay S, Collins C, Galetin A, and Khojasteh SC (2012) Drug-drug interaction potential of marketed oncology drugs: in vitro assessment of time-dependent cytochrome P450 inhibition, reactive metabolite formation and drug-drug interaction prediction. Pharm Res 29:1960-1976.
21. Maldonado JL, Fridlyand J, Patel H, Jain AN, Busam K, Kageshita T, Ono T, Albertson DG, Pinkel D, and Bastian BC (2003) Determinants of BRAF mutations in primary melanomas. J Natl Cancer Inst 95:1878-1890.
22. Obach RS, Walsky RL, and Venkatakrishnan K (2007) Mechanism-based inactivation of human cytochrome p450 enzymes and the prediction of drug-drug interactions. Drug Metab Dispos 35:246-255.
23. Obach RS, Walsky RL, Venkatakrishnan K, Gaman EA, Houston JB, and Tremaine LM (2006) The utility of in vitro cytochrome P450 inhibition data in the prediction of drug-drug interactions. J Pharmacol Exp Ther 316:336-348.
24. Ogilvie BW, Zhang D, Li W, Rodrigues AD, Gipson AE, Holsapple J, Toren P, and Parkinson A (2006) Glucuronidation converts gemfibrozil to a potent, metabolism-dependent inhibitor of CYP2C8: implications for drug-drug interactions. Drug Metab Dispos 34:191-197.
25. Otton SV, Crewe HK, Lennard MS, Tucker GT, and Woods HF (1988) Use of quinidine inhibition to define the role of the sparteine/debrisoquine cytochrome P450 in metoprolol oxidation by human liver microsomes. J Pharmacol Exp Ther 247:242-247.
26. Ouellet D, Grossmann KF, Limentani G, Nebot N, Lan K, Knowles L, Sharma S, Infante JR, LoRusso PM, Pande G, Krachey EC, Blackman SC, and Carson SW. (2013) 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 102 (9): 3100-3109.
27. Polli JW, Hussey E, Bush M, Generaux G, Smith G, Collins D, McMullen S, Turner N, and Nunez DJ (2013) Evaluation of drug interactions of GSK1292263 (a GPR119 agonist) with statins: from in vitro data to clinical study design. Xenobiotica 43:498-508.
28. Proctor NJ, Tucker GT, and Rostami-Hodjegan A (2004) Predicting drug clearance from recombinantly expressed CYPs: intersystem extrapolation factors. Xenobiotica 34:151-178.
29. Quinney SK, Zhang X, Lucksiri A, Gorski JC, Li L, and Hall SD (2010) Physiologically based pharmacokinetic model of mechanism-based inhibition of CYP3A by clarithromycin. Drug Metab Dispos 38:241-248.
30. Reese MJ, Wurm RM, Muir KT, Generaux GT, St John-Williams L, and McConn DJ (2008) An in vitro mechanistic study to elucidate the desipramine/bupropion clinical drug-drug interaction. Drug Metab Dispos 36:1198-1201.
31. Roberts PJ and Der CJ (2007) Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 26:3291-3310.
32. Rodgers T, Leahy D, and Rowland M (2005a) Tissue distribution of basic drugs: accounting for enantiomeric, compound and regional differences amongst beta-blocking drugs in rat. J Pharm Sci 94:1237-1248.
33. Rodgers T, Leahy D, and Rowland M (2005b) Physiologically based pharmacokinetic modeling 1: predicting the tissue distribution of moderate-to-strong bases. J Pharm Sci 94:1259-1276.
34. Rodgers T and Rowland M (2006) Physiologically based pharmacokinetic modelling 2: predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions. J Pharm Sci 95:1238-1257.
35. Rodgers T and Rowland M (2007) Mechanistic approaches to volume of distribution predictions: understanding the processes. Pharm Res 24:918-933.
36. Rowland M and Matin S (1973) Kinetics of drug interactions. J Pharmacokinet Biopharm 1: 553-566.
37. Schneck DW, Birmingham BK, Zalikowski JA, Mitchell PD, Wang Y, Martin PD, Lasseter KC, Brown CD, Windass AS, and Raza A (2004) The effect of gemfibrozil on the pharmacokinetics of rosuvastatin. Clin Pharmacol Ther 75:455-463.
38. Sesardic D, Boobis AR, Murray BP, Murray S, Segura J, de la Torre R, and Davies DS (1990) Furafylline is a potent and selective inhibitor of cytochrome P450IA2 in man. Br J Clin Pharmacol 29:651-663.
39. Shardlow CE, Generaux GT, MacLauchlin CC, Pons N, Skordos KW, and Bloomer JC (2011) Utilizing drug-drug interaction prediction tools during drug development: enhanced decision making based on clinical risk. Drug Metab Dispos 39:2076-2084.
40. Sparreboom A and Verweij J (2009) Advances in cancer therapeutics. Clin Pharmacol Ther 85: 113-117.
41. Störmer E, von Moltke LL, and Greenblatt DJ (2000) Scaling drug biotransformation data from cDNA-expressed cytochrome P-450 to human liver: a comparison of relative activity factors and human liver abundance in studies of mirtazapine metabolism. J Pharmacol Exp Ther 295: 793-801.
42. Stresser DM, Broudy MI, Ho T, Cargill CE, Blanchard AP, Sharma R, Dandeneau AA, Goodwin JJ, Turner SD, and Erve JCL, et al. (2004) Highly selective inhibition of human CYP3Aa in vitro by azamulin and evidence that inhibition is irreversible. Drug Metab Dispos 32:105-112.
43. Suttle B, Grossman K, Richards-Peterson L, Ouellet D, Aktan G, Gordon M, LoRusso P, Infante JR, Sharma S, and Kendra K, et al. (2014) A study of the effects of inhibition of CYP3A4 by ketoconazole (K) and CYP2C8 by gemfibrozil (G) on the pharmacokinetics of dabrafenib (D). Clin Pharmacol Ther 95 (S1):S36.
44. Suzuki H, Kneller B, Haining RL, Trager WF, and Rettie AE (2002) (+)-N-3-Benzyl-nirvanol and (-)-N-3-benzyl-phenobarbital: new potent and selective in vitro inhibitors of CYP2C19. Drug Metab Disp 30: 235-239.
45. Traer E and Deininger MW (2010) How much and how long: tyrosine kinase inhibitor therapy in chronic myeloid leukemia. Clin Lymphoma Myeloma Leuk 10 (Suppl 1):S20-S26.
46. U.S. Food and Drug Administration (2012) Guidance for industry: drug interaction studies - study design, data analysis, implications for losing, and Labeling recommendations. Center for Drug Evaluation and Research, Silver Spring, MD.
47. VandenBrink BM, Foti RS, Rock DA, Wienkers LC, and Wahlstrom JL (2011) Evaluation of CYP2C8 inhibition in vitro: utility of montelukast as a selective CYP2C8 probe substrate. Drug Metab Dispos 39:1546-1554.
48. Varma MV, Lai Y, Feng B, Litchfield J, Goosen TC, and Bergman A (2012) Physiologically based modeling of pravastatin transporter-mediated hepatobiliary disposition and drug-drug interactions. Pharm Res 29:2860-2873.
49. Venkatakrishnan K, Obach RS, and Rostami-Hodjegan A (2007) Mechanism-based inactivation of human cytochrome P450 enzymes: strategies for diagnosis and drug-drug interaction risk assessment. Xenobiotica 37:1225-1256.
50. Venkatakrishnan K, von Moltke LL, Obach RS, and Greenblatt DJ (2003) Drug metabolism and drug interactions: application and clinical value of in vitro models. Curr Drug Metab 4:423-459.
51. Walsky RL, Obach RS, Gaman EA, Gleeson JPR, and Proctor WR (2005) Selective inhibition of human cytochrome P4502C8 by montelukast. Drug Metab Disp 33: 413-418.
52. Yang J, Jamei M, Yeo KR, Tucker GT, and Rostami-Hodjegan A (2007) Prediction of intestinal first-pass drug metabolism. Curr Drug Metab 8:676-684.
53. Yang J, Liao M, Shou M, Jamei M, Yeo KR, Tucker GT, and Rostami-Hodjegan A (2008) Cytochrome p450 turnover: regulation of synthesis and degradation, methods for determining rates, and implications for the prediction of drug interactions. Curr Drug Metab 9: 384-394.
54. Yeung CK, Fujioka Y, Hachad H, Levy RH, and Isoherranen N (2011) Are circulating metabolites important in drug-drug interactions? Quantitative analysis of risk prediction and inhibitory potency. Clin Pharmacol Ther 89:105-113.
55. Yin OQ, Tomlinson B, Chow AH, Waye MM, and Chow MS (2004) Omeprazole as a CYP2C19 marker in Chinese subjects: assessment of its gene-dose effect and intrasubject variability. J Clin Pharmacol 44:582-589.
56. Yu H and Tweedie D (2013) A perspective on the contribution of metabolites to drug-drug interaction potential: the need to consider both circulating levels and inhibition potency. Drug Metab Dispos 41:536-540.