Skip to main content
Erschienen in: Clinical Pharmacokinetics 4/2019

09.08.2018 | Review Article

Clinical Pharmacokinetics and Pharmacodynamics of Dabrafenib

verfasst von: Alicja Puszkiel, Gaëlle Noé, Audrey Bellesoeur, Nora Kramkimel, Marie-Noëlle Paludetto, Audrey Thomas-Schoemann, Michel Vidal, François Goldwasser, Etienne Chatelut, Benoit Blanchet

Erschienen in: Clinical Pharmacokinetics | Ausgabe 4/2019

Einloggen, um Zugang zu erhalten

Abstract

Dabrafenib is a potent and selective inhibitor of BRAF-mutant kinase that is approved, as monotherapy or in combination with trametinib (mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor), for unresectable or metastatic BRAF-mutated melanoma, advanced non-small cell lung cancer and anaplastic thyroid cancer harbouring the BRAFV600E mutation. The recommended dose of dabrafenib is 150 mg twice daily (bid) under fasted conditions. After single oral administration of the recommended dose, the absolute oral bioavailability (F) of dabrafenib is 95%. Dabrafenib shows a time-dependent increase in apparent clearance (CL/F) following multiple doses, which is likely due to induction of its own metabolism through cytochrome P450 (CYP) 3A4. Therefore, steady state is reached only after 14 days of daily dose administration. Moreover, the extent of this auto-induction process is dependent on the dose, which explains why dabrafenib systemic exposure at steady state increases less than dose proportionally over the dose range of 75–300 mg bid. The main elimination route of dabrafenib is the oxidative metabolism via CYP3A4/2C8 and biliary excretion. Among the three major metabolites identified, hydroxy-dabrafenib appears to contribute to the pharmacological activity. Age, sex and body weight did not have any clinically significant influence on plasma exposure to dabrafenib. No dose adjustment is needed for patients with mild renal or hepatic impairment, whereas the impacts of severe impairment on dabrafenib pharmacokinetics remain unknown. Considering that dabrafenib is a substrate of CYP3A4/2C8 and is a CYP3A4/2B6/2C inducer, drug–drug interactions are expected with dabrafenib. The relationship between clinical outcomes and plasma exposure to dabrafenib and hydroxy-dabrafenib should be investigated more deeply.
Literatur
1.
Zurück zum Zitat Cargnello M, Roux PP. Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev. 2011;75:50–83.CrossRefPubMedPubMedCentral Cargnello M, Roux PP. Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev. 2011;75:50–83.CrossRefPubMedPubMedCentral
2.
Zurück zum Zitat Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54.CrossRefPubMed Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54.CrossRefPubMed
3.
Zurück zum Zitat Long GV, Menzies AM, Nagrial AM, Haydu LE, Hamilton AL, Mann GJ, et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol. 2011;29:1239–46.CrossRefPubMed Long GV, Menzies AM, Nagrial AM, Haydu LE, Hamilton AL, Mann GJ, et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol. 2011;29:1239–46.CrossRefPubMed
6.
Zurück zum Zitat Hauschild A, Grob J-J, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380:358–65.CrossRefPubMed Hauschild A, Grob J-J, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380:358–65.CrossRefPubMed
7.
Zurück zum Zitat Long GV, Flaherty KT, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, et al. Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. Ann Oncol. 2017;28:1631–9.CrossRefPubMedPubMedCentral Long GV, Flaherty KT, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, et al. Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. Ann Oncol. 2017;28:1631–9.CrossRefPubMedPubMedCentral
8.
Zurück zum Zitat Corcoran RB, Atreya CE, Falchook GS, Kwak EL, Ryan DP, Bendell JC, et al. Combined BRAF and MEK inhibition with dabrafenib and trametinib in BRAF V600-mutant colorectal cancer. J Clin Oncol. 2015;33:4023–31.CrossRefPubMedPubMedCentral Corcoran RB, Atreya CE, Falchook GS, Kwak EL, Ryan DP, Bendell JC, et al. Combined BRAF and MEK inhibition with dabrafenib and trametinib in BRAF V600-mutant colorectal cancer. J Clin Oncol. 2015;33:4023–31.CrossRefPubMedPubMedCentral
9.
Zurück zum Zitat Johanns TM, Ferguson CJ, Grierson PM, Dahiya S, Ansstas G. Rapid clinical and radiographic response with combined dabrafenib and trametinib in adults with BRAF-mutated high-grade glioma. J Natl Compr Cancer Netw. 2018;16:4–10.CrossRef Johanns TM, Ferguson CJ, Grierson PM, Dahiya S, Ansstas G. Rapid clinical and radiographic response with combined dabrafenib and trametinib in adults with BRAF-mutated high-grade glioma. J Natl Compr Cancer Netw. 2018;16:4–10.CrossRef
13.
Zurück zum Zitat Ouellet D, Grossmann KF, Limentani G, Nebot N, Lan K, Knowles L, 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;102:3100–9.CrossRefPubMed Ouellet D, Grossmann KF, Limentani G, Nebot N, Lan K, Knowles L, 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;102:3100–9.CrossRefPubMed
14.
Zurück zum Zitat Rheault TR, Stellwagen JC, Adjabeng GM, Hornberger KR, Petrov KG, Waterson AG, et al. Discovery of dabrafenib: a selective inhibitor of Raf kinases with antitumor activity against B-Raf-driven tumors. ACS Med Chem Lett. 2013;4:358–62.CrossRefPubMedPubMedCentral Rheault TR, Stellwagen JC, Adjabeng GM, Hornberger KR, Petrov KG, Waterson AG, et al. Discovery of dabrafenib: a selective inhibitor of Raf kinases with antitumor activity against B-Raf-driven tumors. ACS Med Chem Lett. 2013;4:358–62.CrossRefPubMedPubMedCentral
15.
Zurück zum Zitat King AJ, Arnone MR, Bleam MR, Moss KG, Yang J, Fedorowicz KE, et al. Dabrafenib; preclinical characterization, increased efficacy when combined with trametinib, while BRAF/MEK tool combination reduced skin lesions. PLoS One. 2013;8:e67583.CrossRefPubMedPubMedCentral King AJ, Arnone MR, Bleam MR, Moss KG, Yang J, Fedorowicz KE, et al. Dabrafenib; preclinical characterization, increased efficacy when combined with trametinib, while BRAF/MEK tool combination reduced skin lesions. PLoS One. 2013;8:e67583.CrossRefPubMedPubMedCentral
16.
Zurück zum Zitat Laquerre S, Arnone M, Moss K, Yang J, Fisher K, Kane-Carson LS, et al. A selective Raf kinase inhibitor induces cell death and tumor regression of human cancer cell lines encoding B-RafV600E mutation [abstract no. B88]. Mol Cancer Ther. 2009;8(12 Suppl):B88.CrossRef Laquerre S, Arnone M, Moss K, Yang J, Fisher K, Kane-Carson LS, et al. A selective Raf kinase inhibitor induces cell death and tumor regression of human cancer cell lines encoding B-RafV600E mutation [abstract no. B88]. Mol Cancer Ther. 2009;8(12 Suppl):B88.CrossRef
17.
Zurück zum Zitat Gentilcore G, Madonna G, Mozzillo N, Ribas A, Cossu A, Palmieri G, et al. Effect of dabrafenib on melanoma cell lines harbouring the BRAF(V600D/R) mutations. BMC Cancer. 2013;13:17.CrossRefPubMedPubMedCentral Gentilcore G, Madonna G, Mozzillo N, Ribas A, Cossu A, Palmieri G, et al. Effect of dabrafenib on melanoma cell lines harbouring the BRAF(V600D/R) mutations. BMC Cancer. 2013;13:17.CrossRefPubMedPubMedCentral
18.
Zurück zum Zitat Carnahan J, Beltran PJ, Babij C, Le Q, Rose MJ, Vonderfecht S, et al. Selective and potent Raf inhibitors paradoxically stimulate normal cell proliferation and tumor growth. Mol Cancer Ther. 2010;9:2399–410.CrossRefPubMed Carnahan J, Beltran PJ, Babij C, Le Q, Rose MJ, Vonderfecht S, et al. Selective and potent Raf inhibitors paradoxically stimulate normal cell proliferation and tumor growth. Mol Cancer Ther. 2010;9:2399–410.CrossRefPubMed
19.
Zurück zum Zitat Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature. 2010;464:431–5.CrossRefPubMed Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature. 2010;464:431–5.CrossRefPubMed
20.
Zurück zum Zitat Heidorn SJ, Milagre C, Whittaker S, Nourry A, Niculescu-Duvas I, Dhomen N, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell. 2010;140:209–21.CrossRefPubMedPubMedCentral Heidorn SJ, Milagre C, Whittaker S, Nourry A, Niculescu-Duvas I, Dhomen N, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell. 2010;140:209–21.CrossRefPubMedPubMedCentral
21.
Zurück zum Zitat Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature. 2010;464:427–30.CrossRefPubMedPubMedCentral Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature. 2010;464:427–30.CrossRefPubMedPubMedCentral
22.
Zurück zum Zitat Holderfield M, Merritt H, Chan J, Wallroth M, Tandeske L, Zhai H, et al. RAF inhibitors activate the MAPK pathway by relieving inhibitory autophosphorylation. Cancer Cell. 2013;23:594–602.CrossRefPubMed Holderfield M, Merritt H, Chan J, Wallroth M, Tandeske L, Zhai H, et al. RAF inhibitors activate the MAPK pathway by relieving inhibitory autophosphorylation. Cancer Cell. 2013;23:594–602.CrossRefPubMed
23.
Zurück zum Zitat Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507–16.CrossRefPubMedPubMedCentral Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507–16.CrossRefPubMedPubMedCentral
24.
Zurück zum Zitat Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363:809–19.CrossRefPubMedPubMedCentral Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363:809–19.CrossRefPubMedPubMedCentral
25.
Zurück zum Zitat Dubauskas Z, Kunishige J, Prieto VG, Jonasch E, Hwu P, Tannir NM. Cutaneous squamous cell carcinoma and inflammation of actinic keratoses associated with sorafenib. Clin Genitourin Cancer. 2009;7:20–3.CrossRefPubMedPubMedCentral Dubauskas Z, Kunishige J, Prieto VG, Jonasch E, Hwu P, Tannir NM. Cutaneous squamous cell carcinoma and inflammation of actinic keratoses associated with sorafenib. Clin Genitourin Cancer. 2009;7:20–3.CrossRefPubMedPubMedCentral
26.
Zurück zum Zitat Bershas DA, Ouellet D, Mamaril-Fishman DB, Nebot N, Carson SW, Blackman SC, et al. 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. 2013;41:2215–24.CrossRefPubMed Bershas DA, Ouellet D, Mamaril-Fishman DB, Nebot N, Carson SW, Blackman SC, et al. 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. 2013;41:2215–24.CrossRefPubMed
27.
Zurück zum Zitat Menzies A, Long G, Murali R. Dabrafenib and its potential for the treatment of metastatic melanoma. Drug Des Dev Ther. 2012;6:391–405. Menzies A, Long G, Murali R. Dabrafenib and its potential for the treatment of metastatic melanoma. Drug Des Dev Ther. 2012;6:391–405.
28.
Zurück zum Zitat Menzies AM, Kefford RF, Long GV. Paradoxical oncogenesis: are all BRAF inhibitors equal? Pigment Cell Melanoma Res. 2013;26:611–5.CrossRefPubMed Menzies AM, Kefford RF, Long GV. Paradoxical oncogenesis: are all BRAF inhibitors equal? Pigment Cell Melanoma Res. 2013;26:611–5.CrossRefPubMed
29.
Zurück zum Zitat Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367:1694–703.CrossRefPubMedPubMedCentral Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367:1694–703.CrossRefPubMedPubMedCentral
30.
Zurück zum Zitat Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015;386:444–51.CrossRefPubMed Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015;386:444–51.CrossRefPubMed
31.
Zurück zum Zitat Grob JJ, Amonkar MM, Karaszewska B, Schachter J, Dummer R, Mackiewicz A, et al. Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutation-positive melanoma (COMBI-v): results of a phase 3, open-l. Lancet Oncol. 2015;16:1389–98.CrossRefPubMed Grob JJ, Amonkar MM, Karaszewska B, Schachter J, Dummer R, Mackiewicz A, et al. Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutation-positive melanoma (COMBI-v): results of a phase 3, open-l. Lancet Oncol. 2015;16:1389–98.CrossRefPubMed
32.
Zurück zum Zitat Long GV, Hauschild A, Santinami M, Atkinson V, Mandalà M, Chiarion-Sileni V, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med. 2017;377:1813–23.CrossRefPubMed Long GV, Hauschild A, Santinami M, Atkinson V, Mandalà M, Chiarion-Sileni V, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med. 2017;377:1813–23.CrossRefPubMed
33.
Zurück zum Zitat Planchard D, Kim TM, Mazieres J, Quoix E, Riely G, Barlesi F, et al. Dabrafenib in patients with BRAFV600E-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016;17:642–50.CrossRefPubMedPubMedCentral Planchard D, Kim TM, Mazieres J, Quoix E, Riely G, Barlesi F, et al. Dabrafenib in patients with BRAFV600E-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016;17:642–50.CrossRefPubMedPubMedCentral
34.
Zurück zum Zitat Planchard D, Besse B, Groen HJM, Souquet P-J, Quoix E, Baik CS, et al. Dabrafenib plus trametinib in patients with previously treated BRAF V600E -mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol. 2016;17:984–93.CrossRefPubMedPubMedCentral Planchard D, Besse B, Groen HJM, Souquet P-J, Quoix E, Baik CS, et al. Dabrafenib plus trametinib in patients with previously treated BRAF V600E -mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol. 2016;17:984–93.CrossRefPubMedPubMedCentral
35.
Zurück zum Zitat Planchard D, Smit EF, Groen HJM, Mazieres J, Besse B, Helland Å, et al. Dabrafenib plus trametinib in patients with previously untreated BRAF V600E -mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol. 2017;18:1307–16.CrossRefPubMed Planchard D, Smit EF, Groen HJM, Mazieres J, Besse B, Helland Å, et al. Dabrafenib plus trametinib in patients with previously untreated BRAF V600E -mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol. 2017;18:1307–16.CrossRefPubMed
36.
Zurück zum Zitat Subbiah V, Kreitman RJ, Wainberg ZA, Cho JY, Schellens JHM, Soria JC, et al. Dabrafenib and trametinib treatment in patients with locally advanced or metastatic BRAF V600-mutant anaplastic thyroid cancer. J Clin Oncol. 2018;36:7–13.CrossRefPubMed Subbiah V, Kreitman RJ, Wainberg ZA, Cho JY, Schellens JHM, Soria JC, et al. Dabrafenib and trametinib treatment in patients with locally advanced or metastatic BRAF V600-mutant anaplastic thyroid cancer. J Clin Oncol. 2018;36:7–13.CrossRefPubMed
37.
Zurück zum Zitat Long GV, Trefzer U, Davies MA, Kefford RF, Ascierto PA, Chapman PB, et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13:1087–95.CrossRefPubMed Long GV, Trefzer U, Davies MA, Kefford RF, Ascierto PA, Chapman PB, et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13:1087–95.CrossRefPubMed
38.
Zurück zum Zitat Falchook GS, Long GV, Kurzrock R, Kim KB, Arkenau TH, Brown MP, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet. 2012;379:1893–901.CrossRefPubMedPubMedCentral Falchook GS, Long GV, Kurzrock R, Kim KB, Arkenau TH, Brown MP, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet. 2012;379:1893–901.CrossRefPubMedPubMedCentral
39.
Zurück zum Zitat Davies MA, Saiag P, Robert C, Grob J-J, Flaherty KT, Arance A, et al. Dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol. 2017;18:863–73.CrossRefPubMedPubMedCentral Davies MA, Saiag P, Robert C, Grob J-J, Flaherty KT, Arance A, et al. Dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol. 2017;18:863–73.CrossRefPubMedPubMedCentral
40.
Zurück zum Zitat Carlos G, Anforth R, Clements A, Menzies AM, Carlino MS, Chou S, et al. Cutaneous toxic effects of BRAF inhibitors alone and in combination with MEK inhibitors for metastatic melanoma. JAMA Dermatol. 2015;151:1103–9.CrossRefPubMed Carlos G, Anforth R, Clements A, Menzies AM, Carlino MS, Chou S, et al. Cutaneous toxic effects of BRAF inhibitors alone and in combination with MEK inhibitors for metastatic melanoma. JAMA Dermatol. 2015;151:1103–9.CrossRefPubMed
41.
Zurück zum Zitat Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107–14.CrossRefPubMed Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107–14.CrossRefPubMed
42.
Zurück zum Zitat Falchook GS, Long GV, Kurzrock R, Kim KB, Arkenau H-T, Brown MP, et al. Dose selection, pharmacokinetics, and pharmacodynamics of BRAF inhibitor dabrafenib (GSK2118436). Clin Cancer Res. 2014;20:4449–58.CrossRefPubMed Falchook GS, Long GV, Kurzrock R, Kim KB, Arkenau H-T, Brown MP, et al. Dose selection, pharmacokinetics, and pharmacodynamics of BRAF inhibitor dabrafenib (GSK2118436). Clin Cancer Res. 2014;20:4449–58.CrossRefPubMed
43.
Zurück zum Zitat Denton CL, Minthorn E, Carson SW, Young GC, Richards-Peterson LE, Botbyl J, et al. Concomitant oral and intravenous pharmacokinetics of dabrafenib, a BRAF inhibitor, in patients with BRAF V600 mutation-positive solid tumors. J Clin Pharmacol. 2013;53:955–61.CrossRefPubMed Denton CL, Minthorn E, Carson SW, Young GC, Richards-Peterson LE, Botbyl J, et al. Concomitant oral and intravenous pharmacokinetics of dabrafenib, a BRAF inhibitor, in patients with BRAF V600 mutation-positive solid tumors. J Clin Pharmacol. 2013;53:955–61.CrossRefPubMed
44.
Zurück zum Zitat Suttle AB, Grossmann KF, Ouellet D, Richards-Peterson LE, Aktan G, Gordon MS, et al. Assessment of the drug interaction potential and single- and repeat-dose pharmacokinetics of the BRAF inhibitor dabrafenib. J Clin Pharmacol. 2015;55:392–400.CrossRefPubMed Suttle AB, Grossmann KF, Ouellet D, Richards-Peterson LE, Aktan G, Gordon MS, et al. Assessment of the drug interaction potential and single- and repeat-dose pharmacokinetics of the BRAF inhibitor dabrafenib. J Clin Pharmacol. 2015;55:392–400.CrossRefPubMed
45.
Zurück zum Zitat Fujiwara Y, Yamazaki N, Kiyohara Y, Yoshikawa S, Yamamoto N, Tsutsumida A, et al. Safety, tolerability, and pharmacokinetic profile of dabrafenib in Japanese patients with BRAF V600 mutation-positive solid tumors: a phase 1 study. Investig New Drugs. 2018;36:259–68.CrossRef Fujiwara Y, Yamazaki N, Kiyohara Y, Yoshikawa S, Yamamoto N, Tsutsumida A, et al. Safety, tolerability, and pharmacokinetic profile of dabrafenib in Japanese patients with BRAF V600 mutation-positive solid tumors: a phase 1 study. Investig New Drugs. 2018;36:259–68.CrossRef
46.
Zurück zum Zitat Ouellet D, Gibiansky E, Leonowens C, O’Hagan A, Haney P, Switzky J, et al. Population pharmacokinetics of dabrafenib, a BRAF inhibitor: effect of dose, time, covariates, and relationship with its metabolites. J Clin Pharmacol. 2014;54:696–706.CrossRefPubMed Ouellet D, Gibiansky E, Leonowens C, O’Hagan A, Haney P, Switzky J, et al. Population pharmacokinetics of dabrafenib, a BRAF inhibitor: effect of dose, time, covariates, and relationship with its metabolites. J Clin Pharmacol. 2014;54:696–706.CrossRefPubMed
47.
Zurück zum Zitat Mittapalli RK, Vaidhyanathan S, Dudek AZ, Elmquist WF. Mechanisms limiting distribution of the threonine-protein kinase B-RaF(V600E) inhibitor dabrafenib to the brain: implications for the treatment of melanoma brain metastases. J Pharmacol Exp Ther. 2013;344:655–64.CrossRefPubMedPubMedCentral Mittapalli RK, Vaidhyanathan S, Dudek AZ, Elmquist WF. Mechanisms limiting distribution of the threonine-protein kinase B-RaF(V600E) inhibitor dabrafenib to the brain: implications for the treatment of melanoma brain metastases. J Pharmacol Exp Ther. 2013;344:655–64.CrossRefPubMedPubMedCentral
48.
Zurück zum Zitat Qiu J-G, Zhang Y-J, Li Y, Zhao J-M, Zhang W-J, Jiang Q-W, et al. Trametinib modulates cancer multidrug resistance by targeting ABCB1 transporter. Oncotarget. 2015;6:15494–509.PubMedPubMedCentral Qiu J-G, Zhang Y-J, Li Y, Zhao J-M, Zhang W-J, Jiang Q-W, et al. Trametinib modulates cancer multidrug resistance by targeting ABCB1 transporter. Oncotarget. 2015;6:15494–509.PubMedPubMedCentral
49.
Zurück zum Zitat Vaidhyanathan S, Mittapalli RK, Sarkaria JN, Elmquist WF. Factors influencing the CNS distribution of a novel MEK-1/2 inhibitor: implications for combination therapy for melanoma brain metastases. Drug Metab Dispos. 2014;42:1292–300.CrossRefPubMedPubMedCentral Vaidhyanathan S, Mittapalli RK, Sarkaria JN, Elmquist WF. Factors influencing the CNS distribution of a novel MEK-1/2 inhibitor: implications for combination therapy for melanoma brain metastases. Drug Metab Dispos. 2014;42:1292–300.CrossRefPubMedPubMedCentral
50.
Zurück zum Zitat Ascierto PA, Minor D, Ribas A, Lebbe C, O’Hagan A, Arya N, et al. Phase II trial (BREAK-2) of the BRAF inhibitor dabrafenib (GSK2118436) in patients with metastatic melanoma. J Clin Oncol. 2013;31:3205–11.CrossRefPubMed Ascierto PA, Minor D, Ribas A, Lebbe C, O’Hagan A, Arya N, et al. Phase II trial (BREAK-2) of the BRAF inhibitor dabrafenib (GSK2118436) in patients with metastatic melanoma. J Clin Oncol. 2013;31:3205–11.CrossRefPubMed
51.
Zurück zum Zitat Rousset M, Dutriaux C, Bosco-Lévy P, Prey S, Pham-Ledard A, Dousset L, et al. Trough dabrafenib plasma concentrations can predict occurrence of adverse events requiring dose reduction in metastatic melanoma. Clin Chim Acta. 2017;472:26–9.CrossRefPubMed Rousset M, Dutriaux C, Bosco-Lévy P, Prey S, Pham-Ledard A, Dousset L, et al. Trough dabrafenib plasma concentrations can predict occurrence of adverse events requiring dose reduction in metastatic melanoma. Clin Chim Acta. 2017;472:26–9.CrossRefPubMed
52.
Zurück zum Zitat Park JJ, Boddy AV, Liu X, Harris D, Lee V, Kefford RF, et al. Pharmacokinetics of dabrafenib in a patient with metastatic melanoma undergoing haemodialysis. Pigment Cell Melanoma Res. 2017;30:68–71.CrossRefPubMed Park JJ, Boddy AV, Liu X, Harris D, Lee V, Kefford RF, et al. Pharmacokinetics of dabrafenib in a patient with metastatic melanoma undergoing haemodialysis. Pigment Cell Melanoma Res. 2017;30:68–71.CrossRefPubMed
54.
Zurück zum Zitat Lawrence SK, Nguyen D, Bowen C, Richards-Peterson L, Skordos KW. The metabolic drug–drug interaction profile of Dabrafenib: in vitro investigations and quantitative extrapolation of the P450-mediated DDI risk. Drug Metab Dispos. 2014;42:1180–90.CrossRefPubMed Lawrence SK, Nguyen D, Bowen C, Richards-Peterson L, Skordos KW. The metabolic drug–drug interaction profile of Dabrafenib: in vitro investigations and quantitative extrapolation of the P450-mediated DDI risk. Drug Metab Dispos. 2014;42:1180–90.CrossRefPubMed
55.
Zurück zum Zitat Suttle B, Grossmann K, Richards-Peterson L, Ouellet D, Aktan G, Gordon M, et al. A study of the effects of inhibition of CYP3A4 BY ketoconazole (K) and CYP2C8 by gemfibrozil (G) on the pharmacokinetics dabrafenib (D).: PII-085. Clin Pharmacol Ther. 2014;95:S89–90. Suttle B, Grossmann K, Richards-Peterson L, Ouellet D, Aktan G, Gordon M, et al. A study of the effects of inhibition of CYP3A4 BY ketoconazole (K) and CYP2C8 by gemfibrozil (G) on the pharmacokinetics dabrafenib (D).: PII-085. Clin Pharmacol Ther. 2014;95:S89–90.
56.
Zurück zum Zitat van Leeuwen RWF, Jansman FGA, Hunfeld NG, Peric R, Reyners AKL, Imholz ALT, et al. Tyrosine kinase inhibitors and proton pump inhibitors: an evaluation of treatment options. Clin Pharmacokinet. 2017;56:683–8.CrossRefPubMedPubMedCentral van Leeuwen RWF, Jansman FGA, Hunfeld NG, Peric R, Reyners AKL, Imholz ALT, et al. Tyrosine kinase inhibitors and proton pump inhibitors: an evaluation of treatment options. Clin Pharmacokinet. 2017;56:683–8.CrossRefPubMedPubMedCentral
57.
Zurück zum Zitat Levavasseur M, Darras S, Mortier L, Goeminne C, Auffret M, Bertrand M. Drug interaction between dabrafenib and immunosuppressive drugs: about one case. Melanoma Res. 2016;26:532–4.CrossRefPubMed Levavasseur M, Darras S, Mortier L, Goeminne C, Auffret M, Bertrand M. Drug interaction between dabrafenib and immunosuppressive drugs: about one case. Melanoma Res. 2016;26:532–4.CrossRefPubMed
58.
Zurück zum Zitat Long GV, Grob J-J, Nathan P, Ribas A, Robert C, Schadendorf D, et al. Factors predictive of response, disease progression, and overall survival after dabrafenib and trametinib combination treatment: a pooled analysis of individual patient data from randomised trials. Lancet Oncol. 2016;17:1743–54.CrossRefPubMed Long GV, Grob J-J, Nathan P, Ribas A, Robert C, Schadendorf D, et al. Factors predictive of response, disease progression, and overall survival after dabrafenib and trametinib combination treatment: a pooled analysis of individual patient data from randomised trials. Lancet Oncol. 2016;17:1743–54.CrossRefPubMed
59.
Zurück zum Zitat Schadendorf D, Long GV, Stroiakovski D, Karaszewska B, Hauschild A, Levchenko E, et al. Three-year pooled analysis of factors associated with clinical outcomes across dabrafenib and trametinib combination therapy phase 3 randomised trials. Eur J Cancer. 2017;82:45–55.CrossRefPubMed Schadendorf D, Long GV, Stroiakovski D, Karaszewska B, Hauschild A, Levchenko E, et al. Three-year pooled analysis of factors associated with clinical outcomes across dabrafenib and trametinib combination therapy phase 3 randomised trials. Eur J Cancer. 2017;82:45–55.CrossRefPubMed
60.
Zurück zum Zitat Menzies AM, Ashworth MT, Swann S, Kefford RF, Flaherty K, Weber J, 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;26:415–21.CrossRefPubMed Menzies AM, Ashworth MT, Swann S, Kefford RF, Flaherty K, Weber J, 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;26:415–21.CrossRefPubMed
61.
Zurück zum Zitat Yang S-K, Hong M, Baek J, Choi H, Zhao W, Jung Y, et al. A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nat Genet. 2014;46:1017–20.CrossRefPubMedPubMedCentral Yang S-K, Hong M, Baek J, Choi H, Zhao W, Jung Y, et al. A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nat Genet. 2014;46:1017–20.CrossRefPubMedPubMedCentral
62.
Zurück zum Zitat Yip VLM, Alfirevic A, Pirmohamed M. Genetics of immune-mediated adverse drug reactions: a comprehensive and clinical review. Clin Rev Allergy Immunol. 2015;48:165–75.CrossRefPubMed Yip VLM, Alfirevic A, Pirmohamed M. Genetics of immune-mediated adverse drug reactions: a comprehensive and clinical review. Clin Rev Allergy Immunol. 2015;48:165–75.CrossRefPubMed
63.
Zurück zum Zitat Kulkarni D, Song K, Briley L, King K, Dabrowski C, Mookerjee B, et al. Pyrexia in dabrafenib-treated melanoma patients is not associated with common genetic variation or HLA polymorphisms. Pharmacogenomics. 2016;17:459–62.CrossRefPubMed Kulkarni D, Song K, Briley L, King K, Dabrowski C, Mookerjee B, et al. Pyrexia in dabrafenib-treated melanoma patients is not associated with common genetic variation or HLA polymorphisms. Pharmacogenomics. 2016;17:459–62.CrossRefPubMed
64.
Zurück zum Zitat Nebot N, Arkenau HTT, Infante JR, Chandler JC, Weickhardt A, Lickliter JD, et al. Evaluation of the effect of dabrafenib and metabolites on QTc interval in patients with BRAF V600-mutant tumours. Br J Clin Pharmacol. 2018;84:764–75.CrossRefPubMedPubMedCentral Nebot N, Arkenau HTT, Infante JR, Chandler JC, Weickhardt A, Lickliter JD, et al. Evaluation of the effect of dabrafenib and metabolites on QTc interval in patients with BRAF V600-mutant tumours. Br J Clin Pharmacol. 2018;84:764–75.CrossRefPubMedPubMedCentral
65.
Zurück zum Zitat Verheijen RB, Yu H, Schellens JHM, Beijnen JH, Steeghs N, Huitema ADR. Practical recommendations for therapeutic drug monitoring of kinase inhibitors in oncology. Clin Pharmacol Ther. 2017;102:765–76.CrossRefPubMedPubMedCentral Verheijen RB, Yu H, Schellens JHM, Beijnen JH, Steeghs N, Huitema ADR. Practical recommendations for therapeutic drug monitoring of kinase inhibitors in oncology. Clin Pharmacol Ther. 2017;102:765–76.CrossRefPubMedPubMedCentral
66.
Zurück zum Zitat Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372:30–9.CrossRefPubMed Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372:30–9.CrossRefPubMed
Metadaten
Titel
Clinical Pharmacokinetics and Pharmacodynamics of Dabrafenib
verfasst von
Alicja Puszkiel
Gaëlle Noé
Audrey Bellesoeur
Nora Kramkimel
Marie-Noëlle Paludetto
Audrey Thomas-Schoemann
Michel Vidal
François Goldwasser
Etienne Chatelut
Benoit Blanchet
Publikationsdatum
09.08.2018
Verlag
Springer International Publishing
Erschienen in
Clinical Pharmacokinetics / Ausgabe 4/2019
Print ISSN: 0312-5963
Elektronische ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-018-0703-0

Weitere Artikel der Ausgabe 4/2019

Clinical Pharmacokinetics 4/2019 Zur Ausgabe