David Balakirouchenane(1),(2), Monia Guidi(3),(4),(5) Sarah Guégan(6),(7), Perrine Courlet(5), Anne Jouinot(8), Alicja Puszkiel(1), Valentine Heidelberger(9), Ouidad Zehou(10), Nihel Khoudour(1), Nora Kramkimel(6), Nathalie Franck(6), Olivier Huillard(11), Jennifer Arrondeau(11), Michel Vidal(1),(2), Francois Goldwasser(11), Eve Maubec(9), Nicolas Dupin(6),(7), Selim Aractingi(6),(7), Chantal Csajka(3),(4),(12), Benoit Blanchet(1),(2)
(1)Department of Pharmacokinetics and Pharmacochemistry, Cochin Hospital, AP-HP, CARPEM 75014 Paris, France, (2)UMR8038 CNRS, U1268 INSERM, Faculty of Pharmacy, University of Paris, PRES Sorbonne Paris Cité, 75006 Paris, France, (3)Center for Research and Innovation in Clinical Pharmaceutical Sciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland, (4)Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, University of Lausanne, Geneva & Lausanne, Switzerland, (5)Service of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, Switzerland, (6)Department of Dermatology, Cochin Hospital AP-HP, Paris, France, (7)Cochin Institute, INSERM U1016, University of Paris 75014 Paris, France, (8) University of Paris, Cochin Institute, INSERM, CNRS, F-75014 PARIS, France, (9)Department of Dermatology, Avicenne Hospital AP-HP, Bobigny, France, (10)Department of Dermatology, Henri Mondor Hospital AP-HP, Créteil, France, (11)Department of Medical Oncology, Cochin Hospital AP-HP, Paris, France, (12)School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland
Objectives: Dabrafenib (DAB), a BRAF inhibitor, has significantly improved survival outcomes in patients with BRAFV600 metastatic melanoma. The oral route of DAB has also changed quality of life in comparison with chemotherapy. However, patients from « real-life » exhibit a large inter-individual variability (IIV) in clinical outcomes such as toxicity [1] and efficacy [2], which can result in severe dose-limiting toxicities (DLT) and disease progression. DAB undergoes oxidative metabolism via cytochrome P450 (CYP) 3A4 and CYP2C8 to form an active metabolite, hydroxy-dabrafenib (OHD). Metabolite pharmacokinetics (PK) and its influence on toxicity was rarely studied in previous researches [3, 4] since OHD is not marketed.The aims of this study were to describe the PK profile of DAB and OHD, to identify variability factors in their PK, and to investigate a potential exposure–response relationship for safety in BRAF-mutated metastatic melanoma patients treated with DAB and trametinib.
Methods: Sparse PK data were obtained from patients treated with DAB included in a prospective, observational and multicentric study. DAB and OHD concentrations were quantified using a validated high-performance liquid chromatography-tandem mass spectrometry, and the population PK analysis was performed using NONMEM. Plasma concentrations were converted into their molar equivalent and DAB and OHD were modeled simultaneously, assuming DAB elimination occurs exclusively via irreversibleconversion to OHD. The absorption rate constant was fixed to 1.8 h-1according to a previously published value [5] to allow an adequate estimate of PK parameters.The effect of relevant covariates (body weight, body mass index, free-fat mass, body surface area, age, aspartate aminotransferase and alanine aminotransferase, total bilirubin, albumin, C-reactive protein, sex, intake of proton-pump inhibitors (PPI), and cotreatment with trametinib) was explored using linear or allometric equations as appropriate. Systemic exposures to DAB and OHD (area under the curve, AUCDABand AUCOHD, respectively) were calculated with classic equations. The exposure-response relationship for safety study was conducted in 52 patients and the onset of DLT was considered as the clinical endpoint. Finally, the last AUC before the onset of DLT was compared with the average AUC estimated over the treatment course in patients who did not experience any DLT. Univariate Fisher and Wilcoxon models were carried out to identify which parameters contribute to the onset of DTL.
Results: DAB (n=424) and OHD (n=424) concentrations collected in 73 patients were best described by a two-compartment model for each molecule, drug exclusive elimination via irreversible conversion to OHD and first-order OHD elimination. A first-order absorption with a lag time adequately described the absorption phase. Apparent clearances of DAB (CL/F) and OHD (CLm/F) with IIV (%CV) were of 19.3 L/h (16.0%) and 23.2 L/h (24.0%), respectively. An inter-occasion variability on CL/F was estimated to be 17.4% (12.0%). Multivariate analyses identified age as influential covariate for both CL/F and CLm/F and sex for CL/F. CL/F was reduced by 17% in women vsmen and by 55% when comparing 20-years to 90-years old patients. A similar decrease (51%) is observed in CLm/F under the same age variation. The intake of PPI or trametinib did not have any impact on DAB and OHD PK. The safety analysis highlights that patients experiencing DLT were overexposed to DAB compared to patients without DLT (9624 ng·h/mL vs 7485 ng·h/mL, respectively, p<0.01).
Conclusions: The present study showed a moderate IIV in DAB and OHD PK that remained unexplained after inclusion of covariates, including intake of PPI. Our results suggest that early drug monitoring could be helpful to prevent the onset of DLT, especially in fragile patients such as the elderly.
References:
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[2] Knispel S, Zimmer L, Kanaki T, Ugurel S, Schadendorf D, Livingstone E. The safety and efficacy of dabrafenib and trametinib for the treatment of melanoma. Expert Opin Drug Saf. 2018 Jan;17(1):73-87.
[3] Menzies AM, Ashworth MT, Swann S, Kefford RF, Flaherty K, Weber J, Infante JR, Kim KB, Gonzalez R, Hamid O, Schuchter L, Cebon J, Sosman JA, Little S, Sun P, Aktan G, Ouellet D, Jin F, Long GV, Daud A. 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 Feb;26(2):415-21.
[4] Kim HY, Duong JK, Gonzalez M, Long GV, Menzies AM, Rizos H, Lim SY, Lee J, Boddy AV. Pharmacokinetic and cytokine profiles of melanoma patients with dabrafenib and trametinib-induced pyrexia. Cancer Chemother Pharmacol. 2019 Apr;83(4):693-704.
[5] Ouellet D, Gibiansky E, Leonowens C, O’Hagan A, Haney P, Switzky J, Goodman VL. Population pharmacokinetics of dabrafenib, a BRAF inhibitor: effect of dose, time, covariates, and relationship with its metabolites. J Clin Pharmacol. 2014 Jun;54(6):696-706.
Reference: PAGE () Abstr 9281 [www.page-meeting.org/?abstract=9281]
Poster: Drug/Disease Modelling - Oncology