TDM du Sorafenib. Dr Benoit BLANCHET UF de Pharmacocinétique et Pharmacochimie Hôpital Cochin 1
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1 TDM du Sorafenib Dr Benoit BLANCHET UF de Pharmacocinétique et Pharmacochimie Hôpital Cochin 1
2 Sorafenib Indications : Hépatocarcinome Carcinome rénal métastatique Cancer de la thyroïde réfractaire à l iode Tous grades (%) Grades 3-4 (%) SMP HTA 14 4 Diarrhée 43 5 Fatigue 34 8 Principales toxicités (Etude EU-ARCCS) Rini B, Br J Cancer 27 Beck et al., Annal Oncol 211
3 Pharmacocinétique Biodisponibilité a (%) Influence nourriture 29% AUC si repas riche en lipides Fixation protéique (%) ~ 99 Métabolisme Métabolite actif CYP3A4/UGT1A9 M2 (17% dans plasma vs 73% sorafenib) Cycle entérohépatique Oui Elimination Biliaire Demi-vie (heures) 2-39 Substrat protéines d efflux Pg-P, BCRP Pharmacocinétique linéaire oui > 4 mg x 2/j a Biodisponibilité relative Overview sorafenib 3
4 Variabilité pharmacocinétique TABLE 5 PK inter- and intrapatient variability of TKIs a TKI Interpatient variability (CV%) Intrapatient variability (CV%) Refs C trough AUC b CL/F (l/hour) C trough AUC b CL/F (l/hour) Axitinib N/A 17 94% % 2 22% 2 33% 2 22% [21,22,24 26] Dabrafenib 119% 38 68% 59% N/A N/A N/A [29,3] Erlotinib 38 76% % 1 129% N/A 16 24% N/A [4,42,47,51 72] Gefitinib % % 79 9% 2 49% 14% N/A [75,77,78,81 98] Imatinib 25 64% 21 66% 17 88% 15 27% 12% N/A [4,15 123] Lapatinib 55 97% % 48% N/A 3 36% N/A [ ,145,16 162] Pazopanib 11 9% 19 77% N/A N/A N/A N/A [158,163,165,167,168,17,171] Regorafenib 57% 43-88% N/A N/A 34% N/A [172, ] Sorafenib 25 14% % 13 8% N/A 31 47% N/A [92,177 18,184 21] Sunitinib 34 59% 13 49% 28 46% N/A N/A N/A [29,216,22 236] Vandetanib 2 56% 8 99% 8 55% N/A 8% N/A [ ] Vemurafenib N/A 28 52% 32 54% N/A N/A N/A [ ] a Abbreviations: %CV, coefficient of variation; CL/F, apparent oral clearance; C trough, minimum plasma concentration level; N/A, not available. b AUC 1 following a single dose or AUC over the dosing interval at steady state. De wit et al., Drug Discovery, 215 4
5 Facteur de variabilité : absorption intestinale,7 C 25 Absolute bioavailability,6,5,4,3,2 Sorafenib AUC (mg/l.h) ,1 5 4 (n=88) 8 (n=187) 12 (n=35) 16 (n=38) >16 (n=24) 4 (n=88) 8 (n=187) 12 (n=35) 16 (n=38) >16 (n=24) Sorafenib daily dose (mg) Sorafenib daily dose (mg) Dose (mg/j) AUC 25th 75th Augmentation AUC (%) 4 x 2 67,8 47, 1, 5,2 2 x 3 71,3 5,4 12,5 6 x 2 81,6 55, x 3 11,7 7,5 15,1 24,6 8 x 2 91,5 62,1 139,5 Chez non-répondeurs 4 x 3 11,7 7,5 15,1 1,9**! 3 prises par jour pour dose > 8 mg/j 4 x 4 135, ,2 Hornecker et al., Invest New Drugs 212 5
6 Facteur de variabilité : polymorphismes génétiques Figure 1. Dose-normalized sorafenib AUC versus UGT1A genotype. Each UGT1A9 1/ 3 carrier also carried UGT1A1 (TA) 6 /(TA) 7 (AUC ¼ 17.3 and 2.2 ng/mlh/mg) while the single UGT1A9 3/ 3 carrier also carried UGT1A1 (TA) 6 /(TA) 6 (AUC ¼ ng/mlh/mg, as indicated by ). UGT1A-impaired implies patients with deficient UGT1A1 or UGT1A9 metabolism based on genetics. Excluded patients (n ¼ 38) are described in the Supplementary Results section and n ¼ 82 individuals were Peer et al., Clin Cancer Research 212 6
7 Facteur de variabilité : sarcopénie Incidence of DLT (%) All Dose Limiting Toxicities (DLT) p<.6 Incidence of DLT (%) Diarrhea (grade 3/4) p<.5 Sarcopenic Non-sarcopenic Sarcopenic Non-sarcopenic Incidence of DLT (%) Hand Foot Syndrom (grade 3/4) ns Sarcopenic Non-sarcopenic Lean Body Mass (kg) Toxicity present Toxicity absent Dose Limiting Toxicity AUC à J28: 12,4 (sarcopéniques) vs. 53,7 mg/l.h (p =,1) Mir et al., Plos one, 212 7
8 Facteur de variabilité : albuminémie Albuminémie : facteur de variabilité de la clairance > Si hypoalbuminémie, augmentation clairance od et al., Pharm res 212 8
9 Facteur de variabilité : interactions médicamenteuses Grade 3 anorexia Grade 2 diarrhea 16 Sorafenib AUC (mg/l.h) Felodipine introduction (1 mg/day) +SD mean 4 - SD Time after sorafenib initiation (days) Lathia et al., Cancer Chemotherapy Pharmacol 26 Gomo et al., Invest New Drugs 211 Interaction médicamenteuse : imprévisible Inhibiteur/substrat CYP3A4 et inducteur Noda et al., Cancer Chemotherapy Pharmacol 213 9
10 Relation PK/PD : toxicités précoces Univariate analysis Multivariate analysis Variable No Yes p-value OR (95% CI) p-value Any toxicity $ grade 3 Gender.24 NS Female, n (%) 5 (33.3) 1 (66.7) Male, n (%) 25 (67.6) 12 (32.4) CYP3A A.G, n(%).5 NS GG (*3/*3) 24 (63) 14 (37) AG (*1/*3) 6 (67) 3 (33) AA (*1/*1) () 4 (1) Cumulated sorafenib AUC (mg/l.h) 2,25 3, ( ).19 [1,845 2,858] [2,7 4,19] Hand Foot Skin Reaction $ grade 2 Gender ( ).18 Female, n (%) 5 (33.3) 1 (66.7) Male, n (%) 25 (52.) 12 (48.) ECOG PS 1 [1 2] 1 [ 1].43 NS Cumulated sorafenib AUC (mg/l.h) 2,25 3,38.42 NS [1,789 2,858] [2,7 4,365] Diarrhea $ grade 2 UGT1A T.A.43 NT* wt/wt, n (%) 43 (93) 3 (7) wt/m, n (%) 2 (5) 2 (5) m/m, n (%) () () UGT1A C.T ( ).15 wt/wt, n (%) 42 (93) 3 (7) wt/m, n (%) 2 (5) 2 (5) m/m, n (%) () () Hypertension $ grade 2 Albumin (g/l) 37 [34 4] 41 [37 42].6 NS Daily dose of sorafenib (mg/m 2 ) 392 [ ] 22 [ ].53 NS Boudou-Rouquette et al., Plos one 212 1
11 Relation PK/PD : syndrome mains pieds Peer et al., Clin Cancer Research
12 Relation PK/PD : hypertension et SMP Fukudo et al., Clinical Pharmacokinetics,
13 Relation PK/PD : efficacité CHC * p=.8 (vs day 3) ** p =.7 (vs day 3) * ** Arrondeau et al., Invest New Drugs,
14 Relation PK/PD : efficacité CHC Fukudo et al., Clinical Pharmacokinetics,
15 Relation PK/PD : efficacité mélanome Change from baseline in target lesions diameter (%) * * * * ** * * Target lesions control : 7% Figure 3 Investigator-assessed tumour regression (i.e., maximum change from baseline in target lesions diameter). (n ¼ 27) Patients with RECIST progressive disease are indicated by an asterix. Clear grey: AUCmax o1 mg l 1 h 1 ; dark grey: AUCmaxX1 mg l 1 h 1. * * * Progression-free survival (probability) Group AUCmax <1 mg l 1 h 1 AUCmax >1 mg l 1 h 1 Log-rank P = Time (days) n Median time (weeks) 12 1 (95% CI: 6 19) (95% CI: 14 29) Pecuchet et al., British Journal of Cancer
16 TDM et escalade de dose AUC 12h (mg l 1 h 1 ) Daily dose bid (mg) Figure 2 Effect of dose escalation on intra patient sorafenib AUC (mg l 1 h 1 ). Median AUCs from 19 patients are represented. In red: increased exposure; in orange: stable exposure; in green: decreased exposure. Pecuchet et al., British Journal of Cancer
17 Bénéfice du TDM dans le cancer de la thyroïde TDM A 1 n Median PFS, days (months) 75 Sorafenib Placebo (1 8) 175 (5 8) PFS probability (%) 5 HR 59, 95% CI p< 1 25 Number at risk Sorafenib Placebo Days from randomisation Median PFS : 26 mois (18-32) (n=8) Gain de PFS de 15 mois par rapport à l essai DECISION Brose et al., Lancet 215; Boudou-Rouquette et al., Lancet
18 Take home messages Suivi Thérapeutique Pharmacologique Progression Toxicité Interactions médicamenteuses Observance C Faible : optimisation de la dose C Correcte : recherche de résistance pharmacologique et changement de traitement Populations à risque: Insuffisance hépatique, sarcopéniques, patients âgés Inhibiteurs et inducteurs CYP3A4 Médecines complémentaires 18
19 Pr F. Goldwasser: «La médecine de précision ne se réduit pas à l'analyse de la tumeur (la "cible") mais également à l'analyse du comportement de la "flèche", le médicament» 19
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