Therapeutic Drug Monitoring (TDM) of Tyrosine Kinase Inhibitors (TKI) in MRCC

Réunion GSO Uro 19 Février 2014

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TDM “Therapeutic Drug Monitoring”

• Determination of plasma concentrations as a “routine” practice in order to adapt the individual dose

• Prerequisite of TDM :1) Prolonged treatment: daily oral dosage2) Large interindividual PK variability, and limited PK intra-

individual PK variability3) Low therapeutic index4) Pharmacodynamic effects (efficacy and/or toxicity) dose-

dependent, and particularly concentration-dependent5) Possibility to define optimal concentrations

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Inibs

• Imatinib: bcr-abl (Chronic Myeloid Leukemia), cKit (Gastro Instestinal Stromal Tumor)

• Nilotinib: bcr-abl (Chronic Myeloid Leukemia)

• Erlotinib: EGFR (lung cancer)• Sunitinib: VEGFR, cKit, … (renal cancer)• Pazopanib: VEGFR, cKit, … (renal cancer)

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2) PK variability

– elimination: clearance (CL)– (distribution: volume of distribution (Vd))– oral bioavailability (F)

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Which PK parameters ?

Cmean,ss

=F(Dose/)/CL

Elimination of inibs• Liver metabolism (active or inactive metabolite)

– CYP3A4, CYP3A5 (pharmacogenetics)– Drug-Drug Interactions (DDI) : e.g., CYP3A4 inducers

(carbamazepine, dexamethasone)

• Substrate of efflux transporters : ABCB1 (P-gp), ABCG2 (BCRP)– Biliary and digestive elimination (parent compounds,

metabolites)– DDI– pharmacogenetics

• Elimination Clearance (CL)– Ratio 10 between extreme values (CV50-70%)– Liver impairment, elderly patients, children, …– Non predictable in a specific patient

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2010

elimination

enzymatic inductors

P-gp

OCT1(imatinib)

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Pharmacokinetics of pazopanib administered in combination with bevacizumab

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[...]336 3600 24(Day 1) (Day 15)

Time (h)

Cmin = avant la prise:400 mg ou 600 mg

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* 77122ng/mL

a b

Oral bioavailability (F) 100% (imatinib), low (pazopanib: 15%) • Food effect for pazopanib, nilotinib :

– drug dissolution is increased with food– Recommendation: fasted conditions in order to limit the intra-

individual variability

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3) Low therapeutic index ?• No: minimum biological active dose (not MTD = maximal

tolerated dose)• In fact, Yes• clinical practice: dose modifications in function of

tolerance, e.g.:

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Eur J Cancer 2006

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4) Pharmacodynamic effects (efficacy and/or toxicity) dose-dependent, and particularly concentration-dependent

4) Pharmacodynamic (PD) effects (efficacy and/or toxicity) dose-dependent, and particularly concentration-dependent:

• Inded, if PD is not dependent of the dose for a large range of doses : « all or nothing » effect corresponding to drug or no-drug), then TDM would not be useful

• However, if PD is not dependent of the dose for a small range of doses : the cause may be the large interindivual PK variability justifying particularly a TDM

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Plasma Conc.

Dose

Subgroup ( n=58/377) of patients with KIT exon 9 mutation: dose effect

So, there is not only “Pharmacokinetics” in the life

But, there is also the “Pharmacokinetics” …

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Blood 2007

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5) Possibility to define optimal concentrations

PK-PD relationship

(GIST)

Wang et al, J Clin Oncol 2009

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2011

Higher clearance (L.h-1.kg-1) in children:Children: 0.16 0.07 L.h-1.kg-1

Adolescents: 0.10 0.06 L.h-1.kg-1

Adults: 0.09 0.04 L.h-1.kg-1

Ligand-receptor interaction

Effect is dependent of the intracellular concentrations

Relationship between plasma concentrations and intracellular concentrations

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«these PK-PD Relationships: why they were expected according to some theorical aspects »

Imatinib (OCT1 expression) vs. Sunitinib, Pazopanib (more lipophilic)

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Metastatic renal cancer

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Relation PK-PD pazopanib• twenty (77%) of the 26 patients with residual pazopanib

concentrations at steady-state (C24,ss) ≥ 15 µg/mL developed hypertension, whereas hypertension developed in only 11 (39%) of the 28 patients who had C24,ss< 15 µg/mL [Phase 1, Hurwitz et al Clin Cancer Res 2009]

• of the 6 patients with renal cell carcinoma (RCC) that had either a partial response or stable disease, 5 (83%) achieved a C24,ss ≥ 15 µg/mL, then all 4 (100%) patients with RCC and progressive disease had C24,ss< 15 µg/mL

• Analysis of phase 2 studies suggests that an optimal threshold for C24,ss may be close to 20 µg/ml [B. Suttle, H. A. Ball, M. Molimard, et al; Relationship between exposure to pazopanib (P) and efficacy in patients (pts) with advanced renal cell carcinoma (mRCC) J Clin Oncol 28:15s, 2010 (suppl; abstr 3048)]

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(n = 6) (n = 16)(n = 16)(n = 8)

a b

Figure 4

PK of pazopanib (in combination with bevacizumab)

Mise en place du Suivi Thérapeutique Pharmacologique du sunitinib et du pazopanib

dans les cancers du rein métastatiques• Un essai clinique observationnel consistant à monitorer à la fois les données

pharmacocinétiques (concentrations plasmatiques de pazopanib ou de sunitinib) et données cliniques (d’efficacité et de tolérance)

• 100 patients porteurs d’un cancer du rein métastatique traités dans les principaux centres du Cancérôpole GSO (3 centres ont d’ores-et-déjà indiqué leur intérêt pour ce projet)

• méthode innovante reposant sur le concept de variables latentes [Laffont CM, Concordet D, Pharm Res 2011] développée par l’équipe du Pr D Concordet (UMR181 Institut National de la Recherche Agronomique): analyse simultanée de la toxicité et l’efficacité et mises en relation avec les données de concentrations plasmatiques observées chez les patients.

• Définir un intervalle optimal pour les valeurs de concentrations plasmatiques de pazopanib et de sunitinib.

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Principaux aspects méthodologiques (1)

• Patients : Seront inclus 100 patients (50 pour chaque médicament) traités dans les principaux Centres du GSO prenant en charge les cancers du rein métastatiques (CHU de Bordeaux et CLCCs de Montpellier et Toulouse sont déjà impliqués).

• Les prélèvements sanguins seront réalisés à J1 (1er jour de traitement) et à l’occasion de chaque consultation ou hospitalisation pour effets indésirables ; micro-prélèvements sur papier buvard (Pharmaco ; CHU Bordeaux)

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Principaux aspects méthodologiques (2)

• Pharmacocinétiques : Les données pharmacocinétiques seront analysées selon la méthodologie de pharmacocinétique de population (approche non linéaire à effet mixte) : seront ainsi déterminés les paramètres pharmacocinétiques moyens, leurs variabilités inter- et intra-individuelles, et les paramètres individuelles par estimation bayésienne (Pharmaco, ICR).

• Les relations pharmacocinétique-pharmacodynamique (PK-PD) seront déterminées grâce à l’analyse basée sur le concept de variable latente [Laffont CM, Concordet D, Pharm Res 2011] .

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Equipes et Centres• Implication des Services Cliniques et Bureaux d’Essais Cliniques

des, au moins, 3 Centres : CHU de Bordeaux (Pr A Ravaud), Centre Val d’Aurelle (Dr D Tosi), Institut Claudius-Regaud (Dr C Chevreau) ; Investigations cliniques

• Laboratoires de Pharmacologie du CHU de Bordeaux (Pr M Molimard) et Institut Claudius-Regaud (Pr E Chatelut) ; réalisation des dosages

• EA4553 (Pr E Chatelut) en collaboration avec UMR181 Institut National de la Recherche Agronomique de Toulouse (Pr D Concordet) : analyse des données pharmacocinétiques et pharmacocinétiques-pharmacodynamiques.

• …

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EA4553 : articles PK ou PK-PD inibs• 1 Chatelut E, Gandia P, Gotta V, Widmer N: Long-term prospective population PK study

in GIST patients--letter. Clin Cancer Res 2013;19:949.• 2 Gandia P, Arellano C, Lafont T, Huguet F, Malard L, Chatelut E: Should therapeutic drug

monitoring of the unbound fraction of imatinib and its main active metabolite N-desmethyl-imatinib be developed? Cancer Chemother Pharmacol 2013;71:531-536.

• 3 Arellano C, Gandia P, Lafont T, Jongejan R, Chatelut E: Determination of unbound fraction of imatinib and N-desmethyl imatinib, validation of an UPLC-MS/MS assay and ultrafiltration method. J Chromatogr B Analyt Technol Biomed Life Sci 2012;907:94-100.

• 4 White-Koning M, Civade E, Geoerger B, Thomas F, Le Deley MC, Hennebelle I, Delord JP, Chatelut E, Vassal G: Population analysis of erlotinib in adults and children reveals pharmacokinetic characteristics as the main factor explaining tolerance particularities in children. Clin Cancer Res 2011;17:4862-4871.

• 5 Geoerger B, Hargrave D, Thomas F, Ndiaye A, Frappaz D, Andreiuolo F, Varlet P, Aerts I, Riccardi R, Jaspan T, Chatelut E, Le Deley MC, Paoletti X, Saint-Rose C, Leblond P, Morland B, Gentet JC, Meresse V, Vassal G: Innovative Therapies for Children with Cancer pediatric phase I study of erlotinib in brainstem glioma and relapsing/refractory brain tumors. Neuro Oncol 2011;13:109-118.

• 6 Dehours E, Riu B, Valle B, Chatelut E, Recher C, Fourcade O, Huguet F: Overdose with 16,000 mg of imatinib mesylate. Leuk Res 2010;34:e286-e287.

• 7 Thomas F, Rochaix P, White-Koning M, Hennebelle I, Sarini J, Benlyazid A, Malard L, Lefebvre JL, Chatelut E, Delord JP: Population pharmacokinetics of erlotinib and its pharmacokinetic/pharmacodynamic relationships in head and neck squamous cell carcinoma. Eur J Cancer 2009;45:2316-2323.

• 8 Geoerger B, Morland B, Ndiaye A, Doz F, Kalifa G, Geoffray A, Pichon F, Frappaz D, Chatelut E, Opolon P, Hain S, Boderet F, Bosq J, Emile JF, Le Deley MC, Capdeville R, Vassal G: Target-driven exploratory study of imatinib mesylate in children with solid malignancies by the Innovative Therapies for Children with Cancer (ITCC) European Consortium. Eur J Cancer 2009;45:2342-2351.

• 9 Petain A, Kattygnarath D, Azard J, Chatelut E, Delbaldo C, Geoerger B, Barrois M, Seronie-Vivien S, LeCesne A, Vassal G: Population pharmacokinetics and pharmacogenetics of imatinib in children and adults. Clin Cancer Res 2008;14:7102-7109. 27

Pharmaco CHU Bordeaux: inibs• 1 Bouchet S, Dulucq S, Pasquet JM, Lagarde V, Molimard M, Mahon FX: From in vitro to in vivo:

intracellular determination of imatinib and nilotinib may be related with clinical outcome. Leukemia 2013;27:1757-1759.• 2 Bouchet S, Titier K, Moore N, Lassalle R, Ambrosino B, Poulette S, Schuld P, Belanger C,

Mahon FX, Molimard M: Therapeutic drug monitoring of imatinib in chronic myeloid leukemia: experience from 1216 patients at a centralized laboratory. Fundam Clin Pharmacol 2013;27:690-697.

• 3 Ibrahim AR, Eliasson L, Apperley JF, Milojkovic D, Bua M, Szydlo R, Mahon FX, Kozlowski K, Paliompeis C, Foroni L, Khorashad JS, Bazeos A, Molimard M, Reid A, Rezvani K, Gerrard G, Goldman J, Marin D: Poor adherence is the main reason for loss of CCyR and imatinib failure for chronic myeloid leukemia patients on long-term therapy. Blood 2011;117:3733-3736.

• 4 Bouchet S, Chauzit E, Ducint D, Castaing N, Canal-Raffin M, Moore N, Titier K, Molimard M: Simultaneous determination of nine tyrosine kinase inhibitors by 96-well solid-phase extraction and ultra performance LC/MS-MS. Clin Chim Acta 2011;412:1060-1067.

• 5 Marin D, Bazeos A, Mahon FX, Eliasson L, Milojkovic D, Bua M, Apperley JF, Szydlo R, Desai R, Kozlowski K, Paliompeis C, Latham V, Foroni L, Molimard M, Reid A, Rezvani K, de LH, Guallar C, Goldman J, Khorashad JS: Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol 2010;28:2381-2388.

• 6 Wang Y, Chia YL, Nedelman J, Schran H, Mahon FX, Molimard M: A therapeutic drug monitoring algorithm for refining the imatinib trough level obtained at different sampling times. Ther Drug Monit 2009;31:579-584.

• 7 Cortes JE, Egorin MJ, Guilhot F, Molimard M, Mahon FX: Pharmacokinetic/pharmacodynamic correlation and blood-level testing in imatinib therapy for chronic myeloid leukemia. Leukemia 2009;23:1537-1544.

• 8 Mahon FX, Molimard M: Correlation between trough imatinib plasma concentration and clinical response in chronic myeloid leukemia. Leuk Res 2009;33:1147-1148.

• 9 Dulucq S, Bouchet S, Turcq B, Lippert E, Etienne G, Reiffers J, Molimard M, Krajinovic M, Mahon FX: Multidrug resistance gene (MDR1) polymorphisms are associated with major molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 2008;112:2024-2027.

• 10 Picard S, Titier K, Etienne G, Teilhet E, Ducint D, Bernard MA, Lassalle R, Marit G, Reiffers J, Begaud B, Moore N, Molimard M, Mahon FX: Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 2007;109:3496-3499.

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Financement

• 30 k€ (Conseil Scientifique ICR)• Pfizzer ; GSK (?)• Projet Emergence GSO 15 k€ (?)• GIRCI: API-K ?• …

• Total: 170 k€29

Conclusions• Need to appreciate benefit of TDM vs. Individual

dosing based on (only) clinical information (i.e., side effects). – e.g., nilotinib: from 600 mg/day to 400 mg/day (=

33% decrease of dose)

• TDM: useful information for patients with low concentrations: «an increase of dose » rather than «a switch of drug »

• So many drugs: hard to develop and validate a detailed methodology of TDM for each TKI

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