Pourquoi individualiser les doses de médicaments

Therapeutic Drug Monitoring
(TDM) of Tyrosine Kinase
Inhibitors (TKI) in MRCC
Réunion GSO Uro 19 Février 2014
1
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 dosage
2) Large interindividual PK variability, and limited PK intraindividual PK variability
3) Low therapeutic index
4) Pharmacodynamic effects (efficacy and/or toxicity)
dose-dependent, and particularly concentrationdependent
5) Possibility to define optimal concentrations
2
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)
3
2) PK variability
Which PK parameters ?
– elimination: clearance (CL)
– (distribution: volume of distribution (Vd))
– oral bioavailability (F)
Cmean,ss
=F(Dose/t)/CL
t
4
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 (CV50-70%)
–
Liver impairment, elderly patients, children, …
–
Non predictable in a specific patient
5
2010
P-gp
OCT1
(imatinib)
enzymatic inductors
elimination
6
Pharmacokinetics of pazopanib administered in combination with bevacizumab
[...]
0
(Day 1)
24
336
(Day 15)
360
Time (h)
7
Cmin = avant la prise:
400 mg ou 600 mg
* 77122ng/mL
a
b
8
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 intraindividual 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.:
10
4) Pharmacodynamic effects (efficacy and/or toxicity)
dose-dependent, and particularly concentrationEur J Cancer 2006
dependent
11
4) Pharmacodynamic (PD) effects (efficacy and/or toxicity) dosedependent, 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
Plasma Conc.
12
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”
…
13
5) Possibility to define optimal concentrations
Blood 2007
14
Wang et al, J Clin Oncol 2009
PK-PD
relationship
(GIST)
15
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
16
«these PK-PD Relationships: why they were
expected according to some theorical aspects »
Ligand-receptor interaction
Effect is dependent of the
intracellular concentrations
Relationship between plasma
concentrations and intracellular
concentrations
Imatinib (OCT1 expression) vs. Sunitinib, Pazopanib (more
lipophilic)
17
18
Metastatic renal cancer
19
20
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)]
21
Figure 4
PK of pazopanib (in combination with bevacizumab)
a
b
(n = 8)
(n = 16)
(n = 6)
(n = 16)
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 ; microprélèvements 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 pharmacocinétiquespharmacodynamiques.
• …
26
EA4553 : articles PK ou PK-PD inibs
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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, SeronieVivien S, LeCesne A, Vassal G: Population pharmacokinetics and pharmacogenetics of imatinib in children and adults.
Clin Cancer Res 2008;14:7102-7109.
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Pharmaco CHU Bordeaux: inibs
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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 longterm 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
28
and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 2007;109:3496-3499.
Financement
•
•
•
•
•
30 k€ (Conseil Scientifique ICR)
Pfizzer ; GSK (?)
Projet Emergence GSO 15 k€ (?)
GIRCI: API-K ?
…
• Total:  170 k€
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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
30