1. Réunion GSO Uro 19 Février 2014
Therapeutic Drug Monitoring (TDM) of Tyrosine Kinase Inhibitors (TKI) in MRCC
Réunion GSO Uro 19 Février 2014
I will try to convince that one day every TKI will be monitored …

2. TDM “Therapeutic Drug Monitoring”
Determination of plasma concentrations as a “routine” practice in order to adapt the individual dose
Prerequisite of TDM :
Prolonged treatment: daily oral dosage
Large interindividual PK variability, and limited PK intra-individual PK variability
Low therapeutic index
Pharmacodynamic effects (efficacy and/or toxicity) dose-dependent, and particularly concentration-dependent
5) Possibility to define optimal concentrations
Just to remind you what is the definition of TDM
I’m going to consider with you each of the condition (the prerequisite) necessary to justify TDM regarding to the TKI
No doubt about the point 1 …. We will discuss the other points

3. 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)
For each: the target and the corresponding disease

4. 2) PK variability elimination: clearance (CL)
Which PK parameters ?
elimination: clearance (CL)
(distribution: volume of distribution (Vd))
oral bioavailability (F)
Cmean,ss
=F(Dose/t)/CL t
I’m going to show … and you probably akready know
But, which PK parameter it’s important to consider: the clearance which describe the capacity of elimination is important, but not the volume of distribution
F, also relevant and we will condirer it in termes of intrapatient variability
The oral bioavailablity is also a relevant parameter that could be also responsible of variability, and particularly of an intra-… which may represente a limit for TDM

5. 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
This slide describe the pathways of elimination of TKI and their corresponding factors of variability:
Hepatic metabolism
Active biliary excretion due to ABC transporters
The results of that is a ratio around and of coefficient of variation ; this variability may due to …
But whatever it’s not predictable

6. 2010 P-gp OCT1 (imatinib) enzymatic inductors elimination
by condering an hepatocyte, There are some additional proteins involved in the PK of TKI: nuclear receptor such as … that are responsible of enzymatic induction ; pharmacogenetic factors are probably involved and some polymorphisms start to be described
But also, for the less lipohilic such as imatinib: OCT1
enzymatic inductors
elimination

7. Pharmacokinetics of pazopanib administered in combination with bevacizumab
[...]
336
360 24
(Day 1)
(Day 15)
Time (h)

8. Cmin = avant la prise: 400 mg ou 600 mg
* 77122ng/mL a b

9. 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
A variability between drugs
And a food effect has been shown for some TKI
In the perpstive to perform a TDM for these drugs, it”s particularly important to respect these recommandations

10. 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.:
Point 4 was TDM is justified only for drugs …
Inintially, years ago … Even some people were telling we just need to give a minimum biological active dose ; these drugs are not like cytotoxic ; it’s not usefull to give the MTD
In fact, we know now TKI have side effects ; moreover, side effects that require a decrease of the dose

11. 4) Pharmacodynamic effects (efficacy and/or toxicity) dose-dependent, and particularly concentration-dependent
Eur J Cancer 2006
For imatinib administered to patients with gastrointestinal tumors, the efficacy was similar whatever the dose any dose 400 and 800 mg per day

12. 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
I need to comment this condition ; Indeed, in case if PD is not …: there are two situations
The first one: … some years ago, many people were thinking it’s the case for TKI ; in this case, there is no benefit to expect from TDM
But, if PD … for a small range of dose, there could be an other explonation …
Plasma Conc.
Dose

13. 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” …
; but it was easy to observe this dose effect when considering patents with a particular pharmacogenomic status of their tumour cells

14. 5) Possibility to define optimal concentrations
Blood 2007
A similar result was previously for the same dose in CMLeukemia : most of the patients wo did not respond to imatinib had residual plasma concentration below justifying that to be well treated with this dose the dose should be enough to be associated with conc over this cut-off value

15. PK-PD relationship (GIST)
Wang et al, J Clin Oncol 2009
PK-PD relationship (GIST)
It has been shown retrospectively by the company: you can see the Novartis data of imatinib in GIST correponding to patients treated … with PK evaluation
Here is the distribution of the residual Conc after 1 month of treatment ; there is a PK variability since there are not all the yellow data on the left … and there is a consequence in term of activity ; the PFS is the worst for the quartile of patients with the lower concentrations

16. 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
The relationship between plasma erlotinib AUC and the grade of skin toxicity was very, very similar between adults and pediatric patients
Here is the probability to have for example a grade 2 or more skin toxicity depending of the AUC

17. Ligand-receptor interaction
«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
I would make a pause and address the question according to theorical concepts
The pharmacologic effect of these drugs is the result of their competition with ATP at the intracellular level of their target R ; since the intracellular conc are dependent of the extracellular conc corresponding to the plasma concentraztions, it’s not surprising to observe these PK-PD relationships !
Since active transport has been described for imatinib, we may expect better relationship between plasma concentration of lipophilic drugs : indeed, for them , since the passive diffusion is the main mecchanism, we may expect stronger PK-PD relationship …
Imatinib (OCT1 expression) vs. Sunitinib, Pazopanib (more lipophilic)

19. Metastatic renal cancer
Pfizzer lab has proved that by correlating the probality of response and …

21. 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)]

22. PK of pazopanib (in combination with bevacizumab)
Figure 4
PK of pazopanib (in combination with bevacizumab)
(n = 6)
(n = 16)
(n = 8) a b

23. 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.

24. 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)

25. 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] .

26. 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. …

27. 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:
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:
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:
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:
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:
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:
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:

28. 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:
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:
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:
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:
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:
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:
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:
8 Mahon FX, Molimard M: Correlation between trough imatinib plasma concentration and clinical response in chronic myeloid leukemia. Leuk Res 2009;33:
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:
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:

29. Financement 30 k€ (Conseil Scientifique ICR) Pfizzer ; GSK (?)
Projet Emergence GSO 15 k€ (?)
GIRCI: API-K ? …
Total:  170 k€

30. 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
For patients with concentrations higher than the optimal conc: TDM result would allow a more rational decrese of dose (more rational means in this case more mathematimal than an empiric decrease of dose
TDM would be partircularly useful for patients with concentrations lower than …