Etienne Chatelut

Institut Claudius Regaud, Tolosa de Llenguadoc, Midi-Pyrénées, France

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Publications (179)758.69 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Neutropenia is a major dose-limiting side effect of chemotherapy and is closely related to febrile neutropenia which mainly occurs during the first cycle. Our objectives were to establish model-based decision rules from early absolute neutrophil counts (ANC) to anticipate prolonged high grade neutropenia at cycle 1 and to prevent it through delayed granulocyte colony stimulating factor (G-CSF) administration in carboplatin-treated patients.
    Pharmaceutical Research 09/2014; DOI:10.1007/s11095-014-1493-1 · 3.95 Impact Factor
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    ABSTRACT: A selective and accurate analytical method is needed to quantify tamoxifen and its phase I metabolites in a prospective clinical protocol, for evaluation of pharmacokinetic parameters of tamoxifen and its metabolites in adjuvant treatment of breast cancer. The selectivity of the analytical method is a fundamental criteria to allow the quantification of the main active metabolites (Z)-isomers from (Z)'-isomers. An UPLC-MS/MS method was developed and validated for the quantification of (Z)-tamoxifen, (Z)-endoxifen, (E)-endoxifen, Z'-endoxifen, (Z)'-endoxifen, (Z)-4-hydroxytamoxifen, (Z)-4'-hydroxytamoxifen, N-desmethyl tamoxifen, and tamoxifen-N-oxide. The validation range was set between 0.5ng/mL and 125ng/mL for 4-hydroxytamoxifen and endoxifen isomers, and between 12.5ng/mL and 300ng/mL for tamoxifen, tamoxifen N-desmethyl and tamoxifen-N-oxide. The application to patient plasma samples was performed.
    Journal of Pharmaceutical and Biomedical Analysis 08/2014; 100C:254-261. DOI:10.1016/j.jpba.2014.07.033 · 2.83 Impact Factor
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    ABSTRACT: Most of oral targeted therapies are tyrosine kinase inhibitors (TKIs). Oral administration generates a complex step in the pharmacokinetics (PK) of these drugs. Inter-individual PK variability is often large and variability observed in response is influenced not only by the genetic heterogeneity of drug targets, but also by the pharmacogenetic background of the patient (e.g. cytochome P450 and ABC transporter polymorphisms), patient characteristics such as adherence to treatment and environmental factors (drug–drug interactions). Retrospective studies have shown that targeted drug exposure, reflected in the area under the plasma concentration–time curve (AUC) correlates with treatment response (efficacy/toxicity) in various cancers. Nevertheless levels of evidence for therapeutic drug monitoring (TDM) are however heterogeneous among these agents and TDM is still uncommon for the majority of them. Evidence for imatinib currently exists, others are emerging for compounds including nilotinib, dasatinib, erlotinib, sunitinib, sorafenib and mammalian target of rapamycin (mTOR) inhibitors. Applications for TDM during oral targeted therapies may best be reserved for particular situations including lack of therapeutic response, severe or unexpected toxicities, anticipated drug–drug interactions and/or concerns over adherence treatment. Interpatient PK variability observed with monoclonal antibodies (mAbs) is comparable or slightly lower to that observed with TKIs. There are still few data with these agents in favour of TDM approaches, even if data showed encouraging results with rituximab, cetuximab and bevacizumab. At this time, TDM of mAbs is not yet supported by scientific evidence. Considerable effort should be made for targeted therapies to better define concentration–effect relationships and to perform comparative randomised trials of classic dosing versus pharmacokinetically-guided adaptive dosing.
    European Journal of Cancer 08/2014; 50(12). DOI:10.1016/j.ejca.2014.04.015 · 4.82 Impact Factor
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    ABSTRACT: First, to evaluate the peritoneal (IP), plasma ultrafiltrated (UF) and protein-bound (B) pharmacokinetics (PK) of oxaliplatin after intraperitoneal hyperthermic chemoperfusion (HIPEC) following cytoreductive surgery. Second, to evaluate the relationship between oxaliplatin exposure and observed toxicity. IP, UF, and B concentrations from 75 patients treated by 30-min oxaliplatin-based HIPEC procedures were analysed according to a pharmacokinetic modelling approach using NONMEM. Oxaliplatin was administered in a 5 % dextrose solution (2 L/m(2)) at 360 (n = 58) or 460 mg/m(2) (n = 17). The most frequently observed toxicities were related to the peritoneal, systemic exposures and to the parameters corresponding to the oxaliplatin absorption from peritoneal cavity into plasma. IP (n = 536), UF (n = 669) and B (n = 661) concentrations were simultaneously described according to a five-compartment PK model with irreversible nonlinear binding from UF to B according to a Michaelis-Menten equation. The mean (+/- SD) maximum fraction of dose absorbed and elimination half-life from the peritoneum was 53.7 % (+/- 8.5) and 0.49 h (+/- 0.1), respectively. The mean (+/- SD) ratio AUC(IP)/AUC(UF) was 5.3 (+/- 2) confirming the pharmacokinetic advantage of the procedure. Haemoperitoneum (22.7 %), neuropathy (18.7 %), grade 3/4 thrombocytopenia (13.3 %) were the most frequently reported toxicities. AUC(UF) accounts for approximately 12 % of the variation in the maximum percentage of platelet decrease (r = 0.35, p = 0.002). Thrombocytopenia was correlated with higher AUC(UF), partly dependent on the extent and rate of oxaliplatin absorption. Despite a common dose administered, variability in peritoneal and systemic oxaliplatin exposures are observed, leading to differences in haematological toxicity between patients.
    Cancer Chemotherapy and Pharmacology 07/2014; 74(3). DOI:10.1007/s00280-014-2525-6 · 2.57 Impact Factor
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    ABSTRACT: Background In the clinical development of oncology drugs, the recommended dose is usually determined using a 3 + 3 dose-escalation study design. However, this phase I design does not always adequately describe dose-toxicity relationships. Methods 125 patients, with either solid tumours or lymphoma, were included in the study and 1217 platelet counts were available over three treatment cycles. The data was used to build a population pharmacokinetic/pharmacodynamic (PKPD) model using a sequential modeling approach. Model-derived Recommended Doses (MDRD) of abexinostat (a Histone Deacetylase Inhibitor) were determined from simulations of different administration schedules, and the higher bound for the probability of reaching these MDRD with a 3 + 3 design were obtained. Results The PKPD model developed adequately described platelet kinetics in both patient populations with the inclusion of two platelet baseline counts and a disease progression component for patients with lymphoma. Simulation results demonstrated that abexinostat administration during the first 4 days of each week in a 3-week cycle led to a higher MDRD compared to the other administration schedules tested, with a maximum probability of 40 % of reaching these MDRDs using a 3 + 3 design. Conclusions The PKPD model was able to predict thrombocytopenia following abexinostat administration in both patient populations. A model-based approach to determine the recommended dose in phase I trials is preferable due to the imprecision of the 3 + 3 design.
    Investigational New Drugs 05/2014; 32(5). DOI:10.1007/s10637-014-0118-1 · 2.93 Impact Factor
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    ABSTRACT: Most anticancer drugs are characterised by a steep dose-response relationship and narrow therapeutic window. Inter-individual pharmacokinetic (PK) variability is often substantial. The most relevant PK parameter for cytotoxic drugs is the area under the plasma concentration versus time curve (AUC). Thus it is somewhat surprising that therapeutic drug monitoring (TDM) is still uncommon for the majority of agents. Goals of the review were to assess the rationale for more widely used TDM of cytotoxics in oncology. There are several reasons why TDM has never been fully implemented into daily oncology practice. These include difficulties in establishing appropriate concentration target ranges, common use of combination chemotherapies for many tumour types, analytical challenges with prodrugs, intracellular compounds, the paucity of published data from pharmacological trials and 'Day1=Day21' administration schedules. There are some specific situations for which these limitations are overcome, including high dose methotrexate, 5-fluorouracil infusion, mitotane and some high dose chemotherapy regimens. TDM in paediatric oncology represents an important challenge. Established TDM approaches includes the widely used anticancer agents carboplatin, busulfan and methotrexate, with 13-cis-retinoic acid also recently of interest. Considerable effort should be made to better define concentration-effect relationships and to utilise tools such as population PK/PD models and comparative randomised trials of classic dosing versus pharmacokinetically guided adaptive dosing. There is an important heterogeneity among clinical practices and a strong need to promote TDM guidelines among the oncological community.
    European journal of cancer (Oxford, England: 1990) 05/2014; 50(12). DOI:10.1016/j.ejca.2014.04.014 · 4.82 Impact Factor
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    ABSTRACT: Therapeutic drug monitoring (TDM) can be defined as the measurement of drug in biological samples to individualise treatment by adapting drug dose to improve efficacy and/or reduce toxicity. The cytotoxic drugs are characterised by steep dose-response relationships and narrow therapeutic windows. Inter-individual pharmacokinetic (PK) variability is often substantial. There are, however, a multitude of reasons why TDM has never been fully implemented in daily oncology practice. These include difficulties in establishing appropriate concentration target, common use of combination chemotherapies and the paucity of published data from pharmacological trials. The situation is different with targeted therapies. The large interindividual PK variability is influenced by the pharmacogenetic background of the patient (e.g. cytochrome P450 and ABC transporters polymorphisms), patient characteristics such as adherence to treatment and environmental factors (drug-drug interactions). Retrospective studies have shown that targeted drug exposure correlates with treatment response in various cancers. Evidence for imatinib currently exists, others are emerging for compounds including nilotinib, dasatinib, erlotinib, sunitinib, sorafenib and mammalian target of rapamycin (mTOR) inhibitors. Applications for TDM during oral targeted therapies may best be reserved for particular situations including lack of therapeutic response, severe or unexpected toxicities, anticipated drug-drug interactions and concerns over adherence treatment. There are still few data with monoclonal antibodies (mAbs) in favour of TDM approaches, even if data showed encouraging results with rituximab and cetuximab. TDM of mAbs is not yet supported by scientific evidence. Considerable effort should be made for targeted therapies to better define concentration-effect relationships and to perform comparative randomised trials of classic dosing versus pharmacokinetically-guided adaptive dosing.
    European journal of cancer (Oxford, England: 1990) 05/2014; 50(12). DOI:10.1016/j.ejca.2014.04.013 · 4.82 Impact Factor
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    ABSTRACT: Voriconazole (VOR) is a triazole antifungal used in the curative treatment of invasive fungal infections (IFI) and the prophylactic treatment of opportunistic fungal infections in immunocompromised patients. It is a drug for which therapeutic drug monitoring (TDM) is highly recommended. In order to determine the best TDM marker, the pharmacologically active form of the drug, represented by the unbound plasma concentration (Cu) and fraction (fu), has been studied using a method based on ultrafiltration and ultra performance liquid chromatography. As albumin is a likely factor inducing fluctuations in fu, the correlation between albumin levels and fu was carried out. Similarly, correlations between trough plasma concentrations (total concentration (Ct) and Cu) and both efficacy and safety markers were determined. Efficacy evaluation was based on monitoring fungal antigens and cultures, while safety was monitored by measuring bilirubin levels. In vitro, using blank human plasma, the mean fu was determined at 32.3 ± 5.5% while in patients' plasmas treated with VOR, the median (5-95 percentiles) of the unbound VOR fraction was 22.95 % (14.95 - 38.42 %). A high correlation was found (rho=0.956, p<0.001) between Ct and Cu, though there was no correlation between serum albumin levels and fu, except for some patients with severe hypoalbuminemia (< 25 g/L). Based on efficacy/safety correlations, a therapeutic window has been defined ranging from 4.5 to 6.5 mg/L and 1.5 and 2.0 mg/L for trough Ct and Cu, respectively. For the first time, the relevance of new pharmacokinetic parameters such as Cu and fu have been explored and discussed, and our results support the current TDM protocol for VOR.
    Therapeutic drug monitoring 05/2014; DOI:10.1097/FTD.0000000000000095 · 1.93 Impact Factor
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    ABSTRACT: A combination of monoclonal antibody that binds and inhibits effects induced by vascular endothelial growth factor and tyrosine kinase inhibitor of vascular endothelial growth factor receptor represents a promising concept to block pathological angiogenesis completely. A phase I study combining daily oral pazopanib and bevacizumab (given iv every 2 weeks) was performed in order to determine the maximum tolerated dose of the two drugs in combination. Pazopanib pharmacokinetics were evaluated to compare pharmacokinetic parameters given alone and those observed on the day of the bevacizumab administration. Plasma pazopanib concentrations were obtained in 25 patients treated at two dose levels (400 or 600 mg) at Day 1 (given alone) and Day 15 (the day of the 7.5 mg/kg bevacizumab infusion), and analyzed using the NONMEM program. The apparent oral clearance (CL/F, mean value of 0.60 L/h) presented an inter-individual variability of 40 %, and an inter-occasion of 27 %. A modest but statistically significant decrease in CL/F was observed from Day 1 to Day 15 (-16.4, 95 % confidence interval of -8.5 to -27.2 %). However, trough pazopanib concentrations observed at Day 16 (24 h after the bevacizumab iv infusion) were not significantly higher than those observed just before the beginning of the bevacizumab iv infusion, suggesting that the pharmacokinetic change between Day 1 and Day 15 was not due to an interaction of bevacizumab. Overall, the mean observed concentrations at the maximum tolerated pazopanib dose (600 mg) at both Day 1 and Day 15 were higher than those observed at 800 mg once daily level (corresponding to the recommended dose when given alone) during the first-in-man phase 1 study of pazopanib in monochemotherapy. This first population pharmacokinetic analysis of pazopanib shows that inter-individual and inter-study pharmacokinetic variability emphasize the need for further evaluation of therapeutic drug monitoring for pazopanib as suggested for other tyrosine kinase inhibitors.
    Cancer Chemotherapy and Pharmacology 04/2014; DOI:10.1007/s00280-014-2455-3 · 2.57 Impact Factor
  • E Chatelut, F Puisset
    Clinical Pharmacology &#38 Therapeutics 04/2014; 95(4):359-61. DOI:10.1038/clpt.2014.7 · 7.39 Impact Factor
  • M. -N. Paludetto, E. Chatelut
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    ABSTRACT: L’irinotécan et le cisplatine sont deux médicaments anticancéreux dont les effets indésirables fréquents et sévères — toxicité hématologique et digestive pour l’irinotécan, ototoxicité pour le cisplatine — présentent une importante variabilité interindividuelle d’origine en partie génétique. Différentes études ont été mises en place pour identifier les déterminants génétiques de ces toxicités afin de prédire le risque de survenue d’effets indésirables et adapter le traitement en fonction du niveau de risque. Pour l’irinotécan, des recommandations de dose commencent à émerger des nombreux travaux réalisés sur les polymorphismes de l’UDP-glucuronosyl-transférase 1A1 (UGT1A1), principale enzyme impliquée dans la détoxification du métabolite actif de l’irinotécan, le SN-38. La découverte récente du rôle d’autres enzymes (notamment de la même sous-famille UGT1A) et transporteurs (en particulier de la superfamille ABC, ATP Binding Cassette) intervenant dans la pharmacocinétique de l’irinotécan risque de complexifier l’élaboration de telles recommandations. Pour le cisplatine, la détermination des gènes d’intérêt est encore en cours, car les résultats des différentes études restent controversés. Plusieurs gènes impliqués dans les processus intracellulaires de l’ototoxicité ont été évoqués, tels que les gènes des glutathions Stransférases (GST), de la mégaline, de la thiopurine méthyltransférase (TPMT), de la catéchol O-méthyltransférase (COMT) et du transporteur ABCC3, ces trois derniers ayant été intégrés dans un modèle de prédiction de l’ototoxicité. Pour l’irinotécan comme pour le cisplatine, des études complémentaires sont donc encore nécessaires pour atteindre une individualisation complète du traitement.
    Oncologie 02/2014; 16. DOI:10.1007/s10269-014-2374-2 · 0.08 Impact Factor
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    ABSTRACT: Most anticancer drugs are characterised by a steep dose–response relationship and narrow therapeutic window. Inter-individual pharmacokinetic (PK) variability is often substantial. The most relevant PK parameter for cytotoxic drugs is the area under the plasma concentration versus time curve (AUC). Thus it is somewhat surprising that therapeutic drug monitoring (TDM) is still uncommon for the majority of agents. Goals of the review were to assess the rationale for more widely used TDM of cytotoxics in oncology. There are several reasons why TDM has never been fully implemented into daily oncology practice. These include difficulties in establishing appropriate concentration target ranges, common use of combination chemotherapies for many tumour types, analytical challenges with prodrugs, intracellular compounds, the paucity of published data from pharmacological trials and ‘Day1 = Day21’ administration schedules. There are some specific situations for which these limitations are overcome, including high dose methotrexate, 5-fluorouracil infusion, mitotane and some high dose chemotherapy regimens. TDM in paediatric oncology represents an important challenge. Established TDM approaches includes the widely used anticancer agents carboplatin, busulfan and methotrexate, with 13-cis-retinoic acid also recently of interest. Considerable effort should be made to better define concentration–effect relationships and to utilise tools such as population PK/PD models and comparative randomised trials of classic dosing versus pharmacokinetically guided adaptive dosing. There is an important heterogeneity among clinical practices and a strong need to promote TDM guidelines among the oncological community.
  • Florent Puisset, Antonin Schmitt, Etienne Chatelut
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    ABSTRACT: Platinum compounds represent a pharmacological class essential for the treatment of certain types of cancer. Cisplatin, carboplatin, and oxaliplatin, share some physiochemical and pharmacological properties, in particular the ability to form DNA adducts. Carboplatin may be considered as an analog of cisplatin, but its pharmacokinetic properties, side-effects, and intrinsic activity are significantly different from those of cisplatin. The choice of one of these two compounds may be made rationally based on the individual patient's characteristics.
    Anticancer research 01/2014; 34(1):465-470. · 1.87 Impact Factor
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    ABSTRACT: Therapeutic drug monitoring (TDM) can be defined as the measurement of drug in biological samples to individualise treatment by adapting drug dose to improve efficacy and/or reduce toxicity. The cytotoxic drugs are characterised by steep dose–response relationships and narrow therapeutic windows. Inter-individual pharmacokinetic (PK) variability is often substantial. There are, however, a multitude of reasons why TDM has never been fully implemented in daily oncology practice. These include difficulties in establishing appropriate concentration target, common use of combination chemotherapies and the paucity of published data from pharmacological trials. The situation is different with targeted therapies. The large interindividual PK variability is influenced by the pharmacogenetic background of the patient (e.g. cytochrome P450 and ABC transporters polymorphisms), patient characteristics such as adherence to treatment and environmental factors (drug–drug interactions). Retrospective studies have shown that targeted drug exposure correlates with treatment response in various cancers. Evidence for imatinib currently exists, others are emerging for compounds including nilotinib, dasatinib, erlotinib, sunitinib, sorafenib and mammalian target of rapamycin (mTOR) inhibitors. Applications for TDM during oral targeted therapies may best be reserved for particular situations including lack of therapeutic response, severe or unexpected toxicities, anticipated drug–drug interactions and concerns over adherence treatment. There are still few data with monoclonal antibodies (mAbs) in favour of TDM approaches, even if data showed encouraging results with rituximab and cetuximab. TDM of mAbs is not yet supported by scientific evidence. Considerable effort should be made for targeted therapies to better define concentration–effect relationships and to perform comparative randomised trials of classic dosing versus pharmacokinetically-guided adaptive dosing.
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    ABSTRACT: We describe here the case of a 60-year old male patient treated for an extensive local progression of a pleiomorphic sarcoma on the right tibial crest with second-line trabectedin. Two cycles were administrated before a major liver toxicity was retrieved, with both cytolytic and cholestatic hepatitis quickly associated with irreversible jaundice. The radiological, histological, chemistry and pharmacogenetic investigations led us to diagnose chronic hepatobiliary toxicity with portal fibrosis, cholangiolitis damages and chronic hepatopathy. The patient had a deficient variant genotype of ABCC2 (c.-24TT, c.4488CT and c.4544GA), which has been suggested to play a role in excretion of toxic metabolites of trabectedin. This case report is, to our knowledge, the first description of trabectedin's irreversible liver toxicity in a human patient. Supported by a thorough review of the literature, this hepatitis is thought to have resulted from a multihit process involving genetic variants of ABC proteins and comedication.
    Pharmacogenomics 09/2013; 14(12):1389-96. DOI:10.2217/pgs.13.124 · 3.43 Impact Factor
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    ABSTRACT: Granulocyte colony-stimulating factor (G-CSF) is often used in cancer patients receiving cytotoxic drugs to prevent or reduce high grade neutropenia. We propose a pharmacokinetic/pharmacodynamic model to describe myelotoxicity in both G-CSF treated and non-treated patients that shall increase our understanding of G-CSF effects. The model was built from absolute neutrophil counts (ANC) obtained in 375 carboplatin-treated patients, 47 of whom received G-CSF. It includes some prior information on G-CSF taken from the literature. Simulations were performed to understand differences in G-CSF effects and explore the impact of G-CSF formulation. Our model well described the data in all patients. Model simulations showed that G-CSF was not as beneficial as expected in some patients. Furthermore, a longer and stronger effect was observed for the pegylated formulation in comparison with the daily standard formulation even if the latter was given for 11 consecutive days. The proposed model allows a mechanistic interpretation of G-CSF effects on ANC and raises the question of a systematic beneficial effect of G-CSF treatment. Other studies are needed to confirm these findings and help identifying patients for whom G-CSF is beneficial.
    Pharmaceutical Research 06/2013; 30(11). DOI:10.1007/s11095-013-1099-z · 3.95 Impact Factor
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    ABSTRACT: PURPOSE: A population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the thrombocytopenia (dose-limiting toxicity) of abexinostat, a new histone deacetylase inhibitor. An optimal administration schedule of the drug was determined using a simulation-based approach. METHODS: Early PK and PK/PD data were analysed using a sequential population modeling approach (NONMEM 7), allowing for the description of a PK profile and platelet-count decrease after abexinostat administration with various administration schedules. Simulations of platelet count with several administration schedules over 3-week treatment cycles (ASC) and over a day (ASD) were computed to define the optimal schedule that limits the depth of thrombocytopenia. RESULTS: An intermediate PK/PD model accurately described the data. The administration of abexinostat during the first 4 days of each week in a 3-week cycle resulted in fewer adverse events (with no influence of ASD on platelet count profiles), and corresponded to the optimal treatment schedule. This administration schedule was clinically evaluated in a phase I clinical trial and allowed for the definition of a new maximum tolerated dose (MTD), leading to a nearly 30% higher dose-intensity than that of another previously tested schedule. Lastly, a final model was built using all of the available data. CONCLUSIONS: The final model, characterizing the dose-effect and the dose-toxicity relationships, provides a useful modeling tool for clinical drug development.
    Pharmaceutical Research 06/2013; DOI:10.1007/s11095-013-1089-1 · 3.95 Impact Factor
  • Clinical Cancer Research 02/2013; 19(4). DOI:10.1158/1078-0432.CCR-12-3445 · 8.19 Impact Factor
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    ABSTRACT: PURPOSE: The European Society for Medical Oncology recommends therapeutic drug monitoring (TDM) for imatinib, based on total plasma concentrations in cases of sub-optimal response, failure, or adverse events. Imatinib is highly bound to alpha-1 acid glycoprotein (AGP) in the plasma. We determined the unbound plasma fraction of both imatinib and its main active metabolite (N-desmethyl-imatinib) in plasma from 44 patients. The objective was to quantify the inter-individual variability of the protein binding of imatinib in order to discuss the potential benefits and limits of TDM of free plasma concentrations. PATIENTS AND METHODS: The quantification of unbound fraction of imatinib and N-desmethyl-imatinib was performed using plasma ultrafiltration coupled with LC-MS/MS measurement. 60 pre-dose plasma samples were obtained at steady state within TDM in 44 chronic myeloid leukemia patients. RESULTS: The mean unbound fractions of imatinib and N-desmethyl-imatinib were 2.94 and 5.10 %, respectively, with inter-individual variability (CV in %) of 57 % for imatinib and 71 % for the metabolite. For 11 patients, repeated blood sampling gave a mean intra-individual variability of 28 % for imatinib and 34 % for N-desmethyl-imatinib. No correlation was observed between these measured individual imatinib unbound fraction values and those obtained using an equation based on AGP levels previously proposed by Widmer et al. The mean N-desmethyl-imatinib/imatinib ratio was determined for both total (0.69) and unbound (1.10) concentrations, with inter-individual variabilities of 71 and 86 %, respectively. CONCLUSION: The large inter-individual variability for the unbound fraction of both imatinib and N-desmethyl-imatinib warrants further evaluation of the pharmacokinetic-pharmacodynamic relationship as a potential relevant marker of imatinib therapeutic outcomes.
    Cancer Chemotherapy and Pharmacology 11/2012; DOI:10.1007/s00280-012-2035-3 · 2.57 Impact Factor
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    ABSTRACT: Imatinib is a small-molecule tyrosine kinase inhibitor with large inter-individual but low intra-individual pharmacokinetic variability with consistent concentration–efficacy and concentration–toxicity relationships. For these reasons imatinib therapeutic drug monitoring is based on total plasma concentrations. However, since a significant impact of unbound imatinib concentrations on clinical response and/or toxicity evaluation has been suggested, the quantification of free fraction of imatinib and its active metabolite are of interest for therapeutic monitoring. Hence a reliable method for both separation and assay of the free fraction is needed. Using plasma samples spiked with imatinib (from 1000 to 7500 ng/mL) and its metabolite (from 1000 to 2500 ng/mL), an ultrafiltration procedure and an UPLC assay which give reproductive values for unbound fractions of imatinib (mean 3.0 ± 1.0%) and metabolite N-desmethyl imatinib (3.6 ± 1.8%) have been developed. The validation of the analytical UPLC–MS/MS method associated to ultrafiltration for quantification of imatinib and N-desmethyl imatinib was reported. The LOQ was set at 10 ng/mL for imatinib and 20 ng/mL for N-desmethyl imatinib, intraday CV (%) ranged from 2.7 to 4.8% for imatinib and from 5.4 to 12.4% for N-desmethyl imatinib and interday CV (%) ranged from 5.6 to 6.5% for imatinib and from 5.4 to 16.1% for N-desmethyl imatinib. Methodological modifications were attempted to overcome non specific binding (NSB) on the ultrafiltration device. Two types of devices previously used for unbound determination of drugs were tested. Our results clearly showed that the methodology and the features of devices used for ultrafiltration could totally compromise the determination of unbound concentrations of a drug.
    Journal of Chromatography B 10/2012; 907:94-100. DOI:10.1016/j.jchromb.2012.09.007 · 2.69 Impact Factor

Publication Stats

3k Citations
758.69 Total Impact Points

Institutions

  • 1989–2014
    • Institut Claudius Regaud
      Tolosa de Llenguadoc, Midi-Pyrénées, France
    • Paul Sabatier University - Toulouse III
      • Groupe de Pharmacologie clinique et expérimentale des médicaments anticancéreux - EA 3035
      Tolosa de Llenguadoc, Midi-Pyrénées, France
    • University of Toulouse
      Tolosa de Llenguadoc, Midi-Pyrénées, France
  • 2008
    • Centre Oscar Lambret
      Lille, Nord-Pas-de-Calais, France
  • 2007
    • Memorial Sloan-Kettering Cancer Center
      New York, New York, United States
    • Ospedali Riuniti di Bergamo
      Bérgamo, Lombardy, Italy
    • Slotervaartziekenhuis
      Amsterdamo, North Holland, Netherlands
  • 2006
    • Institut de Cancérologie Gustave Roussy
      Villejuif, Île-de-France, France
  • 1993–2003
    • Centre Antoine-Lacassagne
      Nice, Provence-Alpes-Côte d'Azur, France
  • 2000
    • Centre Eugène Marquis
      Roazhon, Brittany, France
  • 1998
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 1993–1994
    • University of California, San Diego
      • Department of Medicine
      San Diego, California, United States