Clinical pharmacodynamic factors in docetaxel toxicity

Neutropenia is the main dose-limiting toxicity occurring in docetaxel treatment. The objective of this study was to identify pharmacodynamic (PD) factors responsible for the neutropaenia caused by docetaxel. Data were obtained from 92 patients treated with docetaxel as a monochemotherapy in two different treatment centres. A semiphysiological population pharmacokinetic–pharmacodynamic (PK/PD) model was applied to describe the time course of neutrophils and the neutropaenic effect of docetaxel. The plasma docetaxel concentration was assumed to inhibit the proliferation of neutrophil precursors through a linear model: Drug effect=Slope × Conc. Slope corresponds to the patients' sensitivity to the neutropaenic effect of docetaxel. Covariate analysis was performed by testing the relationship between the patients' characteristics and Slope using the program NONMEM. The neutropaenic effect of docetaxel showed a high interindividual variability. Three significant PD covariates were identified: serum α1-acid glycoprotein levels (AAG), level of chemotherapy pretreatment, and treatment centre. Extensive pretreatment was associated with an increase in Slope values meaning a higher haematotoxicity. An increase in AAG was associated with a decrease of both Slope and docetaxel plasma clearance. Patients treated in one centre had both higher Slope and docetaxel clearance. The centre effect (most likely due to a bias in the PK part of the study between the two centres) reveals the robustness of the PK/PD model. Individual dosing of docetaxel should be based on previous chemotherapy but not on the AAG level since it has a similar influence on PD and PK docetaxel parameters. This methodology should be applied to further investigate elderly patients and to identify more precisely the characteristics of previous chemotherapy that contribute to the cumulative myelotoxicity

Dose banding as an alternative to body surface area-based dosing of chemotherapeutic agents

Background: Dose banding is a recently suggested dosing method that uses predefined ranges (bands) of body surface area (BSA) to calculate each patients dose by using a single BSA-value per band. Thus, drugs with sufficient long-term stability can be prepared in advance. The main advantages of dose banding are to reduce patient waiting time and improve pharmacy capacity planning; additional benefits include reduced medication errors, reduced drug wastage, and prospective quality control. This study compares dose banding with individual BSA dosing and fixed dose according to pharmacokinetic criteria.Methods:Three BSA bands were defined: BSA1.7 m2, 1.7 m2 BSA1.9 m 2, BSA1.9 m2 and each patient dose was calculated based on a unique BSA-value per band (1.55, 1.80, and 2.05 m 2, respectively). By using individual clearance values of six drugs (cisplatin, docetaxel, paclitaxel, doxorubicin, irinotecan, and topotecan) from 1012 adult cancer patients in total, the AUCs corresponding to three dosing methods (BSA dosing, dose banding, and fixed dose) were compared with a target AUC for each drug.Results:For all six drugs, the per cent variation in individual dose obtained with dose banding compared with BSA dosing ranged between 14% and 22%, and distribution of AUC values was very similar with both dosing methods. In terms of reaching the target AUC, there was no significant difference in precision between dose banding and BSA dosing, except for paclitaxel (32.0% vs 30.7%, respectively; P=0.05). However, precision was significantly better for BSA dosing compared with fixed dose for four out of six drugs.Conclusion:For the studied drugs, implementation of dose banding should be considered as it entails no significant increase in interindividual plasma exposure

Pharmacokinetic Modeling of an Induction Regimen for In Vivo Combined Testing of Novel Drugs against Pediatric Acute Lymphoblastic Leukemia Xenografts

Current regimens for induction therapy of pediatric acute lymphoblastic leukemia (ALL), or for re-induction post relapse, use a combination of vincristine (VCR), a glucocorticoid, and l-asparaginase (ASP) with or without an anthracycline. With cure rates now approximately 80%, robust pre-clinical models are necessary to prioritize active new drugs for clinical trials in relapsed/refractory patients, and the ability of these models to predict synergy/antagonism with established therapy is an essential attribute. In this study, we report optimization of an induction-type regimen by combining VCR, dexamethasone (DEX) and ASP (VXL) against ALL xenograft models established from patient biopsies in immune-deficient mice. We demonstrate that the VXL combination was synergistic in vitro against leukemia cell lines as well as in vivo against ALL xenografts. In vivo, VXL treatment caused delays in progression of individual xenografts ranging from 22 to >146 days. The median progression delay of xenografts derived from long-term surviving patients was 2-fold greater than that of xenografts derived from patients who died of their disease. Pharmacokinetic analysis revealed that systemic DEX exposure in mice increased 2-fold when administered in combination with VCR and ASP, consistent with clinical findings, which may contribute to the observed synergy between the 3 drugs. Finally, as proof-of-principle we tested the in vivo efficacy of combining VXL with either the Bcl-2/Bcl-xL/Bcl-w inhibitor, ABT-737, or arsenic trioxide to provide evidence of a robust in vivo platform to prioritize new drugs for clinical trials in children with relapsed/refractory ALL

Therapeutic Drug Monitoring of Tyrosine Kinase Inhibitors in the Treatment of Advanced Renal Cancer

Seven tyrosine kinase inhibitor compounds with anti-angiogenic properties remain key drugs to treat advanced renal cell carcinoma. There is a strong rationale to develop therapeutic drug monitoring for these drugs. General considerations of such monitoring of the several groups of anticancer drugs are given, with a focus on oral therapy. Pharmacokinetics and the factors of inter- and intraindividual variabilities of these tyrosine kinase inhibitors are described together with an exhaustive presentation of their pharmacokinetic/pharmacodynamic relationships. The latter was observed in studies where every patient was treated with the same dose, and the results of several prospective studies based on dose individualization support the practice of increasing individual dosage in case of low observed plasma drug concentrations. Finally, the benefits and limits of therapeutic drug monitoring as a routine practice are discussed

Mélanome métastasique, vémurafénib et photosensibilité (15 mois de pratique à l'institut Claudius Régaud)

TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

Structure et organisation de l'hospitalisation à domicile des patients traités par anticancéreux (exemple de Toulouse)

TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

Impact de la nutrition parentérale lors du traitement d'induction des leucémies aiguës myéloïdes

TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

Place de la vaccination Gardasil® -Cervarix® dans la prévention du cancer du col de l'utérus

Avec près de 500 000 nouveaux cas diagnostiqués chaque année dans le monde et 270 000 décès, le cancer du col de l'utérus est un véritable problème de santé publique. Il représente la deuxième cause de cancer chez la femme dans le monde. Avec 3 387 nouveaux cas estimés au cours de l'année 2000 et environ 900 décès par an, il reste en France le troisième cancer de la femme jeune. L'histoire naturelle de ce cancer est de nos jours bien connue. Le rôle étiologique des infections à certains papillomavirus humains (HPV-16 et 18) a été mis en évidence dans 70% des cancers du col utérin. Cette association entre infection HPV et cancer du col a été la base du développement des vaccins prophylactiques Gardasil® et Cervarix®. Les essais cliniques ont démontré une prévention de 70% à 82% des cas de cancers du col utérin associés aux types viraux du vaccin, dans la population per protocole. Les autorités Françaises ont recommandé une vaccination en trois doses, des jeunes filles de 14 ans et celles de 15 à 24 ans n'ayant jamais eu de rapports sexuels, ou au plus tard dans l'année suivant leur premier rapport. L'arrivée de cette vaccination suscite un espoir majeur pour la santé des femmes et devrait permettre de faire un nouveau grand pas dans la prévention. La vaccination constitue un complément au dépistage par frottis cervico-utérin dans la prévention du cancer du col. Mais, à ce jour des interrogations persistent pour positionner la vaccination dans la stratégie de prévention : population cible, effets indésirables à long terme, accessibilité du vaccin, impact sur l'incidence des cancers du col utérin, effet de la vaccination sur le comportement des jeunes filles vaccinées vis-à-vis du dépistageTOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF