Modélisation pharmacocinétique/pharmacodynamique par une approche de population de l'effet du G-CSF chez des patients traités avec du carboplatine

Une des stratégies pour limiter les neutropénies induites par la chimiothérapie est l utilisation de granulocyte-colony stimulating factor (G-CSF). Nous avons développé, par une approche de population, un nouveau modèle pharmacocinétique/pharmacodynamique capable de décrire la cinétique des neutrophiles des patients traités au carboplatine, qu ils aient ou non reçu du G-CSF. Les simulations réalisées à partir de ce modèle ont montré que le G-CSF n était pas bénéfique chez tous les patients et que la formulation à action longue semblerait plus efficace que les autres formulations. Nous avons également établi des règles de décision permettant d une part de prédire le risque de neutropénie sévère, et d autre part d identifier précocement les patients pour lesquels le G-CSF peut avoir un effet bénéfique.Granulocyte colony-stimulating factor (G-CSF) is often used in cancer patients receiving cytotoxic drugs to prevent or reduce high grade neutropenia. We developed a new population pharmacokinetic/pharmacodynamic model to describe neutrophil time-course in carboplatin-treated patients, whether or not they received G-CSF. Model simulations showed that G-CSF was not as beneficial as expected in some patients and that the onceper- cycle formulation was more efficient than other formulations. Model-based decision rules were also built to anticipate prolonged high grade neutropenia and early identify patients for whom G-CSF was beneficial.TOULOUSE-INP (315552154) / SudocSudocFranceF

What opportunities do the New EU international investment agreements offer for developing countries?

Purpose: Cancer chemotherapy, although based on body surface area, often causes unpredictable myelosuppression, especially severe neutropenia. The aim of this study was to evaluate qualitatively and quantitatively the influence of patient-specific characteristics on the neutrophil concentration-time course, to identify patient subgroups, and to compare covariates on system-related pharmacodynamic variable between drugs. Experimental Design: Drug and neutrophil concentration, demographic, and clinical chemistry data of several trials with docetaxel (637 patients), paclitaxel (45 patients), etoposide (71 patients), or topotecan (191 patients) were included in the covariate analysis of a physiology-based pharmacokinetic-pharmacodynamic neutropenia model. Comparisons of covariate relations across drugs were made. Results: A population model incorporating four to five relevant patient factors for each drug to explain variability in the degree and duration of neutropenia has been developed. Sex, previous anticancer therapy, performance status, height, binding partners, or liver enzymes influenced system-related variables and alpha(1)-acid glycoprotein, albumin, bilirubin, concomitant cytotoxic agents, or administration route changed drug-specific variables. Overall, female and pretreated patients had a lower baseline neutrophil concentration. Across-drug comparison revealed that several covariates (e.g., age) had minor (clinically irrelevant) influences but consistently shifted the pharmacodynamic variable in the same direction. Conclusions: These mechanistic models, including patient characteristics that influence drug-specific parameters, form the rationale basis for more tailored dosing of individual patients or subgroups to minimize the risk of infection and thus might contribute to a more successful therapy. In addition, nonsignificant or clinically irrelevant relations on system-related parameters suggest that these covariates could be negligible in clinical trails and daily use

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

Pharmacodynamic therapeutic drug monitoring for cancer: challenges, advances, and future opportunities

In the modern era of cancer treatment, with targeted agents superseding more traditional cytotoxic chemotherapeutics, it is becoming increasingly important to use stratified medicine approaches to ensure that patients receive the most appropriate drugs and treatment schedules. In this context, there is significant potential for the use of pharmacodynamic biomarkers to provide pharmacological information, which could be used in a therapeutic drug monitoring setting. This review focuses on discussing some of the challenges faced to date in translating preclinical pharmacodynamic biomarker approaches to a clinical setting. Recent advances in important areas including circulating biomarkers and pharmacokinetic/pharmacodynamic modeling approaches are discussed, and selected examples of anticancer drugs where there is existing evidence to potentially advance pharmacodynamic therapeutic drug monitoring approaches to deliver more effective treatment are discussed. Although we may not yet be in a position to systematically implement therapeutic drug monitoring approaches based on pharmacodynamic information in a cancer patient setting, such approaches are likely to become more commonplace in the coming years. Based on ever-increasing levels of pharmacodynamic information being generated on newer anticancer drugs, facilitated by increasingly advanced and accessible experimental approaches available to researchers to collect these data, we can now look forward optimistically to significant advances being made in this area

Factors for Hematopoietic Toxicity of Carboplatin: Refining the Targeting of Carboplatin Systemic Exposure

Purpose Area under the curve (AUC) dosing is routinely carried out for carboplatin, but the chosen target AUC values remain largely empirical. This multicenter pharmacokinetic-pharmacodynamic (PK-PD) study was performed to determine the covariates involved in the interindividual variability of carboplatin hematotoxicity that should be considered when choosing individual target AUCs.Patients and Methods Three hundred eighty-three patients received carboplatin as part of established regimens. A semi-physiologic population PK-PD model was applied to describe separately the time course of absolute neutrophil and platelet counts using NONMEM software. The plasma ultrafiltrable carboplatin concentration (CCarbo) was assumed to inhibit the proliferation of blood cell precursors through a linear model: drug effect = slope × CCarbo. The slope corresponds to the patients\u27 sensitivity to carboplatin hematotoxicity. The relationships between the patients\u27 sensitivity to the neutropenic or thrombopenic effects of carboplatin and various covariates, including associated chemotherapies, demographic, biologic, and pharmacogenetic data, were studied. Results The sensitivity of carboplatin-induced thrombocytopenia decreased in the case of concomitant paclitaxel chemotherapy (slope decreased by 24%), whereas it increased with coadministration of etoposide and gemcitabine (slope increased by 45% and 133%, respectively). For neutropenia, the sensitivity increased when carboplatin was combined with other cytotoxics (slope increased by 76%). Conclusion This study provides useful information to clinicians to better estimate the hematopoietic toxicity of carboplatin and thus choose more rationally carboplatin target AUCs as a function of pretreatment or concomitantly administered chemotherapies. For example, an AUC of 5 mg/mL · min is associated with a risk of grade 3 or 4 thrombocytopenia of 2% in combination with paclitaxel versus 38% with gemcitabine in a non-pretreated patient

Prognostic impact of vitamin B6 metabolism in lung cancer

Patients with non-small cell lung cancer (NSCLC) are routinely treated with cytotoxic agents such as cisplatin. Through a genome-wide siRNA-based screen, we identified vitamin B6 metabolism as a central regulator of cisplatin responses in vitro and in vivo. By aggravating a bioenergetic catastrophe that involves the depletion of intracellular glutathione, vitamin B6 exacerbates cisplatin-mediated DNA damage, thus sensitizing a large panel of cancer cell lines to apoptosis. Moreover, vitamin B6 sensitizes cancer cells to apoptosis induction by distinct types of physical and chemical stress, including multiple chemotherapeutics. This effect requires pyridoxal kinase (PDXK), the enzyme that generates the bioactive form of vitamin B6. In line with a general role of vitamin B6 in stress responses, low PDXK expression levels were found to be associated with poor disease outcome in two independent cohorts of patients with NSCLC. These results indicate that PDXK expression levels constitute a biomarker for risk stratification among patients with NSCLC.publishedVersio

Etude pharmacocinétique du carboplatine en association avec le labradimil chez les enfants atteints de tumeurs cérébrales

Le Labradimil, analogue des bradykinines, permet d'augmenter de façon sélective et transitoire la perméabilité de la barrière hémato-encéphalique et la délivrance de molécules hydrophiles, telles que le Carboplatine, auprès de cibles thérapeutiques que sont les tumeurs cérébrales. Dans cette étude, associant Carboplatine et Labradimil, 21 enfants de 4 à 18 ans atteints de tumeurs cérébrales, ont été traités par des doses de 100 à 600 ng/kg IBW/jour de Labradimil, sans signes de toxicité apparentée. En revanche, l'AUC observée du Carboplatine était en moyenne 44% supérieure à l'AUC cible, entraînant une thrombopénie importante. Ni l'analyse des résultats de l'étude ni les données bibliographiques n'ont permis d'expliquer une diminution de la clairance rénale ou extra rénale du Carboplatine lors de l'association avec le Labradimil. Par ailleurs, la formule de Calvert n'a pas été validée chez des patients présentant un débit de filtration glomérulaire aussi faible (< 80 ml/min/1,73m2).TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

Modèle pharmacocinétique-pharmacodynamique pour décrire la neutropénie induite par le topotecan

LIMOGES-BU Médecine pharmacie (870852108) / SudocLYON1-BU Santé (693882101) / SudocSudocFranceF

Variabilité du cytochrome p450 2b6 entre deux populations d'Afrique subsaharienne et conséquences sur la pharmacocinétique de l'efavirenz

Cette étude avait pour objectif d'évaluer le risque d'interaction pharmacocinétique (PK) réciproque entre la vinorelbine (VRL) et le cisplatine (CDDP), la néphrotoxicité cumulative du CDDP pouvant potentialiser l'hématotoxicité de la VRL. La PK et le profil de toxicité de l'association ont été étudiés sur 3 cycles consécutifs dans une étude de phase I chez des patients atteints de tumeurs solides. Le traitement était : VRL orale 60 mg/m J1/J8 + CDDP 100 mg/m J1 toutes les 3 semaines. La PK de la VRL a été comparée entre jours et cycles et la PK du CDDP entre les cycles et avec des données publiées. Aucune différence statistiquement significative sur les paramètres PK n'a été détectée chez 11 patients. Le profil de toxicité de l'association chez 13 patients était conforme avec les données connues sur la VRL orale ou le CDDP. L'absence d'interaction PK réciproque entre la VRL orale et le CDDP a donc été démontrée sur 3 cycles consécutifs.TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

La schizophrénie et son traitement

La schizophrénie touche 1% de la population, en particulier les jeunes. Les hallucinations, le délire, les troubles du comportement et le repli sur soi en sont les principaux symptômes. L'abus de substance (cannabis, alcool, tabac) et le suicide sont des facteurs fréquemment associés à cette maladie. L'étiologie de la schizophrénie est inconnue mais il existe de nombreuses hypothèses: différents neurotransmetteurs seraient impliqués, en particulier la dopamine, des lésions histopathologiques et des facteurs génétiques. Les antipsychotiques sont utilisés pour le traitement de la schizophrénie. Ils interagissent tous avec les voies dopaminergiques. Les antipsychotiques atypiques (ou de deuxième génération) semblent être plus efficaces et surtout entraîner moins d'effets indésirables que ceux de première génération. La ziprasidone, antipsychotique atypique, est revue plus en détail.TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF