Agents anti-infectieux et fonction réna!e: vers des posologies sur mesure [Antimicrobial agents and renal elimination: towards individual dosage adjustment?].

The efficacy and safety of anti-infective treatments are associated with the drug blood concentration profile, which is directly correlated with a dosing adjustment to the individual patient's condition. Dosing adjustments to the renal function recommended in reference books are often imprecise and infrequently applied in clinical practice. The recent generalisation of the KDOQI (Kidney Disease Outcome Quality Initiative) staging of chronically impaired renal function represents an opportunity to review and refine the dosing recommendations in patients with renal insufficiency. The literature has been reviewed and compared to a predictive model of the fraction of drug cleared by the kidney based on the Dettli's principle. Revised drug dosing recommendations integrating these predictive parameters are proposed.

Natural gene-expression variation in Down syndrome modulates the outcome of gene-dosage imbalance.

Down syndrome (DS) is characterized by extensive phenotypic variability, with most traits occurring in only a fraction of affected individuals. Substantial gene-expression variation is present among unaffected individuals, and this variation has a strong genetic component. Since DS is caused by genomic-dosage imbalance, we hypothesize that gene-expression variation of human chromosome 21 (HSA21) genes in individuals with DS has an impact on the phenotypic variability among affected individuals. We studied gene-expression variation in 14 lymphoblastoid and 17 fibroblast cell lines from individuals with DS and an equal number of controls. Gene expression was assayed using quantitative real-time polymerase chain reaction on 100 and 106 HSA21 genes and 23 and 26 non-HSA21 genes in lymphoblastoid and fibroblast cell lines, respectively. Surprisingly, only 39% and 62% of HSA21 genes in lymphoblastoid and fibroblast cells, respectively, showed a statistically significant difference between DS and normal samples, although the average up-regulation of HSA21 genes was close to the expected 1.5-fold in both cell types. Gene-expression variation in DS and normal samples was evaluated using the Kolmogorov-Smirnov test. According to the degree of overlap in expression levels, we classified all genes into 3 groups: (A) nonoverlapping, (B) partially overlapping, and (C) extensively overlapping expression distributions between normal and DS samples. We hypothesize that, in each cell type, group A genes are the most dosage sensitive and are most likely involved in the constant DS traits, group B genes might be involved in variable DS traits, and group C genes are not dosage sensitive and are least likely to participate in DS pathological phenotypes. This study provides the first extensive data set on HSA21 gene-expression variation in DS and underscores its role in modulating the outcome of gene-dosage imbalance.

L'approche de l'homéostasie du sodium par le dosage du lithium trace

Le rein participe directement ou indirectement à de nombreux processus pathologiques s'accompagnant d'une rétention hydrosodée. L'étude des mécanismes impliqués et de leur localisation intrarénale est un élément important pour l'élaboration d'un diagnostic et d'une thérapeutique rationnelle. Des outils sont nécessaires à cette fin. Il y a 25 ans, Thomsen et Schou ont proposé la clairance du lithium comme marqueur de la réabsorption de fluide et de sodium au niveau du tubule rénal proximal. L'administration de lithium exogène semble cependant perturber l'homéostasie électrolytique rénale en entraînant une natriurèse transitoire. Depuis peu, la possibilité existe de quantifier le lithium présent en trace dans le corps humain et de déterminer ainsi sa clairance rénale. Cette nouvelle approche évite toute altération de l'homéostasie du sodium et ouvre un vaste champ d'étude. Il permet de préciser certains problèmes diagnostiques, d'éclairer des mécanismes physiopathologiques, et mène ainsi à des thérapies plus judicieuses.

Feasibility of Therapeutic Drug Monitoring (TDM) for Imatinib: Preliminary considerations on the dosage adjustment approach for CML patients enrolled in the Imatinib Concentration Monitoring (I-COME) study

Background: As imatinib pharmacokinetics are highly variable, plasma levels differ largely between patients under the same dosage. Retrospective studies in chronic myeloid leukemia (CML) patients showed significant correlations between low levels and suboptimal response, and between high levels and poor tolerability. Monitoring of plasma levels is thus increasingly advised, targeting trough concentrations of 1000 μg/L and above. Objectives: Our study was launched to assess the clinical usefulness of systematic imatinib TDM in CML patients. The present preliminary evaluation questions the appropriateness of dosage adjustment following plasma level measurement to reach the recommended trough level, while allowing an interval of 4-24 h after last drug intake for blood sampling. Methods: Initial blood samples from the first 9 patients in the intervention arm were obtained 4-25 h after last dose. Trough levels in 7 patients were predicted to be significantly away from the target (6 <750 μg/L, and 1 >1500 μg/L with poor tolerance), based on a Bayesian approach using a population pharmacokinetic model. Individual dosage adjustments were taken up in 5 patients, who had a control measurement 1-4 weeks after dosage change. Predicted trough levels were confronted to anterior model-based extrapolations. Results: Before dosage adjustment, observed concentrations extrapolated at trough ranged from 359 to 1832 μg/L (median 710; mean 804, CV 53%) in the 9 patients. After dosage adjustment they were expected to target between 720 and 1090 μg/L (median 878; mean 872, CV 13%). Observed levels of the 5 recheck measurements extrapolated at trough actually ranged from 710 to 1069 μg/L (median 1015; mean 950, CV 16%) and had absolute differences of 21 to 241 μg/L to the model-based predictions (median 175; mean 157, CV 52%). Differences between observed and predicted trough levels were larger when intervals between last drug intake and sampling were very short (~4 h). Conclusion: These preliminary results suggest that TDM of imatinib using a Bayesian interpretation is able to bring trough levels closer to 1000 μg/L (with CV decreasing from 53% to 16%). While this may simplify blood collection in daily practice, as samples do not have to be drawn exactly at trough, the largest possible interval to last drug intake yet remains preferable. This encourages the evaluation of the clinical benefit of a routine TDM intervention in CML patients, which the randomized Swiss I-COME study aims to.