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Background: High-dose methotrexate is used for treating several types of cancer. However, it is associated with a high risk of acute kidney injury (AKI), especially in patients with high MTX concentrations. Although therapeutic drug monitoring is performed to monitor MTX concentrations, it is unclear what concentration should be considered critical, thus requiring rescue protocols to prevent nephrotoxicity.Methods: Patients treated with high-dose methotrexate for lymphoma or acute lymphoblastic leukemia and those benefited from therapeutic drug monitoring were included. The relationship between MTX concentrations and the presence or absence of AKI was assessed. MTX concentrations were analyzed using a population pharmacokinetic approach. Specific attention was given to morphological covariates because MTX doses are individualized according to body surface area (BSA).Results: In total, 328 patients and 657 cycles of treatment were analyzed. Higher MTX concentrations were observed in the AKI+ group. For cycle 1, all patients showing an MTX concentration .6 mM at 36 hours or .2 mM at 48 hours after infusion developed nephrotoxicity. The final pharmacokinetic model had 2 compartments and included the effect of age on clearance (CL) and of body weight on peripheral distribution volume. None of the morphological covariates tested on CL led to significant improvement in the model. Higher MTX concentrations were observed in patients with extreme BSA values ($2 m 2 ) or body mass index ($25 kg/m 2 ). Patients with AKI who received at least 1 cycle had higher BSA and BMI. Conclusions:The results from this study provide additional information on the relationship between MTX concentration and nephrotoxicity. Patients with a plasma MTX concentration .6 mM at 36 hours were more likely to manifest AKI. In addition, the results suggest that overweight patients have a high AKI risk and that BSAbased adjustment of MTX dose is not appropriate.

Therapeutic drug monitoring of ibrutinib is based on the area under the curve of concentration vs. time (AUCIBRU) instead of trough concentration (Cmin,ss) because of a limited accumulation in plasma. Our objective was to identify a limited sampling strategy (LSS) to estimate AUCIBRU associated with Bayesian estimation. The actual AUCIBRU of 85 patients was determined by the Bayesian analysis of the full pharmacokinetic profile of ibrutinib concentrations (pre-dose T0 and 0.5, 1, 2, 4 and 6 h post-dose) and experimental AUCIBRU were derived considering combinations of one to four sampling times. The T0–1–2–4 design was the most accurate LSS (root-mean-square error RMSE = 11.0%), and three-point strategies removing the 1 h or 2 h points (RMSE = 22.7% and 14.5%, respectively) also showed good accuracy. The correlation between the actual AUCIBRU and Cmin,ss was poor (r2 = 0.25). The joint analysis of dihydrodiol-ibrutinib metabolite concentrations did not improve the predictive performance of AUCIBRU. These results were confirmed in a prospective validation cohort (n = 27 patients). At least three samples, within the pre-dose and 4 h post-dose period, are necessary to estimate ibrutinib exposure accurately.

A set of requirements which allows a clear understanding of the origin of molecular additivity rules is presented. These requirements are: (a) to find good decompositions into loges of the molecules concerned; (b) to associate with each loge i a fraction Ai of the molecular property under consideration in such a way that the molecular property A satisfies the relation: (c) to show that the various Ai remain approximately constant in the family of molecules studied. This possibility of satisfying these requirements is discussed in the case of the Faraday effect. It is shown that in this case from the experimental viewpoint molecular additivity rules are observed at least within certain limits which are carefully specified. Furthermore, starting from a variational theory of the Faraday effect it is shown that it is always possible to satisfy requirement (b) when requirement (a) is satisfied. Therefore the additive properties of the Faraday effect are clearly understood when it is possible to satisfy both requirements (a) and (c). On présente un nombre de conditions pour expliquer l'origine des règles d'additivité moléculaire. Il est nécessaire: (a) de trouver de bonnes decompositions en loges des molecules en question; (b) d'associer à chaque loge i une fraction Ai de la propriété moléculaire considéréé de sorte que la propriété moléculaire A satisfait is à relation (c) de montrer qu'approximativement les Ai restent constantes dans la famille de molécules étudiée. On discute la possibilité de satisfaire à ces conditions dans le cas de l'effet Faraday. On montre que dans ce cas‐ci du point de vue expérimental les règles d'additivité moléculaire sont observées au moins entre certaines limites, qui sont bien précisées. De plus, partant d'une théorie de variations de l'effet Faraday on montre qu'il est toujours possible de satisfaire a la condition (b) quand la condition (a) est remplie. Les proprétés additives de l'effet Faraday sont donc bien comprises quand it est possible de remplir les conditions (a) et (c). Eine Reihe von Forderungen fair die Erklarung der Ursprung molekularer Additivitätsregeln wurde darstellt. Dafür ist es notwendig: (a) gute Zerlegungen der Moleküle in Logen zu fulden; (b) zu jeder Loge i ein Bruchteil Ai der molekularen Eigenschaft A so dass (c) zu zeigen dass die Ai ungefähr konstant in der studierten Molektülfamilie bleiben. Die Möglichkeit diesen Forderungen zu befriedigen wurde im Falle des Faradayeffekts diskutiert. Es wurde gezeigt, dass in diesem Fall, vom experimentalen Standpunkte aus, die molekulare Additivitätsregeln wenigstens innerhalb gewisser, wohl spezifizierter Grenzen beobachtet sind. Ferner wurde es gezeigt, dass es immer möglich ist, Forderung (b) zu befriedigen, wenn (a) befriedigt ist. Darum sind die additiven Eigenschaften des Faraday‐effekts wohl verstanden, wenn es möglich ist sowohl Forderung (a) als Forderung (c) zu befriedigen.

The model previously proposed by Guilhaumou et al. in pediatric patients with solid or hematological malignant disease was externally validated. Simulations have enabled the description of new dosage schedules and creation of a chart to help clinicians adapt vancomycin dosage.

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Ibrutinib is indicated for the treatment of chronic lymphocytic leukemia (CLL). Absolute lymphocyte count (ALC) is a clinical criterion used for the monitoring of CLL. Ibrutinib has several effects on lymphocytes, and has highly variable pharmacokinetics (PK). The objective of this work was to build a PK‐pharmacodynamic (PD) model describing ALC dynamics under ibrutinib treatment in patients with CLL. ALC observations before and after ibrutinib treatment initiation in patients with CLL were included in the analysis. A population PK‐PD model was developed based on physio‐pharmacological knowledge. Individual PK concentrations at each hospital visit were included in the model. The association between PD parameters and lymphocytosis, and between PD parameters and response to treatment were assessed. A total of 94 patients, 658 ALC and 1,501 PK observations were included in model development. The final PK‐PD model accurately described ALC dynamics for different patient profiles. It consisted in two compartments (tissues and blood circulation) with ibrutinib plasmatic concentration inducing two drug effects: stimulation of lymphocyte redistribution and death. Patients with hyperlymphocytosis had significantly higher tissues to circulation baseline lymphocyte count ratio, and lower death effect. Patients who progressed under ibrutinib had significantly lower baseline lymphocyte counts in tissues (2‐fold lower) and blood (3‐fold lower). The first PK‐PD model for ALC in patients with CLL under ibrutinib treatment was developed. This model suggests that estimated lymphocyte counts in tissues and blood could be used as an early predictor of response in patients with CLL.