Axitinib pharmacologic therapeutic monitoring reveals severe under-exposure despite titration in patients with metastatic renal cell carcinoma.

Introduction New therapeutic strategies combining axitinib and immune checkpoint blockers are ongoing in metastatic renal cell carcinoma (mRCC). These strategies do not consider the pharmacokinetic variability of axitinib. We aimed to describe the risk of axitinib under-exposure using routine pharmacologic therapeutic monitoring (PTM). Methods We analyzed axitinib dosage in nine patients with mRCC. Routine axitinib concentration measurements were centralized at Henri Mondor University Hospital (Créteil, France) using a validated method. The primary objective was to describe the evolution of Cmax dosages (1 to 6 h after oral intake) during routine axitinib titration. Results Nine patients with available Cmax axitinib dosages were included. Four out of the nine patients had axitinib titration and Cmax dosages were performed before and after titration. All but one corrected their plasma axitinib exposure after titration, suggesting of a titration success. The last patient was monitored in the Henri Mondor Hospital routine PTM program and a pharmacokinetic profiling was performed after controlled oral intake. Results suggested a poor axitinib absorption. This patient experienced early tumor progression as best response. Conclusion We report a patient with significant axitinib under-exposure, possibly due to a poor absorption. PTM should be evaluated and considered in drug developments evaluating combination therapies based on axitinib.

[Myxomatous mitral valve degeneration: biochemical aspects and physiopathological considerations]. / L'insuffisance mitrale par dégénerescence myxoïde: aspect biochimique et considérations physiopathologiques.

Mitral valve is a complex structure which is submitted to repeated mechanical constraints. In clinical practice, an increasing incidence of mitral insufficiency resulting from myxomatous degeneration is observed. Since myxomatous degeneration is also observed in defined genetic diseases of connective tissues, we propose the hypothesis that idiopathic mitral insufficiency might result from a minor alteration of the interstitial valvular cells and/or their interactions with their support. After a brief review of the role of the extracellular matrix in the heart, some histopathological and biochemical aspects of myxomatous degeneration are presented. Our data and those of the literature will be summarized and a physiopathological hypothesis proposed for myxomatous mitral valve degeneration.

Evaluation of the new heterogeneous ACMIA immunoassay for the determination of whole-blood cyclosporine concentrations in bone marrow, kidney, heart, and liver transplant recipients.

Cyclosporine (CyA) has a narrow therapeutic index. Determination of CyA concentrations correlate with rejection or adverse effects like nephropathy. Cyclosporine is assayed based on either chromatographic or many different immunoenzymologic techniques. The investigators evaluated a new heterogeneous immunoassay of CyA on RxL Dimension. The pretreatment step is automatically performed in the apparatus. Linearity, intra- and interday precision, limit of quantification, dilutions, and stability of the equipment were compared with the EMIT method for patient determinations. The heterogeneous immunoassay showed a good linearity between 0 and 500 ng/mL, and intra- and inter-day precision with a coefficient of variation below 9.2%. The investigators observed reproducible and accurate dilutions of high concentrations (500 to 2000 ng/mL). The correlation with the EMIT technique was valid: ACMIA = 0.964 EMIT + 0.156 (r = .96) for different types of transplant (n = 116). Finally, this new system improves the determination of CyA concentrations.

Sputum itraconazole concentrations in cystic fibrosis patients.

Itraconazole diffusion in sputum was studied in 11 cystic fibrosis patients with allergic bronchopulmonary aspergillosis. There was a high interindividual variability in sputum itraconazole concentration and sputum/serum drug concentration ratio. Three children had sputum drug concentrations before oral administration that were lower than the itraconazole MIC at which 90% of Aspergillus fumigatus strains were inhibited, although their serum drug concentrations were within the therapeutic range.

[Antibiotic therapy in cystic fibrosis. I. Pharmacologic specifics of antibiotics]. / L'antibiothérapie dans la mucoviscidose. I. Particularités pharmacologiques des antibiotiques.

Antibiotherapy is one of the main treatment in cystic fibrosis. Antibiotic administration schedules are different from normal patients because of pharmacokinetic and pharmacodynamic particularities. In moderate disease, the digestive resorption of antibiotics is delayed and their half-life is reduced due to an increase in total clearance. In severe disease, the volume of distribution of antibiotics is increased due to the higher proportion of lean mass in these malnourished patients. Other particularities limit the action of antibiotics such as thick sputum, which limits drug penetration; the property of Pseudomonas aeruginosa to be surrounded by a biofilm; alteration of local antibacterial defense; and inhibition of antibiotics by local factors. Systematic prescription of a biotherapy beta-lactam-aminoglycoside and obtaining high antibiotic concentration in situ might limit this antagonism. In spite of particular therapeutic schedules such as single daily dose for aminoglycoside and continuous infusion for beta-lactams, the intervals between administrations must be narrowed for time-dependent antibiotics, and the total daily dose increased by 20 to 30% for concentration-dependent antibiotics.

Perioperative pharmacokinetics of piperacillin during liver transplantation.

There have been few evaluations of the perioperative pharmacokinetics of antibiotics. Piperacillin (PPR) is a widely prescribed ureidopenicillin of established efficacy against enterobacteria and P. aeruginosa. The serum pharmacokinetics and perioperative safety of PPR were evaluated in 8 patients hospitalized for an orthotopic liver transplantation. The subjects were given a 60 mg/kg infusion of PPR once every 8 hours. PPR was assayed by HPLC and data were analyzed by a noncompartmental method. There were no adverse events during surgery. It seems that kinetics of PPR showed no variation during the anhepatic period. However, transplants notably modified the kinetics of PPR in comparison with data previously published in healthy volunteers. Trends were as follows: flattening of Cmax and prolongation of T1/2 (2.2 h vs 0.92 h). This phenomenon seems to be due to a marked increase in V(area) (44.0 1 vs 16.2 1) while C1 were similar. The increase in V(area) is probably the combined results of multiple factors including blood loss, vascular filling, combined prescription of vasoactive drugs, and, obviously, the surgical procedure itself. Concentrations of PPR were after 4 hours below (i.e. 5/8 patients) the MIC of P. aeruginosa (i.e. < or = 16 micrograms/ml). From 6 hours onwards antibacterial cover was insufficient against the majority of enterobacteria (i.e. < or = 8 micrograms/ml). This inadequate protection included the critical anhepatic period. Measured concentrations achieved by the initial dosage regimen were compared to those obtained by simulation using modified dosing pattern in order to ensure circulating levels constantly of 16 micrograms/ml or more. This leads to a suggested modified dosage pattern in which PPR would be given as 1 dose of 60 mg/kg every 4 hours. Under these conditions the expected concentrations should be constantly over 16 micrograms/ml and any risk of systemic accumulation is excluded.

Study of the bioequivalence of two controlled-release formulations of morphine.

The management and treatment of chronic pain in cancer patients is a clear priority for practitioners regularly confronted by the situation. This investigation was carried out to evaluate the bioavailability of a recent sustained-release (SR) formulation of morphine sulphate (30 mg), Skenan, consisted of capsules, relative to a recognized product, Moscontin which is a matrix tablet SR form. The bioavailability was carried out on 12 healthy male volunteers who received a single dose (30 mg) of the test (T) and the recognized (R) products in a randomized balanced 2-way crossover design. After dosing, serial blood samples were collected for a period of 24 hours. Morphine and its main metabolites (i.e. glucuronides M6G and M3G) were assayed by high-performance liquid chromatography using a ion-pair formation. Data were analyzed by a noncompartmental method and were compared by ANOVA method and, each subject taken as his own control, by the Wilcoxon T test. Mean bioavailability of the T formulation was greater than that of R. The parametric confidence intervals (90%) of the mean values of the pharmacokinetics characteristics for T:R ratio were in each case without the bioequivalence acceptable ranges of 0.8-1.25 and 0.70-1.43 respectively for AUCs (i.e. AUCo-->24h and AUCo-->infinity) and Cmax, while confidence intervals symmetric of Westlake (CIW90%) was invariably greater than 20%, i.e. 62.8, 71.1 and 39.3% respectively. Further, the test formulation was not found bioequivalent to the reference formulation by Schuirmann's 2 one-sided t-test. These results justify the conclusion of the non-bioequivalence of the two forms at the unit dose of 30 mg. This information must be considered above all as a dosage adjustment tool enabling use of the two forms by application of a correction factor of the order of 15% when prescribing Skenan in comparison with Moscontin. Assessment is needed of the possible clinical consequences of this finding.

[Post-traumatic intramural hematoma of the duodenum]. / Hématome intra-mural du duodénum post-traumatique.

A post-traumatic intramural hematoma of duodenum in a 9 year old child was detected during exploratory laparotomy but left undisturbed. Postoperative follow up during parenteral feeding included surveillance by repeated gastrografin follow through examinations, normal transit being restored by the 12th day. Intramural hematoma of duodenum is usually due to injury and often affects male children. Symptomatology is that of upper digestive occlusion. The principal investigation should be gastro-duodenal follow through examinations with gastrografin, because of the risk of an associated perforation, to reveal possible partial or total duodenal obstruction. Conservative treatment is possible, but in case of failure or in adults surgery is indicated with evacuation of the hematoma and in some cases a gastro-jejunostomy.