Evaluation of Pharmacokinetics and Pharmacodynamics of Deferasirox in Pediatric Patients.

BACKGROUND: Deferasirox (DFX) is commonly used to reduce the chronic iron overload (IO) in pediatric patients. However, the drug is characterized by a large pharmacokinetic variability and approximately 10% of patients may discontinue the treatment due to toxicities. Therefore, the present retrospective study investigated possible correlations between DFX pharmacokinetics and drug-associated toxicities in 39 children (26 males), aged 2-17 years, who underwent an allogeneic hematopoietic stem cell transplantation. METHODS: IO was diagnosed by an abdominal magnetic resonance imaging and DFX was started at a median dose of 500 mg/day. DFX plasma concentrations were measured by a high performance liquid chromatographic method with UV detection and they were analysed by nonlinear mixed-effects modeling. RESULTS: The pharmacometric analysis demonstrated that DFX pharmacokinetics were significantly influenced by lean body mass (bioavailability and absorption constant), body weight (volume of distribution), alanine and aspartate transaminases, direct bilirubin, and serum creatinine (clearance). Predicted DFX minimum plasma concentrations (Ctrough) accounted for 32.4 ± 23.2 mg/L (mean ± SD), and they were significantly correlated with hepatic/renal and hematological toxicities (p-value < 0.0001, T-test and Fisher's exact tests) when Ctrough threshold values of 7.0 and 11.5 mg/L were chosen, respectively. CONCLUSIONS: The population pharmacokinetic model described the interindividual variability and identified Ctrough threshold values that were predictive of hepatic/renal and hematological toxicities associated with DFX.

Alignment of Qx100/Qx200 Droplet Digital (Bio-Rad) and QuantStudio 3D (Thermofisher) Digital PCR for Quantification of BCR-ABL1 in Ph+ Chronic Myeloid Leukemia.

In recent years, the digital polymerase chain reaction has received increasing interest as it has emerged as a tool to provide more sensitive and accurate detection of minimal residual disease. In order to start the process of data alignment, we assessed the consistency of the BCR-ABL1 quantification results of the analysis of 16 RNA samples at different levels of disease. The results were obtained by two different laboratories that relied on The Qx100/Qx200 Droplet Digital PCR System (Bio-Rad) and Quant Studio 3D dPCR System (Thermofisher) platforms. We assessed the compatibility between the estimated values by linear regression, Bland-Altman bias-plot, and Mann-Whitney nonparametric test. The results confirmed the compatibility of the measures, allowing us tocompute an 'alignment factor' (AF), equal to 1.41, which was further validated by a different series of experiments. We conclude that the performed measurements by the two laboratories are comparable, and also equalized through the introduction of an alignment factor.

Daptomycin Plasma and CSF Levels in Patients with Healthcare-Associated Meningitis.

BACKGROUND: There are currently few data concerning the cerebrospinal fluid (CSF) penetration of daptomycin in patients with healthcare-associated meningitis. This study aims (1) to better characterize the pharmacokinetics of daptomycin in humans during a 7-day intravenous (IV) therapy course, and (2) to study the penetration of daptomycin in the CSF after IV infusion at the dose of 10 mg/kg. RESULTS: In this prospective observational study, we enrolled nine patients with an implanted external ventricular drainage and a diagnosis of a healthcare-associated meningitis. Daptomycin was administered at 10 mg/kg for a maximum of 7 days. The pharmacokinetic of daptomycin was studied using a two-compartment population/pharmacokinetic (POP/PK) model and by means of a nonlinear mixed effects modeling approach. A large inter-individual variability in plasma area under the curve (Range: 574.7-1366.3 h mg/L), paralleled by high-peak plasma concentration (Cmax) (all values > 60 mg/L), was noted. The inter-individual variability of CSF-AUC although significant (range: 1.17-6.81 h mg/L) was narrower than previously reported and with a late occurrence of CSF-Cmax (range: 6.04-9.54 h). The terminal half-life between plasma and CSF was similar. tmax values in CSF did not show a high inter-individual variability, and the fluctuations of predicted CSF concentrations were minimal. The mean value for daptomycin penetration obtained from our model was 0.45%. CONCLUSIONS: Our POP/PK model was able to describe the pharmacokinetics of daptomycin in both plasma and CSF, showing that daptomycin (up to 7 days at 10 mg/kg) has minimal penetration into central nervous system. Furthermore, the observed variability of AUC, tmax and predicted concentration in CSF was lower than what previously reported in the literature. Based on the present findings, it is unlikely that daptomycin could reach CSF concentrations high enough to have clinical efficacy; this should be tested in future studies.

Association of the hOCT1/ABCB1 genotype with efficacy and tolerability of imatinib in patients affected by chronic myeloid leukemia.

PURPOSE: The present study was aimed at investigating whether imatinib pharmacogenetics is related to its pharmacodynamics in patients affected by chronic myeloid leukemia. METHODS: Through a procedure based on a sequence of classical statistics methods, we investigated the possible relationships between treatment efficacy/tolerability and combinations of time-independent variables as gender and genetic covariates in the form of single nucleotide polymorphisms (SNPs) or combinations thereof. Moreover, since the drug tolerability has a strong incidence on the discontinuation of the therapy, we investigated whether the time of manifestation of the most frequent toxic effects can be related to time-independent patients' characteristics or not. RESULTS: We found that a combination of two polymorphisms, namely hOCT1 c.480C>G (rs683369) and ABCB1 c.3435C>T (rs1045642), seems to play the role of predictor for imatinib in both efficacy and toxicity. Furthermore, the time of manifestation of edema toxicity is found to be associated to a combination of gender and ABCB1 c.3435C>T, whereas the time of manifestation of cramp toxicity appears related to gender. CONCLUSIONS: The novelty of this study is dual: the achievement of results that potentially have a significant clinical interest and the demonstration that the adoption of composed covariates may represent a unique tool to study different aspects of the treatment with imatinib.