Intracellular and Plasma Trough Concentration and Pharmacogenetics of Telaprevir

Triple therapy for HCV-1 infection consists in boceprevir or telaprevir, ribavirin and PEG-interferon. Telaprevir is a P-glycoprotein substrate and it is metabolized by CYP3A4/5. No data have been published on intracellular penetration of telaprevir. We determined peripheral blood mononuclear cells (PBMCs) and trough plasma S and R telaprevir isomers concentrations; moreover, we evaluated the influence of some single nucleotide polymorphisms (SNPs) on these pharmacokinetic data after 1 month of triple therapy in humans

Evaluation of Posaconazole Pharmacokinetics in Adult Patients with Invasive Fungal Infection

Mortality and morbidity due to invasive fungal infections have increased over the years. Posaconazole is a second-generation triazole agent with an extended spectrum of activity, which shows a high interindividual variability in its plasma levels, rendering dosing in many patients inconsistent or inadequate. Hence, posaconazole therapeutic drug monitoring, which is easily available in clinical practice, may improve treatment success and safety. The aim of the study was to describe posaconazole pharmacokinetics, and to evaluate the utility of therapeutic drug monitoring for therapy and prophylaxis in a cohort of adult patients. A fully validated chromatographic method was used to quantify posaconazole concentration in plasma collected from adult patients at the end of the dosing interval. Associations between variables were tested using the Pearson test. The Mann-Whitney test was used to probe the influence of categorical variables on continuous ones. A high inter-individual variability was shown. Of the 172 enrolled patients, among those receiving the drug by the oral route (N = 170), gender significantly influenced drug exposure: males showed greater posaconazole concentration than females (p = 0.028). This study highlights the importance of therapeutic drug monitoring in those with invasive fungal infections and its significant clinical implications; moreover we propose, for the first time, the possible influence of gender on posaconazole exposure

A Common mdr1 Gene Polymorphism is Associated with Changes in Linezolid Clearance

BACKGROUND: Several factors contribute to the high variability of linezolid plasma exposure in patients. Very recently, it has been suggested that linezolid could be an ABCB1 substrate. Therefore, the present clinical study was aimed at investigating whether ABCB1 polymorphisms could predict linezolid pharmacokinetics in 27 critically ill patients. METHODS: Genotypes were assessed through a real-time polymerase chain reaction allelic discrimination system, and linezolid plasma concentrations, considering trough concentration (Ctrough) and area under the time concentration curve (AUC), were analyzed through a nonlinear mixed-effects modeling approach. RESULTS: A significant effect of abcb1 c.3435C>T polymorphism on linezolid clearance was found, whose values accounted for 13.19L/h in wild-type homozygotes and 7.82 L/h in the remaining individuals. That difference was statistically significant despite the large interindividual variability (60.8%). Terminal half-life and volume of distribution values significantly differed between c.3435CC and c.3435CT/TT patients (2.78 vs. 5.45 h and 37.43 vs. 46.71L, respectively). On the contrary, a modest trend was observed for the difference in AUC and Ctrough based on c.3435C>T genotypes. Simulation according to the final model revealed that the cumulative response fraction for the AUC/MIC parameter was better for .3435CC individuals compared to individuals carrying at least one c.3435T allele with respect to MSSA, MRSA, and S. pneumoniae species. CONCLUSIONS: The obtained results suggest the possible influence of ABCB1 in linezolid pharmacokinetics, bringing new interest for pharmacogenetic analyses in antimicrobial chemotherapy. These analyses could be incorporated in therapeutic protocols for precision medicine, including a combined use of genetic evaluation (for starting dose) and follow-up TDM

Correlation between entecavir penetration in peripheral blood mononuclear cells and HBV DNA decay during treatment of HBeAg-negative chronic hepatitis B

Recently, due to its high effectiveness and tolerability, the treatment of chronic hepatitis B with entecavir became a standard practice. However, limited knowledge is currently available about its pharmacokinetic behavior and intracellular disposition. Recently, our group reported an inverse correlation between entecavir plasma concentrations and the HBV DNA decay at the first and third month of treatment, respectively. \u200b: In this paper we investigated the disposition of entecavir in peripheral blood mononuclear cells (PBMC) and in plasma, in order to evaluate the relationship between intracellular penetration and response, in a cohort of na\uefve patients with HBeAg-negative CHB