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Background Sofosbuvir (SOF) plus daclatasvir (DCV) with or without ribavirin is one of the currently recommended treatment option for chronic hepatitis C. Aims Our objectives were to identify factors associated with SOF/DCV plasma concentrations [C] variations and to evaluate their impact on viral kinetics. Methods 130 consecutive HCV patients initiating SOF/DCV therapy with or without ribavirin were enrolled. Clinical, biological, virological and pharmacological data were collected at baseline, at week 4, 8, 12, and 24 of therapy and 12 weeks after the end of therapy. Results Mean age was 57 years, 68% of patients were males, 69% were infected by HCV genotype 1 and cirrhosis was observed in 76% of patients. Multivariate analysis showed that higher SOF [C] and DCV [C] during treatment were associated with eGFR impairment and absence of cirrhosis. We found a significant correlation between the magnitude of HCV viral load decrease from day 0 to week 4 and a higher SOF [C] at week 4 ( p = 0.032) and a higher DCV [C] at week 8 ( p = 0.013). Conclusions Pharmacological monitoring showed significant associations between elevated SOF or DCV [C] and absence of cirrhosis, decreased eGFR and viral load decrease during the first month of treatment. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Chronic hepatitis C virus (HCV) infection is the most common chronic liver disease in patients with end stage renal disease (ESRD) and is well known as a frequent cause of mortality and graft loss among haemodialysed and kidney transplant patients. Up to now, there are no data on antiviral efficacy and tolerability of available protease inhibitors (telaprevir and boceprevir) in HCV infected haemodialysed patients. Methods: We report 4 cases of HCV infected haemodialysed patients, who have not responded to a prior course of pegylated interferon (Peg-IFN) and ribavirin (RBV) and who were listed for kidney transplantation (KTx). These 4 patients received a second-line antiviral treatment with Peg-IFN, RBV and telaprevir. Results: After 12 weeks of triple therapy, tolerability was acceptable and HCV-RNA became undetectable in 3/4 patients. Mild side-effects included anaemia leading to increasing the doses of erythropoietin (EPO). Dose of RBV ranged from 200mg three times a week to 200mg/day. Conclusion: Triple therapy with a first generation protease inhibitor could be the new standard for the treatment of HCV patients with ESRD. This needs to be confirmed by larger series. [Copyright &y& Elsevier]

Abstract: Background: Minucci et al. have proposed in 2010 a rapid, simple and cost-effective HRM method on the LightCycler 480® apparatus (Roche) for the determination of the 6/6, 6/7 and 7/7 genotypes of the (TA)n UGT1A1 promoter polymorphism. However, they have not studied the n=5 and n=8 alleles which can be quite frequent in sickle-cell disease patients. Methods: The aim of our study was to test this HRM protocol to all the 10 possible (TA)n UGT1A1 genotypes (i.e. 5/5, 5/6, 5/7, 5/8, 6/6, 6/7, 6/8, 7/7, 7/8 and 8/8) by using our SCD cohort of patients. Results: All genotypes could be unambiguously identified except 6/7 and 6/8 which give a similar HRM profile. For those two genotypes, the differentiation necessitates either a direct Sanger sequencing or a second PCR protocol followed by a 3% agarose gel migration. Conclusions: For the (TA)n UGT1A1 promoter genotyping of African patients, each lab has to wonder what is the best way between (i) direct Sanger sequencing of all patients and (ii) HRM protocol for all patients followed by a complementary analysis to differentiate the 6/7 and 6/8 genotypes. [Copyright &y& Elsevier]

In the context of the COVID-19 pandemic, several drugs have been repurposed as potential candidates for the treatment of COVID-19 infection. While preliminary choices were essentially based on in vitro potency, clinical translation into effective therapies may be challenging due to unfavorable in vivo pharmacokinetic properties at the doses chosen for this new indication of COVID-19 infection. However, available pharmacokinetic and pharmacokinetic-pharmacodynamic studies suffer from severe limitations leading to unreliable conclusions, especially in term of dosing optimization. In this paper we propose to highlight these limitations and to identify some of the major requirements that need to be addressed in designing PK and PK-PD studies in this era of COVID. A special attention should be paid to pre-analytical and analytical requirements and to the proper collection of covariates affecting dose-exposure relationships (co-medications, use of specific organ support techniques and other clinical and para-clinical data). We also promote the development of population PK and PK-PD models specifically dedicated to COVID-19 patients since those previously developed for other diseases (SEL, malaria, HIV) and clinical situations (steady-state, non-ICU patients) are not representative of severe patients. Therefore, implementation of well-designed PK and PD studies targeted to COVID-19 patients is urgently needed. For that purpose we call for multi-institutional collaborative work and involvement of clinical pharmacologists in multidisciplinary research consortia. • Available pharmacokinetic and pharmacodynamic studies on COVID-19 repurposed drugs suffer from severe limitations. • This may lead to unreliable conclusions, especially in term of dosing optimization. • We propose to identify the major requirements that need to be addressed in designing PK and PD studies in this era of COVID. [ABSTRACT FROM AUTHOR]