Reply: Response to: Cumulative Exposure to Infliximab, But Not Trough Concentrations, Correlate With Rate of Infection

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Increased inhibition of cytochrome P450 3A4 with the tablet formulation of posaconazole

International audienceBeing a substrate of the cytochrome P450 3A4 (CYP3A4) isoenzyme, sirolimus metabolism is decreased when posaconazole is administered concomitantly. However, because of the poor bioavailability of the oral suspension of posaconazole with which low plasma concentrations are obtained, CYP3A4 inhibition is weak and a 50–75% dose reduction of sirolimus is sufficient to avoid sirolimus overdosage. The new tablet formulation allows reaching posaconazole concentrations 3–4 fold higher than those obtained with the oral suspension. Based on a case of sirolimus overdosage following posaconazole tablets administration, we modelled the inhibition of sirolimus clearance by posaconazole, and then simulated several dosage regimens of sirolimus taken together with posaconazole tablets. We were able to describe well the interaction, and found a value of IC50 of posaconazole towards sirolimus clearance of 0.68 μg/mL. The simulations showed that even a 80% decrease of the daily dose of sirolimus is unsuitable in many cases with trough concentrations of posaconazole of 2 μg/mL. A decrease of 40% of the dose with spacing administrations of 3 days may be considered. The clinicians and pharmacologists must be warned that the use of posaconazole tablets may result in an inhibition of CYP3A4 of greater magnitude than with the oral suspension

Sirolimus severe overdosage following co-treatment with the new tablet formulation of posaconazole (Noxafil (R)): a case report

International audienceMeeting Abstract: PM1-007, 20e congrès de la Société Française de Pharmacologie et de Thérapeutique, Nancy, 19-21 avril 201

Liposomal amphotericin B pharmacokinetics in a patient treated with extracorporeal membrane oxygenation

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Tacrolimus: Does direct glucuronidation matter? An analytical and pharmacological perspective

International audienceTacrolimus, the gold standard of immunosuppressive treatment indicated to prevent graft rejection in solid organ recipients, is extensively metabolized. While impact of phase I metabolism on the drug pharmacokinetics has been widely discussed, little is known on its glucuronidation mediated by uridine diphosphate glucuronyltransferases (UGT). The impact of glucuronidation in the field of therapeutic drug monitoring might be underestimated mainly because glucuronide metabolite is presumed to be a non-active and short half-life drug.As part of an on-going pharmacokinetic study conducted in our center (CYPTAC’H, NCT01388387) we performed extensive kinetic profiles of tacrolimus whole-blood concentrations in liver transplant recipient patients

Population pharmacokinetics and exposure–response relationship of trastuzumab and bevacizumab in early-stage breast cancer

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Pharmacokinetic and pharmacodynamic profile of beta-lactam antibiotics in patients treated for infective endocarditis a five-year retrospective study

International audienc

Vancomycin collection in heparin plasma tube: is there an influence of heparin on vancomycin concentration?

International audienceMeeting Abstract: PM1-039, 20e congrès de la Société Française de Pharmacologie et de Thérapeutique, Nancy, 19-21 avril 201

Safety study and therapeutic drug monitoring of the oral tablet formulation of posaconazole in patients with haematological malignancies

International audiencePurposePosaconazole is a triazole antifungal widely used for prophylaxis of invasive fungal disease (IFI). Posaconazole tablets allow reaching higher plasma levels than the oral suspension, but safety data with this formulation in real life are scarce. This study aimed at evaluating the safety profile, the pharmacokinetic variability, and the concentration–toxicity relationship of posaconazole tablets in patients with haematological malignancies.MethodsSixty neutropenic patients treated with posaconazole tablets for prophylaxis of IFI were prospectively included in the study. Adverse drug reactions (ADR) were recorded and analyzed by the Regional Pharmacovigilance Centre to assess posaconazole implication. Blood samples were drawn once a week and plasma trough concentrations (C min) were assayed by LC–MS/MS. The rates of ADR by quartile of C min were compared.ResultsEighteen patients (30%) experienced at least one ADR attributed to posaconazole. Liver function test (LFT) abnormalities were encountered in 20% of patients and resulted in four (6.7%) treatment discontinuations. Posaconazole median (range) C min was 1.36 ( 2 µg/mL. Rates of ADR by quartile of C min were not different.ConclusionsPosaconazole was well tolerated; however, LFT abnormalities were frequent. ADR occurrence was not linked to posaconazole exposure. Because posaconazole concentrations were highly variable, TDM can be helpful to avoid underexposure to the drug and increase its efficacy in preventing IFI. Conversely, a large proportion of patients was overexposed and might have benefited of a dose reduction

A high performance liquid chromatography tandem mass spectrometry for the quantification of tacrolimus in human bile in liver transplant recipients

International audienceTacrolimus whole-blood concentrations imperfectly reflect concentrations at the effect site. Tacrolimus concentrations in the transplanted organ could be more relevant to predict rejection events. Because liver biopsy cannot be repeatedly performed after liver transplantation, we suggested measuring tacrolimus in the bile to have a cost-effective and clinically implementable surrogate marker of intra-hepatic tacrolimus concentration. We developed and fully validated a liquid chromatography–tandem mass spectrometry method for the determination of tacrolimus in human bile. Sample purification was achieved using protein precipitation and liquid–liquid extraction with ethyl-acetate. Gradient elution was performed using a C18 analytical column with a 5 min run-time. The method was linear from 0.5 ng/mL to 20 ng/mL. In this concentration range, within-day and between-day precisions as well as overall bias were within ±15%. Matrix effect was fully corrected by the internal standard (ascomycin). The assay was optimized to achieve good selectivity in this complex biological matrix. Tacrolimus was found to be stable in bile stored 6 months at −80 °C, after 3 freeze and thaw cycles, 20 h at room temperature and 24 h in extracts kept at 15 °C in the auto-sampler. The method was applied to quantify tacrolimus in bile from liver transplant recipients. It allowed getting preliminary data about tacrolimus excretion profile in bile and showed the lack of correlation between tacrolimus whole blood concentration and tacrolimus liver exposition. This alternative and innovative analytical approach of tacrolimus bio-analysis appears suitable for further studies evaluating relevance of biliary tacrolimus concentration as a new pharmacological marker of immunosuppressive activity. © 2016 Elsevier B.V