RESUMO
PURPOSE: Posaconazole 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. METHODS: Sixty 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. RESULTS: Eighteen 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 (< 0.1-3.44) µg/mL (inter-patient CV = 43.9%). During follow-up, 28.6% of patients had at least one concentration < 0.7 µg/mL, and 35.7% had at least one concentration > 2 µg/mL. Rates of ADR by quartile of C min were not different. CONCLUSIONS: Posaconazole 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.
Assuntos
Triazóis/administração & dosagem , Triazóis/efeitos adversos , Administração Oral , Adulto , Idoso , Antifúngicos/administração & dosagem , Antifúngicos/efeitos adversos , Antifúngicos/farmacocinética , Monitoramento de Medicamentos/métodos , Feminino , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Comprimidos , Triazóis/sangue , Triazóis/farmacocinética , Adulto JovemRESUMO
Posaconazole is extensively used for prophylaxis for invasive fungal infections. The gastro-resistant tablet formulation has allowed the bioavailability issues encountered with the oral suspension to be overcome. However, overexposure is now frequent. This study aimed to (i) describe the pharmacokinetics of posaconazole tablets in a real-life cohort of patients with hematological malignancies and (ii) perform Monte Carlo simulations to assess the possibility that the daily dose can be reduced while keeping a sufficient exposure. Forty-nine consecutive inpatients were prospectively included in the study. Posaconazole trough concentrations (TC) were measured once a week, and biological and demographic data were collected. The concentrations were analyzed by compartmental modeling, and Monte Carlo simulations were performed using estimated parameters to assess the rate of attainment of the target TC after dose reduction. The pharmacokinetics of posaconazole were well described using a one-compartment model with first-order absorption and elimination. The values of the parameters (interindividual variabilities) were as follows: the absorption constant (ka ) was 0.588 h-1 (fixed), the volume of distribution (V/F) was 420 liters (28.2%), and clearance (CL/F) was 7.3 liters/h (24.2%) with 31.9% interoccasion variability. Forty-nine percent of the simulated patients had TC at steady state of ≥1.5 µg/ml and maintained a TC above 1 µg/ml after a reduction of the dose to 200 mg daily. A third of these patients eligible for a dose reduction had TC of ≥1.5 µg/ml as soon as 48 h of treatment. Though posaconazole tablets were less impacted by bioavailability issues than the oral suspension, the pharmacokinetics of posaconazole tablets remain highly variable. Simulations showed that approximately half of the patients would benefit from a reduction of the dose from 300 mg to 200 mg while keeping the TC above the minimal recommended target of 0.7 µg/ml, resulting in a 33% savings in the cost of this very expensive drug.
Assuntos
Antifúngicos/administração & dosagem , Antifúngicos/farmacocinética , Infecções Fúngicas Invasivas/prevenção & controle , Triazóis/administração & dosagem , Triazóis/farmacocinética , Administração Oral , Adulto , Idoso , Feminino , Neoplasias Hematológicas/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Método de Monte Carlo , Estudos Prospectivos , Comprimidos/administração & dosagemRESUMO
Being 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.
Assuntos
Antifúngicos/uso terapêutico , Citocromo P-450 CYP3A/metabolismo , Comprimidos/uso terapêutico , Triazóis/uso terapêutico , Administração Oral , Adulto , Disponibilidade Biológica , Química Farmacêutica/métodos , Citocromo P-450 CYP3A/farmacocinética , Humanos , Suspensões/farmacocinética , Suspensões/uso terapêutico , Comprimidos/farmacocinética , Triazóis/farmacocinética , Adulto JovemRESUMO
Telaprevir is a novel NS3A/4A protease inhibitor approved in combination with ribavirin and peg-interferon alfa for the treatment of genotype-1 chronic hepatitis C. This drug is also known to be a potent cytochrome P450 3A and drug efflux protein ATP-binding cassette B1 (also called P-glycoprotein) inhibitor, and could therefore interact with immunosuppressive drugs. For this reason, a decrease in cyclosporine (CsA) dosage has been proposed when combining this drug with telaprevir. We report herein the case of an unpredictable lack of interaction between CsA and telaprevir in a liver transplant recipient. The decrease in CsA dosage, conducted as recommended in the literature, did not result in stable CsA concentrations but decreased them. However, the decrease in CsA exposure could have been unseen without the measurement of CsA concentrations 2 h after the administration (C2 ) of the drug, because it mainly resulted from the decrease in CsA peak. The mechanism leading to this lack of drug interaction in this patient has not been fully elucidated yet, but is likely to affect the absorption phase. Therapeutic drug monitoring using only CsA trough concentrations could be falsely reassuring, and the addition of the measurement of the C2 may add useful information to adapt CsA dosage in patients co-treated with telaprevir.
Assuntos
Ciclosporina/farmacocinética , Hepatite C Crônica/tratamento farmacológico , Imunossupressores/farmacocinética , Transplante de Fígado/efeitos adversos , Oligopeptídeos/farmacocinética , Inibidores de Serina Proteinase/farmacocinética , Interações Medicamentosas , Monitoramento de Medicamentos , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/cirurgia , Humanos , Interferon-alfa/uso terapêutico , Masculino , Pessoa de Meia-Idade , TransplantadosRESUMO
A large inter-individual variability in methadone pharmacokinetics is observed in patients under maintenance treatment for major addiction to opiates. Therefore an individual dose titration of methadone is necessary, based on clinical response, i.e. symptoms of overdosage or withdrawal syndrome, but these symptoms are unspecific. However, a poor response to methadone treatment (asking for drug compliance) or the possibility of drug interactions may require the determination of methadone blood concentrations. Therapeutic drug monitoring (TDM) of those patients is performed using methadone trough blood concentrations measured by chromatography (GC or HPLC: reference methods) or by immunoassay, which gives more rapid results. A review of the literature led us to use the fluorescence polarisation immunoassay (FPIA technique) performed on a TDx-FLx analyzer. We confirmed the lack of "matrix effect" and FPIA was compared to GC-MS (gas chromatography-mass spectrometry) on patients samples. According to the literature, a methadone trough serum concentration target of 400 ng/mL is recommended; results under 100 ng/mL are considered as clinically ineffective, whereas methadone concentrations above 1000 ng/mL are frequently associated with drug toxicity. The linearity domain of the technique stays between 50 and 500 ng/mL, which is satisfactory. We describe some clinical cases from the Methadone Treatment Center of Tours (Centre Port-Bretagne), which showed that methadone blood concentration measurement may be helpful to achieve the optimal dose of methadone in each patient.