RESUMO
BACKGROUND: Posaconazole delayed-release tablets offer better bioavailability than the liquid suspension, but no post-marketing data are available in immunocompetent hosts such as those with chronic pulmonary aspergillosis (CPA). OBJECTIVES: To explore the pharmacokinetics and adverse event (AE) profile of posaconazole tablets in patients with CPA. METHODS: Patients started on posaconazole tablets at the National Aspergillosis Centre (NAC), Manchester, UK between February 2014 and October 2015 were identified from the NAC database and analysed retrospectively. The medical records were reviewed for factors that could affect posaconazole serum levels and the development of AEs. RESULTS: Seventy-two patients were included; 50 (69%) were male and the mean age was 48.5â±â12 years. Therapeutic levels (≥1 mg/L) were achieved in 90% of cases on 200 mg versus 90% of cases on 300 mg daily (Pâ=ânot significant). Based on multivariate analysis, female sex (Pâ=â0.041), a 100 mg daily dose (Pâ<â0.001), asthma (Pâ=â0.01) and bronchiectasis (Pâ=â0.001) were associated with subtherapeutic levels. Forty-nine (68%) patients developed AEs, mainly fatigue (37%), dyspnoea (18%) and nausea (12%). AEs were present on 115/196 (59%) occasions on 300 mg/day and on 45/115 (39%) occasions on 200 mg/day (Pâ<â0.01). The mean level was 1.81â±â0.96 mg/L for patients reporting no AEs and 1.90â±â1.11 mg/L for those reporting AEs (Pâ=ânot significant). Factors associated with AEs of grade ≥2 were a daily dose of 300 versus 200 mg (Pâ=â0.001) and asthma (Pâ=â0.008). CONCLUSIONS: A lower-than-recommended posaconazole tablet dose achieved therapeutic levels in most patients and was better tolerated. Males were more likely to achieve a therapeutic level. Underlying conditions affected the degree and frequency of AEs.
Assuntos
Antifúngicos/administração & dosagem , Antifúngicos/farmacocinética , Aspergilose Pulmonar/tratamento farmacológico , Aspergilose Pulmonar/microbiologia , Triazóis/administração & dosagem , Triazóis/farmacocinética , Administração Oral , Adulto , Idoso , Doença Crônica , Preparações de Ação Retardada , Monitoramento de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Comprimidos , Resultado do TratamentoRESUMO
The burden of human disease related to medically important fungal pathogens is substantial. An improved understanding of antifungal pharmacology and antifungal pharmacokinetics-pharmacodynamics has resulted in therapeutic drug monitoring (TDM) becoming a valuable adjunct to the routine administration of some antifungal agents. TDM may increase the probability of a successful outcome, prevent drug-related toxicity and potentially prevent the emergence of antifungal drug resistance. Much of the evidence that supports TDM is circumstantial. This document reviews the available literature and provides a series of recommendations for TDM of antifungal agents.