Determination of plasma unbound fraction of voriconazole in patients treated with a prophylactic or a curative treatment.

BACKGROUND: Voriconazole (VOR) is a triazole antifungal used in the curative treatment of invasive fungal infections and the prophylactic treatment of opportunistic fungal infections in immunocompromised patients. It is a drug for which therapeutic drug monitoring (TDM) is highly recommended. METHODS: To determine the best TDM marker, the pharmacologically active form of the drug, represented by the plasma unbound concentration (Cu) and fraction (fu), has been studied using a method based on ultrafiltration and ultra performance liquid chromatography. As albumin (Alb) is a likely factor inducing fluctuations in fu, the correlation between Alb levels and fu was carried out. Similarly, correlations between trough plasma concentrations [total concentration (Ct) and Cu] and both efficacy and safety markers were determined. Efficacy evaluation was based on monitoring fungal antigens and cultures, whereas safety was monitored by measuring bilirubin levels. RESULTS: In vitro, using blank human plasma, the mean fu was determined at 32.3% ± 5.5%, whereas in patients' plasmas treated with VOR, the median (5th-95th percentiles) of the unbound VOR fraction was 22.95% (14.95%-38.42%). A high correlation was found (rho = 0.956, P < 0.001) between Ct and Cu, though there was no correlation between serum Alb levels and fu, except for some patients with severe hypoalbuminemia (<25 g/L). CONCLUSIONS: Based on the efficacy/safety correlations, a therapeutic window has been defined ranging from 4.5 to 6.5 mg/L and 1.5 and 2.0 mg/L for trough Ct and Cu, respectively. For the first time, the relevance of new pharmacokinetic parameters, such as Cu and fu, has been explored and discussed, and our results support the current TDM protocol for VOR.

Ibuprofen concentrations in human mature milk--first data about pharmacokinetics study in breast milk with AOR-10127 "Antalait" study.

BACKGROUND: Analgesics are one of the most prescribed drugs during the postpartum period to prevent and treat pain and inflammatory disease. The focus on analgesics during breastfeeding has increased because of lack of information and fatal codeine intoxication in a breastfed neonate. Ibuprofen has an advantageous benefit-risk ratio profile compared with codeine. There is a lack of information on drug transfer into human milk, thus ibuprofen intake during breastfeeding may be debated. Consequently, there is a dilemma whether to terminate breastfeeding or drug therapy. The objective of this study was to determine the relative infant dose of ibuprofen. METHODS: The first week after the delivery, each woman received ibuprofen to treat pain or inflammatory disorders (mean dose, 1012 ± 96 mg/d). Just after the third dose of ibuprofen, 1 milk sample and 2 blood samples were obtained after 1 week of breastfeeding. Ibuprofen concentrations in breast milk and blood were measured by using high-performance liquid chromatography. RESULTS: Twenty women were included after written informed consent, and 13 gave their breast milk and blood samples. The mean ibuprofen milk concentration was 360 ± 160 mcg/L. The mean fat milk concentration was 3.23 ± 1.15 g per 100 mL, and the mean milk protein concentration 0.87 ± 0.27 g per 100 mL. The ibuprofen transfer infant dose (theoretical infant dose) was 68 mcg·kg-1·d-1 (8-262 mcg·kg-1·d-1), and the relative infant dose was <0.38% (0.04%-1.53%) of the weight-adjusted maternal daily dose, which equals 0.2% of the infant dose. CONCLUSIONS: The results confirm that the transfer of ibuprofen into breast milk decreases with the protein concentration and the duration of lactation. These results suggest that the use of ibuprofen is compatible with prolonged breastfeeding after the early postpartum stage.