Effect of efavirenz treatment on the pharmacokinetics of nelfinavir boosted by ritonavir in healthy volunteers.

AIMS: A once-daily (q.d.) nucleoside-sparing regimen can prevent mitochondrial toxicity, overcome viral resistance and improve compliance. In the present study the effect of efavirenz on the pharmacokinetics and tolerability of once-daily nelfinavir/ritonavir was evaluated in healthy subjects. METHODS: This was a multiple-dose, open-label, single-group, two-period study in 24 healthy subjects. Each received from days 1-10 (period 1): 1875 mg nelfinavir plus 200 mg ritonavir q.d. with a 300-kcal snack. During days 11-20 (period 2) efavirenz 600 mg q.d. was added to the regimen. Blood samples were collected up to 24 h after dosing on days 10 (period 1) and 20 (period 2). High-performance liquid chromatography methods were used for the determination of the concentrations of all compounds. The main pharmacokinetic parameters were calculated using noncompartmental methods. RESULTS: All subjects completed the study. After the first period mean nelfinavir AUC(0-24 h), C(max) and C(24) were 49.6 mg h(-1) l(-1), 5.0 mg l(-1) and 0.37 mg l(-1), and the sum of nelfinavir plus its active metabolite M8 C(24) was 0.83 mg l(-1). The relative bioavailability, expressed as a geometric mean ratio (90% confidence interval) for nelfinavir AUC(0-24 h), C(max) and C(24) of period 2 compared with period 1 was: 1.30 (1.21, 1.40), 1.29 (1.19, 1.40) and 1.48 (1.32, 1.66). The sum of nelfinavir and M8 C(24) in period 2 was 0.99 mg l(-1), an increase of 19%. No serious adverse events occurred. CONCLUSIONS: The studied regimens were well tolerated. Nelfinavir/ritonavir given together with efavirenz resulted in a 48% higher mean C(24) concentration for nelfinavir, and the sum of nelfinavir and M8 C(24) concentrations was 0.99 mg l(-1). Efavirenz exposure in this study was similar to that reported previously, and therefore can be used effectively in combination with ritonavir and nelfinavir.

Pharmaceutical development of a parenteral formulation of the novel anti-tumor agent carzelesin (U-80,244).

The aim of this study was to design a parenteral dosage form for the investigational cytotoxic drug carzelesin. A stable formulation in PET (Polyethylene glycol 400/absolute ethanol/Tween 80, 6:3:1, v/v/v) was developed. The prototype, containing 0.50 mg carzelesin in 2.0 ml PET formulation, was found to be the optimal formulation in terms of solubility, stability and dosage requirements in phase I clinical trials. Quality control of the formulation showed that the pharmaceutical preparation of carzelesin in PET is not negatively influenced by the manufacturing process. Shelf life studies demonstrated that the formulation is stable for at least 1 year, when stored at -30 degrees C in the dark. In addition, the stability of carzelesin in the PET formulation is discussed as a function of temperature, additives and after dilution in infusion fluids.