Pharmacokinetics and pharmacodynamics of nelfinavir administered twice or thrice daily to human immunodeficiency virus type 1-infected children.

We studied the pharmacokinetics and pharmacodynamics of nelfinavir administered 2 or 3 times per day to human immunodeficiency virus type 1 (HIV-1)-infected children receiving highly active antiretroviral therapy containing nelfinavir. The geometric mean trough concentrations of nelfinavir for the thrice- and twice-daily regimens were 1.55 mg/L and 1.11 mg/L, respectively (P=not significant). Nelfinavir concentrations did not correlate with total daily dose, dose per kilogram of weight, age, weight, previous protease inhibitor (PI) experience, or CD4(+) cell percentage. In the 25 PI-naive children, the virus load reductions at 24 weeks of treatment with the twice- and thrice-daily regimens were comparable. A significantly higher percentage of children in the twice-daily group had a trough concentration of nelfinavir of less than the inhibitory concentration of 95% (P=.042). The decrease in the virus load at 24 weeks of treatment was not correlated with the trough concentration of nelfinavir. The variability of trough concentrations was extremely high, particularly among recipients of the twice-daily regimen, resulting in a higher number of patients with subinhibitory concentrations of nelfinavir in this group.

The relationship between ritonavir plasma trough concentration and virological and immunological response in HIV-infected children.

BACKGROUND: We studied a number of factors, including ritonavir plasma levels, and their capability of predicting response to therapy with ritonavir (RTV). METHODS: Eleven HIV-positive children, nucleoside reverse transcriptase inhibitor (NRTI)-experienced, protease inhibitor (PI) naive, receiving RTV in combination with two NRTIs were enrolled in the study. Demographic parameters were: median age (range) 10 (2-13) years, weight 26 (10-38) kg, body surface area (BSA) 0.93 (0.47-1.21) m(2). Baseline values of CD4, percent CD4 and viral load were 137 (2-1390) cells/microL, 9.5 (0.4-32.4)%, and 5.15 (4.30-6.18) log10 copies/mL, respectively. The dose of RTV was 318 (266-409) mg/m(2) twice daily. Peak (3.5 h after administration) and trough (predose) plasma concentrations of RTV were determined on one occasion at steady-state after a morning dose. Virological response to treatment was quantified as the difference between the baseline value of viral load and the value observed at 6 months of therapy (Delta(6)). RESULTS: The relationship between Delta(6) and demographic parameters (age, weight, BSA, and baseline CD4, percent CD4, and viral load) and plasma concentrations of RTV was studied by linear regression. Median (range) Delta(6) was 0.88 (0.77-2.62) log10 copies/mL. Peak and trough of RTV were 14.9 (3.2-31.4) and 5.0 (0.1-15.6) mg/L, respectively. Trough concentration of RTV was the best predictor of Delta(6), although the relationship between these two variables was not statistically significant (r = 0.56, P = 0.075). CONCLUSION: Our observation of a trend for a greater decrease in viral load in patients with higher trough concentration of RTV warrants further pharmacodynamic studies of PI in paediatric patients.

Pharmacokinetics of rifabutin in HIV-infected patients with or without wasting syndrome.

AIMS: The purpose of the study was to compare the pharmacokinetic parameters of rifabutin obtained in a group of patients without wasting syndrome (NWS) with those obtained in a group with wasting syndrome (WS). METHODS: A single dose of 300 mg rifabutin was administered in the fasting state to the patients in both study groups and blood samples were scheduled to be collected at the following times: 0 (predose), 0.5, 1, 2, 3, 4, 6, 8, 24, 48, 72 and 96 h following administration. Data were analysed using noncompartmental methods. The pharmacokinetic parameters of rifabutin in patients with and without wasting syndrome were compared using the Mann-Whitney U-test. RESULTS: Cmax was 0.34+/-0. 14 mg l-1 in NWS patients and 0.55+/-0.16 mg l-1 (P=0.01) in patients with WS. tmax was 4.2+/-1.5 and 3.3+/-2.3 h (P=0.17) in NWS and WS patients, respectively. The AUCs were similar in the two study groups. V/F was 2905+/-1646 l in NWS patients and 1701+/-492 l (P=0.07) for the WS group. These differences are less pronounced following normalization of V/F to patients body weight (43.7+/-20.1 vs 35.4+/-10.3 l kg-1 ). t1/2,lambdaz tended to be shorter in patients with WS (31.4+/-12.9 vs 46.0+/-23.5 h, P=0.12). CONCLUSIONS: Our study suggests that the pharmacokinetics of rifabutin in patients with wasting syndrome are not altered to a degree that is clinically important.

Specific high-performance liquid chromatography assay for determination of rifabutin plasma concentration following Extrelut column extraction.

A specific, precise and accurate assay for determination of rifabutin in human plasma using Extrelut column extraction was developed and validated. Rifabutin concentrations were calculated with a standard curve ranging from 5 to 800 ng ml(-1). using a split-curve approach. Chromatographic peaks were separated by means of a 5 microm Symmetry Shield RP8 using a KH2PO4 (0.05 M) buffer-acetonitrile mobile phase. Detection wavelength was set at 275 nm. Chromatography was carried out at room temperature (20-25 degrees C). The limit of quantification was 5 ng ml(-1). The recovery was over 71%. The intra-day precision of the assay was 5, 7, and 1% while the inter-day precision was 11.2, 8.1, and 5.8% at concentrations of 30, 150 and 500 ng ml(-1), respectively. The accuracy ranged from 99 to 108%. Forty of the drugs most commonly administered to HIV-positive patients were found not to interfere with the assay. The assay has been used in a comparative study of rifabutin pharmacokinetics in HIV-positive patients with or without wasting syndrome. reserved.

Induction of micronuclei and of enzyme-altered foci in the liver of female rats exposed to progesterone and three synthetic progestins.

Progesterone (PG) and three structurally similar synthetic progestins-norethisterone (NE), allylestrenol (AE), and dydrogesterone (DG)-have been compared for their ability to induce the formation of micronuclei and of enzyme-altered foci in the liver of female rats. In the micronucleus assay, carried out in rats given a single p.o. dose of 100 mg kg-1 3 days before partial hepatectomy and sacrificed for cell sampling 2 days later, the frequency of micronucleated hepatocytes was 3.5-fold higher than in controls with PG, 2.8-fold with DG, 2.2-fold with NE and 2.1-fold with AE, but the increase was statistically significant only for PG. In the liver foci assay, performed to evaluate the tumor initiating activity of p. o. dosing with 100 mg kg-1 once a week for 6 successive weeks, the values of the number and area of gamma-glutamyltranspeptidase-positive foci were, as compared to controls, 15.9- and 100-fold higher with NE, and 13.9- and 52-fold higher with AE, but only the increase of area produced by NE was statistically significant; PG and DG did not display in this test any activities. Considered together with previous findings, these results suggest that NE might be biotransformed in the liver into reactive species and thus behave as a weak genotoxic agent.