Antiviral Activity, Pharmacokinetics, and Safety of BMS-488043, a Novel Oral Small-Molecule HIV-1 Attachment Inhibitor, in HIV-1-Infected Subjects

ABSTRACT BMS-488043 is a novel and unique oral small-molecule inhibitor of the attachment of human immunodeficiency virus type 1 (HIV-1) to CD4 + lymphocytes. The antiviral activity, pharmacokinetics, viral susceptibility, and safety of BMS-488043 were evaluated in an 8-day monotherapy trial. Thirty HIV-1-infected study subjects were randomly assigned to sequential, safety-guided dose panels of 800 and 1,800 mg BMS-488043 or a matched placebo in a 4:1 ratio, and the drug was administered every 12 h with a high-fat meal for 7 days and on the morning of day 8. Dose-related, albeit less-than-dose-proportional, increases in plasma BMS-488043 concentrations were observed. Mean plasma HIV-1 RNA decreases from the baseline for the BMS-488043 800- and 1,800-mg dose groups on day 8 were 0.72 and 0.96 log 10 copies/ml, respectively, compared with 0.02 log 10 copies/ml for the placebo group. A lower baseline BMS-488043 50% effective concentration (EC 50 ) in the active-treatment groups was predictive of a greater antiviral response. Although absolute drug exposure was not associated with an antiviral response, the trough concentration ( C trough ), adjusted by the baseline EC 50 ( C trough /EC 50 ), was associated with antiviral activity. During dosing, four subjects experienced >10-fold reductions in viral susceptibility to BMS-488043, providing further support of the direct antiviral mechanism of BMS-488043. BMS-488043 was generally safe and well tolerated. These results suggest that further development of this novel class of oral HIV-1 attachment inhibitors is warranted

Application of Physiologically Based Pharmacokinetic Modeling to Predict Maternal Pharmacokinetics and Fetal Exposure to Oxcarbazepine

Pregnancy is associated with physiological changes that may affect drug pharmacokinetics (PKs). The aim of this study was to establish a maternal–fetal physiologically based pharmacokinetic (PBPK) model of oxcarbazepine (OXC) and its active metabolite, 10,11-dihydro-10-hydroxy-carbazepine (MHD), to (1) assess differences in pregnancy, (2) predict changes in PK target parameters of these molecules following the current dosing regimen, (3) assess predicted concentrations of these molecules in the umbilical vein at delivery, and (4) compare different methods for estimating drug placental penetration. Predictions using the pregnancy PBPK model of OXC resulted in maternal concentrations within a 2-fold error, and extrapolation of the model to early-stage pregnancies indicated that changes in median PK parameters remained above target thresholds, requiring increased frequency of monitoring. The dosing simulation results suggested dose adjustment in the last two trimesters. We generally recommend that women administer ≥ 1.5× their baseline dose of OXC during their second and third trimesters. Test methods for predicting placental transfer showed varying performance, with the in vitro method showing the highest predictive accuracy. Exposure to MHD in maternal and fetal venous blood was similar. Overall, the above-mentioned models can enhance understanding of the maternal–fetal PK behavior of drugs, ultimately informing drug-treatment decisions for pregnant women and their fetuses

Cost-Effectiveness Analysis of Hepatic Arterial Infusion of FOLFOX Combined Sorafenib for Advanced Hepatocellular Carcinoma With Portal Vein Invasion.

BackgroundHepatic arterial infusion (HAI) of oxaliplatin, leucovorin, and fluorouracil (FOLFOX) plus sorafenib has a more desirable effect versus sorafenib for hepatocellular carcinoma (HCC) patients with portal vein invasion. However, considering the high cost of hepatic arterial infusion of chemotherapy (HAIC), this study evaluated the cost-effectiveness of HAIC plus sorafenib (SoraHAIC) versus standard care for HCC patients from the Chinese health system perspective.MethodsA Markov multi-state model was constructed to simulate the disease course and source consumption of SoraHAIC. Costs of primary therapeutic drugs were calculated based on the national bid price, and hepatic artery catheterization fee was collected from the Fujian Provincial Price Bureau. Clinical data, other costs, and utility values were extracted from references. Primary outcomes included life-years (LYs), quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER). The robustness of model was verified by uncertainty sensitivity analyses.ResultsSoraHAIC gained 1.18 QALYs (1.68 LYs) at a cost of $65,254, while the effectiveness and cost of sorafenib were 0.52 QALYs (0.79 LYs) and$14,280, respectively. The ICER of SoraHAIC vs sorafenib was $77,132/QALY ($57,153/LY). Parameter that most influenced the ICER was utility of PFS state. The probabilistic sensitivity analysis (PSA) showed that SoraHAIC was not cost-effective in the WTP threshold of 3*Gross Domestic Product (GDP) per capita of China ($30,492/QALY). But about 38.8$72,000/QALY). When 3*GDP per capita of Fujian ($47,285/QALY) and Gansu Province ($14,595/QALY) were used as WTP threshold, the acceptability of SoraHAIC was 0.3% and 0%, respectively.ConclusionsThe study results indicated that SoraHAIC was not cost-effective in medium-, and low-income regions of China. In developed areas of China (Beijing), there was a 38.8% probability that the SoraHAIC regimen would be cost-effective