Pharmacology and Pharmacokinetics of the Antiviral Agent β-d-2′,3′-Dideoxy-3′-Oxa-5-Fluorocytidine in Cells and Rhesus Monkeys

In silico study supports the efficacy of a reduced dose regimen for stavudine

“…The proportion of activated PBM cells varies between infected individuals and is not usually reported in clinical studies, making it difficult to assess the linearity of d4T-TP versus extracellular d4T using pooled in vivo data from individuals, each with differing activated lymphocyte fractions. Therefore the linearity between d4T and cellular accumulation of d4T-TP was tested in phytohaemagglutinin (PHA) stimulated PBM cells in cell culture, in which the degree of activation is more uniform (Hernandez-Santiago et al, 2005; Hernandez-Santiago et al, 2007a; Hernandez-Santiago et al, 2007b). The concentrations measured in vitro were then compared to average concentrations in humans after normalizing using 8% as an average estimate of dividing lymphocytes measured in infected individuals (Mohri et al, 2001).…”

Pharmacokinetics of the Anti-Human Immunodeficiency Virus Agent 1-(β-d-Dioxolane)Thymine in Rhesus Monkeys

“…High C max values were observed with APD, the DXG prodrug, after oral administration (C max of DXG ϭ 50 to 60 M within 0.25 to 0.5 h) (11) ; k 21 ϭ 0.51 h Ϫ1 ) are suggestive of rapid equilibration of the drug between the central and peripheral compartments. The average t 1/2␤ value of D-DOT in rhesus monkeys (2.16 h) was less than that of D-FDOC (2.48 to 5.12 h) but comparable to that of DXG following APD (1.42 to 1.74 h) and DAPD (1.8 to 2.8 h) dosing and higher than that of AZT (0.8 h), D4T (0.80 to 0.87), and several other nucleosides (7,8,10,11,24,34). The average systemic and renal clearance values (Cl systemic , and Cl renal ) for D-DOT were 0.36 and 0.18 liter ⅐ h Ϫ1 Նkg Ϫ1 , respectively.…”

“…D-DOT was almost completely absorbed (F ϭ 95% Ϯ 12%) after oral dosing. In comparison, D-FDOC (24) and DAPD showed lower bioavailabilities (D-FDOC, F ϭ 38%; DAPD, F ϭ 30%), but AZT was also completely absorbed (90 to 100%) after oral dosing in rhesus monkeys (7,10,24,35). The oral dose of 60 mg/kg was used for AZT and D4T with rhesus monkeys (7,39).…”

“…The toxicities of AZT and D4T in humans undergoing treatment with these drugs are well known despite their usefulness in drug cocktails (1,23,33,36,37,42). Therefore, there is a need to develop TK-dependent nucleoside analogues with limited toxicities that could provide additional treatment options.The objective of this study was to assess the single-dose pharmacokinetics (PK) of D-DOT in rhesus monkeys given 33.3-mg/kg-of-body-weight intravenous and oral doses and to compare the pharmacokinetics with those of other structurally related antiretroviral nucleoside analogs that were previously administered to rhesus monkeys (7,8,10,11,12,24,28,30,34,39). …”

“…The objective of this study was to assess the single-dose pharmacokinetics (PK) of D-DOT in rhesus monkeys given 33.3-mg/kg-of-body-weight intravenous and oral doses and to compare the pharmacokinetics with those of other structurally related antiretroviral nucleoside analogs that were previously administered to rhesus monkeys (7,8,10,11,12,24,28,30,34,39).…”