A pilot pharmacokinetic study of oral azacitidine.

Azacitidine is a pyrimidine nucleoside analog of cytidine with hypomethylating and antileukemia activity. Azacitidine has been shown to have survival benefits in patients with high-risk myelodysplastic syndrome (MDS), and has activity in the treatment of acute myelogenous leukemia (AML). It is administered by subcutaneous (s.c.) or intravenous (i.v.) injection daily at a dose of 75 mg/m(2) for 7 days every 4 weeks. An oral formulation would facilitate dosing, reduce administration side effects and potentially maximize azacitidine pharmacologic action. Previously, oral formulations of this class of agent have failed due to rapid catabolism by cytidine deaminase and hydrolysis in aqueous environments. Development of a film-coated formulation has circumvented this difficulty. In a formulation feasibility pilot study, four subjects with solid malignant tumors, AML or MDS received single oral doses of 60 or 80 mg azacitidine. Subjects demonstrated measurable plasma concentrations of azacitidine, allowing bioavailability comparisons to be made to historical pharmacokinetic data for s.c. azacitidine. Subjects safely tolerated 80 mg, a dose for which the mean bioavailability was 17.4% of historic s.c. exposure. No severe drug-related toxicities were observed. These data suggest that oral azacitidine is bioavailable in humans and should be studied in formal phase 1 trials.

Are lipid values and BMI related to hospitalizations in the hemodialysis population?

OBJECTIVE: To examine the relationship between lipid values and BMI (body mass index) on hospitalizations in hemodialysis (HD) patients. DESIGN: Retrospective (2-year) study. SETTING: Outpatient dialysis center in a large metropolitan city. PATIENTS: This study used 158 HD patients stratified on the basis of ethnicity (non-Black and Black) and diabetic status (nondiabetic and diabetic). INTERVENTION: Subjects were observed for 2 years. Body weight, BMI, lipid parameters, and hospitalization duration were determined 8 times (3-month intervals). MAIN OUTCOME MEASURES: Body weight, BMI, lipid parameters (serum triglyceride concentration, serum total cholesterol, high-density lipoprotein [HDL]-, low-density lipoprotein [LDL]-, very low-density lipoprotein [VLDL]- cholesterol concentrations, serum Apo-protein A1 [Apo-A1] concentration, and serum Apo-protein B [Apo-B] concentration), and morbidity data were recorded. RESULTS: Hemodialysis subjects were hospitalized 2.3 +/- 1.6 times over the 2-year experimental period. Length of hospital stay averaged 6.6 +/- 0.5 days/hospitalization. Length of hospital stay was inversely related to HDL concentration (r = -0.21, P <.05, n = 89), but not significantly related to BMI in HD subjects. BMI was positively associated with LDL concentration (r = +0.28, P <.01, n = 97). Cholesterol concentration was directly associated with LDL concentration (r = +0.52, P <.01, n = 138), VLDL concentration (r = +0.47, P <.01, n = 139), and triglyceride concentration (r = +0.54, P <.01, n = 155). Mean concentration of HDL-cholesterol was inversely related serum triglyceride concentration (r = -0.43, P <.01, n = 140). Although Apo-A1 concentration was directly associated with HDL level (r = +0.39, P <.01, n = 139), Apo-B was inversely related to HDL level (r = -0.37, P <.01, n = 138) and directly related to cholesterol concentration (r = +0.71, P <.01, n = 138), VLDL concentration (r = +0.87, P <.01, n = 138), and triglyceride concentration (r = +0.81, P <.01, n = 138). CONCLUSION: Cardiac disease remains the primary cause of morbidity and mortality in HD patients, and results of the present study suggest that dyslipidemias present in the HD population negatively impact cardiovascular profiles which, in turn, influence the frequency/duration of hospitalizations. Among all lipid parameters analyzed in the present study, increased LDL and decreased HDL concentrations were more strongly related to length of hospital stay than was BMI.

Disposition of the aldose reductase inhibitor AL01576 in rats.

The disposition of the aldose reductase inhibitor AL01576 was studied in rats following intravenous and oral dosing. Single 4-mg/kg intravenous bolus and oral doses of [14C] AL01576 were administered and levels of radioactivity in blood, excreta, and various tissues were determined over a 168-h period. The decline of radioactivity in blood was quite similar for the two routes of administration, with an apparent half-life of approximately 30 h. At 120 to 144 h, a second, slower elimination phase began that was not fully characterized in the 168-h duration of the study. The HPLC analysis of plasma samples revealed intact AL01576 as the only compound in plasma. The mean plasma parent and radioactivity concentrations are in agreement; suggesting the absence of or an insignificant amount of metabolite in the plasma. The urinary and fecal excretion rate data showed a kinetic pattern similar to that of blood radioactivity. Fecal excretion was the primary route of elimination following both intravenous and oral dosing, accounting for 59% of the administered intravenous dose and 61% of the oral dose. Urinary excretion accounted for 32% of the intravenous dose and 29% of the oral dose. Negligible amounts of radioactivity were recovered as expired 14CO2. Experiments with bile-duct cannulated rats confirmed that the major route of elimination of the drug is biliary excretion. The pattern of distribution of [14C] AL01576 in tissues was quite similar following the two routes of administration. Tissue radioactivity concentration peaked at 4 h (the first sampling time) following both routes of administration in all tissues except the GI tract.(ABSTRACT TRUNCATED AT 250 WORDS)