The authors evaluated the intraindividual and interindividual variations in the pharmacokinetics of mycophenolic acid after oral administration of mycophenolate mofetil in 10 liver transplant patients. Mycophenolic acid and its metabolite, mycophenolic acid glucuronide, were measured in plasma and urine by high-pressure liquid chromatography. The plasma protein binding of mycophenolic acid was determined by ultrafiltration. The maximum concentration of mycophenolic acid in plasma increased significantly (P < or = .05) with time from 9.1 +/- 7.2 microg/mL (<1 week) to 36.7 +/- 15.6 microg/mL (1 month). The area under the plasma concentration versus time curve of mycophenolic acid also increased significantly with time, from 50.8 +/- 42.1 microg x h/mL to 118.0 +/- 57.6 microg x h/mL (P < or = .05). The plasma protein binding of mycophenolic acid increased from 92% to 98%, and the apparent oral clearance [CL/F] decreased from 32.9 +/- 21.4 L/h during the first study period to 9.0 +/- 4.4 L/h (P < or = .05) during the third study period. The apparent intrinsic clearance of mycophenolic acid did not change significantly over time. The ratio of the area under the curve of mycophenolic acid glucluronide to mycophenolic acid in plasma decreased with time (25.5 +/- 21.2 vs 8.0 +/- 3.3) but did not reach statistical significance. The increased binding of mycophenolic acid to plasma proteins with time after transplantation appeared to contribute to the intraindividual variation, whereas differences in the ability of the liver to metabolize mycophenolic acid between patients appear to contribute to the large interindividual variation in the pharmacokinetics of mycophenolic acid. The observations in this study support the concept of measuring the unbound concentration of mycophenolic acid to optimize immunosuppressive drug therapy with mycophenolic acid.

The results indicate that KD-247 reduces viral load in patients with chronic HIV-1 infection and further clinical trials are warranted.

Registered at ClinicalTrials. gov as NCT01199328.

The compounded MMF suspension was stable for at least 11 days at all the temperatures studied and for as long as 210 days at 5 degrees C. This formulation appears to be clinically acceptable and provides a convenient dosage form for pediatric patients and for adults during the early postoperative period.

AimsTo investigate the tolerability, safety and pharmacokinetics of S-3304 in healthy volunteers treated with high doses of S-3304 for 28 days. MethodsThirty-two healthy volunteers were recruited. Four male and four female subjects were allocated to one of four doses (800 mg, 1600 mg, 2400 mg and 3200 mg). At each dose six volunteers took active medication and two volunteers took placebo in a double-blind fashion. Volunteers took a single dose on days 1 and 28 for pharmacokinetic purposes, and took twice daily doses from day 3-27. The pharmacokinetics of S-3304 and its hydroxy metabolites were evaluated. Tolerance was based on subjective adverse events, clinical examination, vital signs, ECG and laboratory tests including haematology and biochemistry profiles using CTC grading. ResultsDoses up to 2400 mg twice daily were generally well tolerated. At 3200 mg twice daily, five volunteers including one randomized to placebo were withdrawn from treatment mainly due to alanine aminotransferase (ALT) elevation. Cmax of S-3304 on day 1, whose geometric mean and 95% confidence interval were 66.3 mg ml -1 (48.8, 90.0) for 800 mg, 82.6 mg ml -1 (69.3, 98.6) for 1600 mg, 89.5 mg ml -1 (79.5, 100.7) for 2400 mg, and 110.5 mg ml -1 (88.9, 137.7) for 3200 mg, respectively, was correlated with the log-transformed peak ALT (P < 0.0001 for male and P = 0.048 for female volunteers). ConclusionsIn healthy volunteers the maximum tolerated dose of S-3304 was 2400 mg twice daily. ALT elevation was the most frequent dose-limiting factor and was correlated with Cmax on day 1.