A Pilot Study of the Pharmacokinetics of the Modified-Release Once-Daily Tacrolimus Formulation Administered to Living-Donor Liver Transplant Recipients.

OBJECTIVES: Sustained-release once-daily tacrolimus pharmacokinetics have not yet been characterized in de novo living-donor liver transplant recipients. Here, a 12-week, phase IV, single center, open-label, prospective pilot study was conducted to investigate the pharmacokinetics of this formulation in these patients. MATERIALS AND METHODS: Patients received continuous intravenous infusion of tacrolimus on days 0 to 5 after transplant, which was followed by oral once-daily sustained-release tacrolimus. Two 24-hour pharmacokinetics profiles were generated for 10 patients on days 6 and 14. Secondary endpoints were minimum (trough level) and maximum whole blood concentrations, time to maximum concentration, and incidences of acute rejection, patient and graft survival, and adverse events. RESULTS: Mean doses (± standard deviation) of sustained-release tacrolimus on days 6 and 14 were 0.14 ± 0.03 and 0.17 ± 0.04 mg/kg. Levels were within the recommended range throughout the study. When the actual dose was examined, area under the curve from 0 to 24 hours on day 14 was 1.8-fold higher than that on day 6 (423.9 vs 235.7 ng × h/mL). When tacrolimus was normalized to 0.1 mg/kg, area under the curve from 0 to 24 hours on day 14 was 1.5-fold higher than on day 6 (279.3 vs 183.4 ng × h/mL). When we used the actual dose, we found the correlation coefficient between area under the curve from 0 to 24 hours and trough level to be higher on day 6 (r = 0.87) than on day 14 (r = 0.691). No acute rejections, graft losses, patient deaths, or drug-related adverse events were reported. CONCLUSIONS: Initial intravenous followed by sustained-release tacrolimus was safe and efficacious in living-donor liver transplant recipients. The mean area under the curve from 0 to 24 hours on day 14 was higher than previously reported; this difference may reflect cautious dosing regimens.

Effect of reoperation on long-term outcome of pT1b/T2 gallbladder carcinoma after initial laparoscopic cholecystectomy.

BACKGROUND: A small proportion of gallbladder carcinomas (GBC) are incidentally detected after laparoscopic cholecystectomy (LC). This study intended to analyze the effect of extended reoperation on the long-term outcome of patients with pT1b/T2 GBC who had initially undergone LC. METHODS: A cohort of 203 patients who underwent R0 resection and whose pathology was pT1b or pT2 GBC was divided into 3 groups: open surgery (group I, n = 150), LC only (group II, n = 25), and initial LC and subsequent reoperation (group III, n = 28). RESULTS: Mean ages were 62.3 ± 9.6 years, 65.9 ± 11.8 years, and 57.1 ± 7.7 years in groups I, II, and III, respectively (p = 0.001). The numbers of pT1b and pT2 patients were 75 and 75 in group I, 15 and 10 in group II, and 6 and 22 in group III, respectively. Residual tumors after LC were found in none of 6 pT1b patients and 5 of 22 pT2 patients. Overall 5-year patient survival rate was 70.1 % for all-cause death and 73.5 % for tumor recurrence-associated death (76.0 % in group I, 64.0 % in group II, and 63.0 % in group III [p = 0.607]; 84.4 % in pT1b group I, 68.8 % in pT1b group II, and 83.3 % in pT1b group III [p = 0.649]; 67.6 % in pT2 group I, 50 % in pT2 group II, and 61.9 % in pT2 group III [p = 0.895]). Concurrent bile duct resection in pT2 patients did not affect survival outcomes (p = 0.601). CONCLUSIONS: No definite survival benefit from reoperation was observed in patients with pT1b lesions. Residual tumor was found in 23 % of pT2 patients after reoperation, and the survival outcomes of these patients were comparable to those of the open surgery group. Therefore, reoperation for pT1b GBC following LC can be individually indicated because its indication remains unclear, but it should be highly recommended for pT2 GBC.