Comparison of the influence of cyclosporine and tacrolimus on the pharmacokinetics of prednisolone in adult male kidney transplant recipients

Cyclosporine has been observed to precipitate cushingoid features in kidney transplant recipients already on prednisolone. Some pharmacokinetic studies have demonstrated increased prednisolone exposure in patients on cyclosporine therapy compared with azathioprine, whereas other studies have found no difference. The objective of this study was to determine whether cyclosporine impacts on prednisolone exposure as compared with tacrolimus

Pharmacokinetics of vinorelbine in patients with liver metastases

Background: The main elimination pathway of vinorelbine is hepatic metabolism, and the clearance of vinorelbine could be reduced in patients with liver metastases. Objectives: To study the pharmacokinetics of vinorelbine in patients who have advanced breast cancer with or without liver metastases and to study the relationship between hepatic function and vinorelbine clearance. Patients and Methods: We studied 29 patients with advanced breast cancer: 19 with liver metastases and 10 control patients with extrahepatic metastases (mean age, 61 years; age range, 38 to 81 years), The vinorelbine dose was 30 mg/m(2) as a short intravenous infusion; the dose was reduced by 50% in patients with bilirubin >2 mg/dl. Patients were classified by ultrasonographic estimation of the liver volume replaced by tumor (%LVRT). Standard liver function tests and a monoethylglycinexylidide test (a quantitative liver function test based on lidocaine metabolite formation) were performed. Vinorelbine was assayed in plasma by HPLC with fluorescence detection. Vinorelbine determination was impossible in two patients with more than 75% LVRT because of interferences. Pharmacokinetic parameters were calculated with a noncompartimental method and compared by means of the Kruskal-Wallis test. Results: A lower vinorelbine clearance rate was observed in the five patients with more than 75% LVRT (22.9 L/hr/m(2)) compared with the 10 patients with no liver metastases (48.0 L/hr/m(2)) and the 12 patients with 25% to 75% LVRT (45.3 L/hr/m(2)), Terminal elimination half-life and apparent volume of distribution were not significantly different among groups. The monoethylglycinexylidide test had a significant correlation with vinorelbine clearance, (r(2) = 0.70; P = 10(-4)). Conclusions: These results support vinorelbine dose reduction in patients with severe liver failure but not in patients with moderate secondary liver involvement. The monoethylglycinexylidide test may prove to be useful for vinorelbine dose individualization

Pharmacokinetics of oral etoposide in patients with hepatocellular carcinoma

Etoposide dosage in patients with liver dysfunction remains controversial. Since etoposide has a hepatic component to its clearance (CL) and shows a high degree of protein binding, hepatic impairment could affect etoposide disposition. However, the empiric recommendation that the dose of etoposide be decreased in such patients may reduce systemic exposure and be detrimental to its antitumor activity. To address these issues we studied the pharmacokinetics (PK) of etoposide in patients with hepatocellular carcinoma (HCC) and underlying cirrhosis (n = 17) treated with daily oral etoposide. Unbound etoposide was obtained by ultrafiltration. Etoposide concentrations (total and free drug) were measured by high-performance liquid chromatography (HPLC) and analyzed by noncompartmental equations. The patients had mild or moderate liver dysfunction. Albuminemia was in the normal range for all the patients. Creatininemia was normal in all but two patients. PK results (mean and range) showed that etoposide disposition was unchanged in patients with liver dysfunction. We found slightly high etoposide bioavailability [F, 61% (17-95%)] and clearance [CL, 1.1 (0.7-2.3) 1 h(-1) m(-2)] resulting in a normal degree of systemic exposure (AUC(oral) 27 mu g h ml(-1)). Normal protein binding [PB 93.2% (84.4-98.1%)] contributed to a normal level of exposure to free drug (AUC(f, oral) 1.9 mu g h ml(-1)). The distribution volume [V-ss 8.4 (6.1-13.2) l/m(2)] and the effective half-life [t(1/2eff), 5.1 (3.0-9.6) h] were normal. Median CL and protein binding did not differ in the seven patients with total bilirubin value of > 1.2 mg/dl as compared with the ten patients with total bilirubin levels of less than or equal to 1.2 mg/dl (1.3 versus 1.0 1 h(-1) m(-2) and 92.5% versus 93.4%, respectively). In agreement with this PK finding, we observed no clinical evidence of increased toxicity in patients with hyperbilirubinemia as compared with patients with normal bilirubinemia (mean WBC decrease 38% versus 47%). The only case of severe (grade 4) hematological toxicity was observed in one patient with reduced glomerular filtration. Since the pharmacological effects of etoposide correlate with the level of systemic exposure to the free drug, our data suggest that no dose reduction is needed in patients with HCC. It is even possible to increase the dose intensity in patients with favorable PK parameters under appropriate hematological and therapeutic drug monitoring