ORAL GANCICLOVIR DOSING IN TRANSPLANT RECIPIENTS AND DIALYSIS PATIENTS BASED ON RENAL-FUNCTION

Background An oral formulation of ganciclovir (GCV) was recently appro ved for the prevention of cytomegalovirus disease in solid organ trans plant recipients. This study was designed to determine the bioavailabi lity of GCV and to test a dosing algorithm in transplant and dialysis patients with different levels of renal function, Methods. Pharmacokin etic studies were carried out in 23 patients who were either a recipie nt of an organ transplant or on hemodialysis. Drug dosing was establis hed by the following algorithm based on calculated creatinine clearanc e (CrCl): CrCl = (140-age) x body weight/72 x Cr x 0.85 for women that is, CrCl >50 ml/min, 1000 mg every 8 hr; CrCl. of 25-50 ml/min, 1000 mg every 24 hr; CrCl of 10-24 ml/min, 500 mg every day; CrCl <10 ml/mi n (or on dialysis), 500 mg every other day after dialysis. GCV was tak en within 30 min after a meal, The patients received oral GCV for betw een 12 days and 14 weeks. Serum specimens (or plasma from patients on hemodialysis) obtained at steady state were analyzed for GCV concentra tions by high-performance liquid chromatography, In nine of the transp lant recipients, absolute bioavailability was determined by comparing GCV levels after single oral and intravenous doses of GCV. Results, Th e following GCV concentrations (mean +/- SD) were determined: with CrC l of greater than or equal to 70 ml/min, the minimum steady-state conc entration (C-min) and maximum concentration (C-max) were 0.78+/-0.46 m u g/ml and 1.42+/-0.37 mu g/ml, respectively, with a 24-hr area under the concentration time curve (AUC(0-24)) of 24.7+/-7.8 mu g.hr/ml; wit h CrCl of 50-69 ml/min, the C-min, and C-max were 1.93+/-0.48 and 2.57 +/-0.39 mu g/ml, respectively, with an AUC(0-24) of 52.1+/-10.1 mu g.h r/ml; with CrCl of 25-50 ml/min, the C-min and C-max were 0.41+/-0.27 and 1.17+/-0.32 mu g/ml, respectively, with an AUC(0-24) of 14.6+/-7.4 mu g.hr/ml. For one patient with a CrCl of 23.8 ml/min, the C-min and C-max were 0.32 and 0.7 mu g/ml, respectively, with an AUC(0-24) of 1 0.7 mu g.hr/ml. With CrCl of <10 ml/min, the mean C-min and C-max were 0.75+/-0.42 and 1.59+/-0.55 mu g/ml, respectively, with a mean AUC(0- 24) of 64.6+/-18.8 mu g.hr/ml. Absolute bioavailability, for the nine patients so analyzed, was 7.2+/-2.4%. For those patients with end-stag e renal failure, GCV concentrations fell during dialysis from a mean o f 1.47+/-0.48 mu g/ml before dialysis to 0.69+/-0.38 mu g/ml after dia lysis. Conclusions, The bioavailability of oral GCV in transplant pati ents was similar to that observed in human immunodeficiency virus-infe cted patients. However, levels between 0.5 and 1 mu g/ml (within the I C50 of most cytomegalovirus isolates) could be achieved with tolerable oral doses. The proposed dosing algorithm resulted in adequate levels for patients, with CrCl greater than 50 ml/min and for patients on di alysis. For patients with CrCl between 10 and 50 ml/min, the levels ac hieved were low and these patients would likely benefit from increased doses.