Background. An oral formulation of ganciclovir (GCV) was recently approved for the prevention of cytomegalovirus disease in solid organ transplant recipients. This study was designed to determine the bioavailability of GCV and to test a dosing algorithm in transplant and dialysis patients with different levels of renal function. Methods. Pharmacokinetic studies were carried out in 23 patients who were either a recipient of an organ transplant or on hemodialysis. Drug dosing was established by the following algorithm based on calculated creatinine clearance (CrCI): 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/min (or on dialysis), 500 mg every other day after dialysis. GCV was taken within 30 min after a meal. The patients received oral GCV for between 12 days and 14 weeks. Serum specimens (or plasma from patients on hemodialysis) obtained at steady state were analyzed for GCV concentrations by high-performance liquid chromatography. In nine of the transplant recipients, absolute bioavailability was determined by comparing GCV levels after single oral and intravenous doses of GCV. Results. The following GCV concentrations (mean ± SD) were determined: with CrCl of ≥70 ml/min, the minimum steady-state concentration (C(min)) and maximum concentration (C(max)) were 0.78 ± 0.46 μg/ml and 1.42 ± 0.37 μg/ml, respectively, with a 24-hr area under the concentration time curve (AUC0-24) of 24.7 ± 7.8 μg·hr/ml; with CrCl of 50-69 ml/min, the C(min) and C(max) were 1.93 ± 0.48 and 2.57 ± 0.39 μg/ml, respectively, with an AUC0-24 of 52.1 ± 10.1 μg·hr/ml; with CrCl of 25-50 ml/min, the C(min) and C(max) were 0.41 ± 0.27 and 1.17 ± 0.32 μg/ml, respectively, with an AUC0-24 of 14.6 ± 7.4 μg·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 μg/ml, respectively, with an AUC0-24 of 10.7 μg*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 μg/ml, respectively, with a mean AUC0-24 of 64.6 ± 18.8 μg·hr/ml. Absolute bioavailability, for the nine patients so analyzed, was 7.2 ± 2.4%. For those patients with end-stage renal failure, GCV concentrations fell during dialysis from a mean of 1.47 ± 0.48 μg/ml before dialysis to 0.69 ± 0.38 μg/ml after dialysis. Conclusions. The bioavailability of oral GCV in transplant patients was similar to that observed in human immunodeficiency virus-infected patients. However, levels between 0.5 and 1 mg/ml (within the IC50 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 dialysis. For patients with CrCl between 10 and 50 ml/min, the levels achieved were low and these patients would likely benefit from increased doses.
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