Population pharmacokinetics of ganciclovir after intravenous ganciclovir and oral valganciclovir administration in solid organ transplant patients infected with cytomegalovirus

Abstract

A population pharmacokinetics analysis was performed after intravenous ganciclovir and oral valganciclovir in solid organ transplant patients with cytomegalovirus. Patients received ganciclovir at 5 mg/kg of body weight (5 days) and then 900 mg of valganciclovir (16 days), both twice daily with dose adjustment for renal function. A total of 382 serum concentrations from days 5 and 15 were analyzed with NONMEM VI. Renal function given by creatinine clearance (CL(CR)) was the most influential covariate in CL. The final pharmacokinetic parameters were as follows: ganciclovir clearance (CL) was 7.49.(CL(CR)/57) liter/h (57 was the mean population value of CL(CR)); the central and peripheral distribution volumes were 31.9 liters and 32.0 liters, respectively; intercompartmental clearance was 10.2 liter/h; the first-order absorption rate constant was 0.895 h(-1); bioavailability was 0.825; and lag time was 0.382 h. The CL(CR) was the best predictor of CL, making dose adjustment by this covariate important to achieve the most efficacious ganciclovir exposure.

Trial registration: ClinicalTrials.gov NCT00730769.

Figures

FIG. 1.

Ganciclovir serum concentrations versus time postdose following i.v. administration of ganciclovir (left) and oral administration of valganciclovir (right) in SOT patients. Circles represent observed ganciclovir concentrations. Solid lines represent the smooth line indicating the general data trend.

FIG. 2.

Goodness-of-fit plots for the population pharmacokinetics model. Upper panels show results for i.v. administration of ganciclovir and lower panels show results for oral administration of valganciclovir. Ganciclovir concentrations are given in μg/ml and time in hours from the start of the treatment. DV, observed concentrations; PRED, population predictions; IPRED, individual predictions; CWRES, conditional weighted residuals; dashed line, identity line; solid line, smooth line indicating the general trend of the data.

FIG. 3.

Superimposed values of the observed (DV, open circles), individually predicted (IPRED, solid line), and population-predicted (PRED, dashed lines) ganciclovir serum concentrations versus time postdose in two patients belonging to the population studied, showing CLCR values of 73 and 38 ml/min, respectively, after both i.v. ganciclovir (left) and oral valganciclovir (right) administration.

FIG. 4.

Relationship between ganciclovir exposure (AUC) and estimated CLCR in SOT patients after administration of i.v. ganciclovir (left) and oral valganciclovir (right) according to the manufacturer's recommended dosage. Vertical lines show dosage adjustments based on CLCR. Horizontal lines show the AUCtarget value that was considered efficacious.

FIG. 5.

Simulated ganciclovir serum concentrations versus time. Mean and 95% CIs obtained from 1,000 simulations of ganciclovir serum concentration-time profiles after i.v. administration of ganciclovir (left) and oral administration of valganciclovir (right) to patients showing CLCR values of 20, 60, and 90 ml/min and 66.2 kg of body weight and treated according to the manufacturer's recommendations. Solid lines show 50th-percentile mean predictions, and dotted lines show 2.5th and 97.5th percentiles.