Linear single-dose pharmacokinetics of ganciclovir in newborns with congenital cytomegalovirus infections

Abstract

The pharmacokinetic characteristics of ganciclovir were determined in neonates (age range, 2 to 49 days) after an 1-hour intravenous infusion of a single dose of either 4 mg/kg (n = 14) or 6 mg/kg (n = 13). Twenty-seven newborns with symptomatic cytomegalovirus inclusion disease were enrolled in this open phase I-II pharmacokinetics, safety, and tolerance trial of ganciclovir at one of two doses. Ganciclovir disposition was best described by a one-compartment open model with zero-order input and first-order elimination. The mean elimination half-life (t1/2) for both dose groups was 2.4 hours. The mean apparent volume of distribution (Vd) was 669 +/- 70 ml/kg for the 4 mg/kg group and 749 +/- 59 ml/kg for the 6 mg/kg group. The mean total body clearance (CL) for the 4 mg/kg and 6 mg/kg groups was 189 +/- 28 ml/hr/kg and 213 +/- 21 ml/hr/kg, respectively. No significant differences were observed in Vd or CL between the two groups. The Vd, expressed in milliliters, increased with increasing patient weight (r = 0.689; p = 0.0001). The CL, expressed in milliliters per hour per kilogram, increased with increasing age (r = 0.413; p = 0.032). No significant differences were observed between the two dose groups for the area under the curve normalized for dose (AUC/Dose) or the maximum plasma concentration normalized for dose (Cmax/Dose), indicating that ganciclovir exhibited linear pharmacokinetics in these neonates.

Pharmacokinetic and Pharmacodynamic Assessment of Oral Valganciclovir in the Treatment of Symptomatic Congenital Cytomegalovirus Disease

“…Within 2 weeks, the concentration-time results of the subject were returned to the National Institute of Allergy and Infectious Diseases (NIAID) Collaborative Antiviral Study Group (CASG) Central Unit, and the subject's area under the concentration-time curve value measured over a 12-h period (AUC 12 ) was calculated. This value was then compared with the target AUC 12 range (target value, 27 mg ϫ h/L; range considered to be acceptable, 20 -55 mg ϫ h/L, which denotes the 10th to 90th percentile around the target) that had been derived from an earlier CASG phase 2 investigation of intravenous ganciclovir [17]. If the AUC 12 value of the subject was within the range considered to be acceptable, intravenous ganciclovir was stopped, and oral valganciclovir was restarted at the same dose per kilogram used for the subject's first dose.…”

“…Previous studies of the treatment of infants with symptomatic CMV disease involved administration of intravenous ganciclovir (6 mg/kg every 12 h) for 6 weeks [17,18], demonstrating both virologic [19] and clinical [20,21] benefit. Specifically, infants with symptomatic congenital CMV disease involving the central nervous system (CNS) who are treated with intravenous ganciclovir for 6 weeks experience less hearing loss [20] and may develop fewer neurodevelopmental deficits [21] than infants who are not treated.…”

A candidate live inactivatable attenuated vaccine for AIDS.

“…Ideally, the live inactivatable vaccine would be available for use in adults and would be employable in the neonate, to control accidental and maternal transmission. The safety of GCV use in neonates and infants is well documented (36,37). The molecular cloned viruses described above will also serve as intermediates for future gene therapies that employ a conditionally lethal delivery virus.…”

A rapid and sensitive method for the quantification of ganciclovir in plasma using liquid chromatography/selected reaction monitoring/mass spectrometry

“…A critical component of this approach involves the ability to rapidly and specifically monitor plasma levels of GCV so that appropriate pharmacokinetic models can be constructed and optimal dosing strategies developed. For quantitative analysis of GCV, assays have been performed primarily by high-performance liquid chromatography (HPLC) (Boulieu et al, 1991a,b;Fletcher et al, 1986;Trang et al, 1993). It was reported by Campanero et al (1998) and Page et al (1996) that the limit of quantitation of GCV was at 50 ng/mL in plasma or serum using HPLC with UV detection.…”