Ganciclovir and Valganciclovir Use in Children

Marcia L. Buck, Pharm.D., FCCP, FPPAG

Disclosures

Pediatr Pharm. 2009;15(10) 

In This Article

Pharmacokinetics

Ganciclovir is poorly absorbed after oral administration, with a bioavailability of approximately 5%. Administration with food increased bioavailability slightly to 6–10%. After oral administration of standard adult doses, maximum serum ganciclovir concentrations typically are 0.5 to 1.5 mcg/mL. After IV administration, maximum serum ganciclovir concentrations of 7 to 19 mcg/mL are typically achieved. Oral bioavailability is significantly improved with valganciclovir, with an average value of 59.4±6.1% reported from premarketing clinical trials in adults. The mean maximum serum ganciclovir concentration achieved after valganciclovir administration (with food) was 5.61±1.52 mcg/mL.[2–4]

At steady-state, the volume of distribution of ganciclovir is approximately 0.74±0.15 L/kg. Ganciclovir is only minimally bound to serum proteins (1–2%). Ganciclovir is primarily eliminated through renal glomerular filtration and active tubular secretion. Over 90% of a dose is eliminated as unchanged drug. The average elimination half-life is approximately 3 to 5 hours in adults. Renal impairment significantly reduces ganciclovir clearance. In patients with severe renal impairment, elimination half life may exceed 20 to 50 hours. Hemodialysis reduces ganciclovir serum concentrations by approximately 50%.[2–4]

The pharmacokinetic profile of ganciclovir and valganciclovir in infants and children has been evaluated in several studies. In 1993, Trang and colleagues evaluated the pharmacokinetic characteristics of IV ganciclovir in 27 neonates (2 to 49 days of age).[5] The maximum serum concentration was 5.5±1.6 mcg/mL after a dose of 4 mg/kg and 7.0±1.6 mcg/mL after 6 mg/kg. Mean volume of distribution was 669±70 mL/kg for the 4 mg/kg group and 749±59 mL/kg for the 6 mg/kg group. Volume of distribution increased with increasing weight (r = 0.689, p = 0.0001). The mean elimination half-life was 2.4 hours.

In a 2003 study by Zhang and colleagues conducted in 11 children (mean age 11.0±3.9 years), the maximum concentration after an IV dose of 5 mg/kg given every 12 hours for 15 days was 11.77±2.82 mcg/mL, with an AUC of 42.29±17.57 mcg·hr/mL.[6] Administration of an oral dose of 50 mg/kg every 12 hours for 3 months produced a maximum concentration of 2.70±1.07 mcg/mL and an AUC of 18.97±9.36 mcg·hr/mL. The authors concluded that the doses administered produced adequate serum ganciclovir concentrations for treatment.

The pharmacokinetics of valganciclovir in children were first described in a case report of a 6 year old girl with CMV.[7] A single 4.4 mg/kg IV ganciclovir dose was compared to 13.2 mg/kg and 26.3 mg/kg oral valganciclovir doses. The two doses of valganciclovir provided area under the serum concentration-time curve (AUC) values of 14.3 and 28.7 mcg·hr/mL, respectively. Earlier this year, Zhao and colleagues utilized nonlinear mixed-effects modeling (NONMEM) techniques to evaluate valganciclovir pharmacokinetics in 22 renal transplant patients between 3 and 17 years of age.[8] The model provided an estimated systemic clearance value of 10.1 L/hr (or 0.30 L/hr/kg), with a volume of distribution of 5.2 L, similar to values reported in adults. Based on their model, the authors suggest that a valganciclovir dose of approximately 500 mg once daily would produce an AUC of 43±10.6 mcg·hr/mL, thus achieving adequate concentrations for CMV prophylaxis.

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