Pharmacokinetics in children

Valganciclovir is a prodrug of ganciclovir. It is well absorbed from the gastrointestinal tract and rapidly and extensively metabolised to ganciclovir.

Bioavailability of ganciclovir (when valganciclovir is administered orally) is approximately 60% in all patient populations. The resulting concentration of ganciclovir after administration of oral valganciclovir is comparable to the concentration of ganciclovir after intravenous administration of ganciclovir. Adults: 1800 mg orally (valganciclovir) corresponds to 10 mg/kg intravenously (ganciclovir) in 2 doses

The following table shows pharmacokinetic parameters in adults (mean + SD) compared to the paediatric population for prophylaxis of CMV infection after organ transplantation. The single daily dose of valganciclovir (900mg) in this study was calculated based on the body surface area:

PK Parameter	Adults*	Children and adolescents
	≥18 years (n=160)	<4 months (n=14)	4 months- ≤2 years (n=17)	>2 years - <12 years (n=21)	≥12 years - 16 years (n=25)
AUC0 – 24h (μg ∙ h/ml)	46,3 ± 15,2	68,1 ± 19,8	64,3 ± 29,2	59,2 ± 15,1	50,3 ± 15,0
AUC0 – 24h-range	15,4 – 116,1	34 – 124	34 – 152	36 – 108	22 – 93
Cmax (μg/mL)	5,3 ± 1,5	10,5 ± 3,36	10,3 ± 3,3	9,4 ± 2,7	8,0 ± 2,4
Clearance (L/h)	12,7 ± 4,5	1,25 ± 0,473	2,5 ± 2,4	4,5 ± 2,9	6,4 ± 2,9
t1/2 (h)	6,5 ± 1,4	1,97 ± 0,185	3,1 ±1,4	4,1 ± 1,3	5,5 ± 1,1

* data from study report PV 16000

The following table shows pharmacokinetic parameters (mean + SD) in newborns and infants for the therapy of congenital CMV infection:

PK Parameter	16 mg/kg valganciclovir twice daily (n=19)	16 mg/kg valganciclovir twice daily (n=100)
AUC0 – 12h (μg ∙ h/ml)	38,2 ± 42,7	20,85 ± 5,40
Cmax (μg/mL)	5,44 ± 4,04	-
t1/2 (h)	2,98 ± 1,26	2,98 ± 1,12

SmPC Valcyte

dose recommendation of formulary compared to licensed use (on-label versus off-label)

No information is present at this moment.

Available formulations

No information is present at this moment.

Dosages

Prophylaxis of CMV in organ and stem cell transplants
Oral 1 month up to 18 years [5] [8] [27] [31] [32] [33] [34] [36] [38] 15 mg/kg/day in 1 dose. Max: 900 mg/day. Dose may be increased to 20 mg/kg/day in 1 dose if needed.

(Congenital) CMV infection
Oral Term neonate [13] [14] [15] [16] [18] [28] [35] [40] 32 mg/kg/day in 2 doses. Dose adjustment depending on the effect (CMV viral load) and/or ganciclovir plasma concentration. 1 month up to 18 years [28] [35] [40] 32 mg/kg/day in 2 doses. Dose adjustment depending on the effect (CMV viral load) and/or ganciclovir plasma concentration.

Treatment of CMV infection after organ and stem cell transplantation
Oral 1 month up to 18 years [16] [37] 32 mg/kg/day in 2 doses. Dose adjustment depending on the effect (CMV viral load) and/or ganciclovir plasma concentration.

Preemptive therapy of CMV in organ and stem cell transplants
Oral 1 month up to 18 years [29] [30] [39] 20 mg/kg/day in 2 doses.

Renal impaiment in children > 3 months

Adjustment in renal impairment as specified:

GFR 50-80 ml/min/1.73 m2

100 percentage of single dose and dosing interval : 24 uur

GFR 30-50 ml/min/1.73 m2

Dose adjustment depending on concentration, interval between 2 doses is 48 hours

GFR 10-30 ml/min/1.73 m2

Dose adjustment depending on concentration, interval between 2 doses is 48 hours

GFR < 10 ml/min/1.73 m2

Dose adjustment depending on concentration, interval between 2 doses is 48-96 hours

The complete list of all undesirable drug reactions can be found in the national Summary of Product Characteristics (SmPC) – click here

Side effects in children

Lower incidence of nausea, constipation and rejection of the donor organ. Higher incidences of upper respiratory tract infection, vomiting and pyrexia. [Vaudry 2009: side effects in italic: possibly not related to treatment and it concerns a cross-study comparison]

The most commonly reported adverse reactions in paediatric clinical trials were diarrhoea, nausea, neutropenia, leucopenia and anaemia. The overall safety profile in children and adolescents after organ transplantation was comparable to adults. [SmPC Valcyte]

The complete list of all contra-indications can be found in the national Summary of Product Characteristics (SmPC) – click here

Contra-indications

No information available on specific contra indications in children.

The complete list of all warnings and precautions can be found in the national Summary of Product Characteristics (SmPC) – click here

Warnings & precautions in children

Determine the creatinine level twice a week.

Ganciclovir oral CANNOT be converted 1:1 to valganciclovir oral. The bioavailability of valganciclovir is about 10 times higher.

Potentially carcinogenic and teratogenic.

[SmPC Valcyte]

Therapeutic Drug Monitoring
Similar to ganciclovir -> There is no agreement yet on whether to routinely perform TDM due to the lack of PK/PD data. According to the NVZA, the evidence level for performing TDM is 4 (Level 4: do not perform routine TDM. Consider performing TDM selectively only in special cases, for example, to investigate toxicity, ineffectiveness/compliance or the effect of pharmacokinetic interactions) [NVZA monograph Ganciclovir].. TDM in special populations with unpredictable PK/PD profiles, i.e. patients with unstable renal function, younger children, or patients with suspected resistance may be considered . Despite the uncertainty surrounding the benefits of TDM in general, it may provide some guidance in these cases.

Interactions

The complete list of all interactions can be found in the national Summary of Product Characteristics (SmPC) – click here

Nucleosides and nucleotides excl. reverse transcriptase inhibitors
	Aciclovir Related Medicines Menu">	J05AB01
	Ribavirin Related Medicines Menu">	J05AB04
	Valaciclovir Related Medicines Menu">	J05AB11

Protease inhibitors
	Darunavir Related Medicines Menu">	J05AE10
	Ritonavir Related Medicines Menu">	J05AE03

Nucleoside and nucleotide reverse transcriptase inhibitors
	Entecavir Related Medicines Menu">	J05AF10
	Lamivudine Related Medicines Menu">	J05AF05
	Zidovudine Related Medicines Menu">	J05AF01

Non-nucleoside reverse transcriptase inhibitors
	Nevirapine Related Medicines Menu">	J05AG01

Neuraminidase inhibitors
	Oseltamivir Related Medicines Menu">	J05AH02

Antivirals for treatment of HIV infections, combinations
	Abacavir + lamivudine Related Medicines Menu">	J05AR02
	Lopinavir + ritonavir Related Medicines Menu">	J05AR10

Other antivirals
	Dolutegravir	J05AX12
	Raltegravir	J05AX08

ANTIVIRALS FOR TREATMENT OF HIV INFECTIONS, COMBINATIONS
	Abacavir + lamivudine Related Medicines Menu">	J05AR02
	Lopinavir + ritonavir Related Medicines Menu">	J05AR10

Antivirals for treatment of HCV infections
	Glecaprevir + Pibrentasvir Related Medicines Menu">	J05AP57
	Sofosbuvir Related Medicines Menu">	J05AP08
	Sofosbuvir + Velpatasvir Related Medicines Menu">	J05AP55

References

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21. Hexal, SmPC Valganciclovir HEXAL 450 mg Filmtabletten (90601.00.00), 12/2014
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23. Roche, SmPC Valcyte® 50 mg/ml Pulver zur Herstellung einer Lösung zum Einnehmen (68145.00.00), 03/2015
24. AVOXA, ABDA-Datenbank Wirkstoffdossier Valganciclovir, Letzte Bearbeitung 04/2011, aufgerufen am 13.03.2019
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26. Lexicomp® Drug Interactions, Valganciclovir, accessed 05/2019
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28. Ortiz-Gracia A, et al., Assessment of mitochondrial toxicity in newborns and infants with congenital cytomegalovirus infection treated with valganciclovir. , Arch Dis Child, 2022, 107(7), 686-91
29. Franck B, et al., Population pharmacokinetics of ganciclovir and valganciclovir in paediatric solid organ and stem cell transplant recipients., Br J Clin Pharmacol., 2021, 87(8), 3105-14
30. Ueno T, et al., One Year of Preemptive Valganciclovir Administration in Children After Liver Transplantation., Transplant Proc, 2020, 52(6), 1852-4
31. Patel A, Le K, Panek N. , Evaluation of valganciclovir's neutropenia risk in pediatric solid organ transplant recipients utilizing two dosing regimens., Pediatr Transplant., 2024, ;28(2), e14714
32. Liverman R, et al., Incidence of cytomegalovirus DNAemia in pediatric kidney, liver, and heart transplant recipients: Efficacy and risk factors associated with failure of weight-based dosed valganciclovir prophylaxis., Pediatr Transplant, 2023, 27(4), e14493
33. Peled O, et al., Valganciclovir Dosing for Cytomegalovirus Prophylaxis in Pediatric Solid-organ Transplant Recipients: A Prospective Pharmacokinetic Study., Pediatr Infect Dis J, 2017, 36(8), 745-50
34. Demirhan S, et al., Body surface area compared to body weight dosing of valganciclovir is associated with increased toxicity in pediatric solid organ transplantation recipients., Am J Transplant., 2023, 23(12), 1961-71
35. Mahmud et al., Efficacy and Safety of Valganciclovir in Congenital Cytomegalovirus Infection with Isolated Intrahepatic Cholestasis: A Randomized Controlled Trial., Pediatr Gastroenterol Hepatol Nutr., 2024, 27(5), 298-312
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