Pharmacokinetics in children

 

The following pharmacokinetic parameters have been found in a PopPK study in immunocompromised children (1.4 – 18.1 years) (n=120) undergoing prophylaxis or treatment for HSV-VZV infection during hematopoietic stem cell transplant (HSCT) or chemotherapy, after IV administration [6]:Acyclovir is partially metabolized into 9-carboxymethoxymethylguanine, while the remaining portion is excreted unchanged in the urine. Acyclovir is primarily excreted through the kidneys, with 75-80% of the drug eliminated unchanged via glomerular filtration and tubular secretion. The remaining 10-15% is excreted in the urine as 9-carboxymethoxymethylguanine. In adults with normal renal function, the plasma elimination half-life is approximately 2.9 hours [SmPC, Drugbank].

The body weight and renal function influence the clearance of acyclovir; an increased body weight is associated with higher clearance[Abdalla 2020; Zeng 2009; Maximova 2022]

The following kinetic parameters are available for preterm and term neonates [Hintz M 1982, Sampson MR 2014, Blum MR 1984]: 

PMA	<30 weeks (n=13)	30 - 35 weeks (n=9)	36-41 weeks (n=6)
Dose	20 mg/kg/Tag	20/40/60 mg/kg/Tag	60 mg/kg/Tag
Cmax (mg/l)	10.3 (4.59-110)	8.83 (5.44-29.8)	12.4 (10.8-86.1)
t½ (h)	10.2 (4.73-13.2)	6.55 (4.28-9.26)	3.0 (1.61-3.69)
Cl (l/h/kg)	0.211 (0.095-0.31)	0.449 (0.302-0.812)	0.59 (0.126-0.77)
Vd (l/kg)	2.88 (0.646-5.30)	4.49 (1.87-10.85)	2.55 (0.293-4.09)

 

Dose	5 mg/kg	10 mg/kg	15 mg/kg
Cmax (µM)	30.0 ± 9.9	61.2 ± 18.3	86.1 ± 23.5
t½ (h)	4.03 ± 1.56	4.07 ± 1.53	3.24 ± 0.69
Cl (ml/min/1.73 m²)	122 ± 51	98 ± 34	108 ± 43
Vd (l/1.73 m²)	30.0 ± 2.0	28.9 ± 11.3	24.1 ± 6.3

The following pharmacokinetic parameters have been found in immunocompromised children (1.4 – 18.1 years) (n=18) with cancer, after IV administration [Eksborg 2002]:

	Mean [median] (range)
Dosis mg/kg	[10,5] 4,9-23,3
AUC (µmol/hr/L)	113 (59-224)
AUC (mg/kg)	11.09 (5,33-21,39)
AUC (mg/m2)	0,423 (0,221-0,754)
Cmax (µmol/L)	62,4 (29,2-120,7)
T1/2 (hr)	1,80 (1,20-3,29)

The following pharmacokinetic parameters have been found in a PopPK study in immunocompromised children (1.4 – 18.1 years) (n=120) undergoing prophylaxis or treatment for HSV-VZV infection during hematopoietic stem cell transplant (HSCT) or chemotherapy, after IV administration [Maximova 2022]:

	Mean ± SD
Dose (mg)	334 ±158,2
AUC (mg/hr/L)	26 ± 13,2
Cl (L/hr)	14 ± 5,5
Vd (L)	25,4 ± 8,7
T1/2 (hr)	1,364 ± 0,614

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

HSV/VSV infection
Oral 1 month up to 18 years [4] [6] The bioavailability of oral aciclovir is very poor. For oral application, treatment with valaciclovir is therefore preferred.

Herpes simplex infections (normal and deficient immune response), recurrent Varicella zoster infection (normal immune response)
Intravenous 3 months up to 12 years [5] 30 mg/kg/day in 3 doses. Duration of treatment: 10 days 12 years up to 18 years [5] 15 mg/kg/day in 3 doses. Duration of treatment: 5 dagen

Herpes simplex encephalitis (normal immune system); primary and recurrent Varicella Zoster infection in immuno-compromised children

Intravenous Premature neonates: Gestational age < 37 weeks [8] [25] 60 mg/kg/day in 3 doses. Duration of treatment: Herpes encephalitis: 14-21 days Varicella zoster: 7 days Full-term neonates and infants Term neonate [8] [10] [16] [25] [33] [35] 60 mg/kg/day in 3 doses. Duration of treatment: Herpes encephalitis: 14-21 days Varicella zoster: 7 days 1 month up to 3 months [10] [25] [38] 60 mg/kg/day in 3 doses. Duration of treatment: Herpes encephalitis: 14-21 days Varicella zoster: 7 days 3 months up to 18 years [5] [10] [14] [17] [18] [20] [22] [23] [38] [44] [45] [47] 30 mg/kg/day in 3 doses.

Herpes neonatorum

Intravenous Prematuren Gestational age < 37 weeks [8] [25] [34] 60 mg/kg/day in 3 doses. Duration of treatment: CNS and disseminated disease: 21 days Limited to local disease (skin, eye, mouth): 14 days Term neonate [5] [8] [10] [12] [13] [14] [16] [25] [33] [34] [35] 60 mg/kg/day in 3 doses. Duration of treatment: CNS and disseminated disease: 21 days Limited to local disease (skin, eye, mouth): 14 days

Herpes-simplex-Enzephalitis (immunkompetent); primäre/rezidivierende Varicella-Zoster-Infektion (immungeschwächt)
Intravenous Premature neonates: Gestational age < 37 weeks [8] [25] 60 mg/kg/day in 3 doses. Term neonate [8] [10] [16] [35] 60 mg/kg/day in 3 doses. 1 month up to 3 months [38] 60 mg/kg/day in 3 doses. 3 months up to 18 years [29] 45 mg/kg/day in 3 doses.

Renal impaiment in children > 3 months

Adjustment in renal impairment as specified:

GFR 50-80 ml/min/1.73 m2

No dose adjustment needed.

GFR 30-50 ml/min/1.73 m2

100 percentage of single dose and dosing interval : 12 uur

GFR 10-30 ml/min/1.73 m2

100 percentage of single dose and dosing interval : 24 uur

GFR < 10 ml/min/1.73 m2

50 percentage of single dose and dosing interval : 24 uur Generalized recommendations cannot be given. Discuss with the paediatric nephrologist.

Clinical consequences

Risk of neurological reactions, including hallucinations, convulsions and coma. Increase of urea and creatinine concentrations, followed by renal failure; in this case, the infusion time should be extended.

Adjusting the dose influences the trough level. If the trough level is not high enough, the antiviral effect may not be sufficient; this can lead to resistance.

Patients on dialysis

Hemodialysis: 50% of normal single dose and interval between doses: 24 hours. Administer on dialysis days after dialysis

CVVH: 100% of the normal dose and interval between two doses: 24 hours, based on drugconcentration levels.

 

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

In neonates: watch for neutropenia (in about 20%; usually resolves spontenously during use or after discontinuation) and reduction in renal function (nephrotoxic in about 6%).

Anecdotal reports have described neurotoxicity and nephrotoxicity in children older than 3 months receiving doses of 60 mg/kg/day. Issues of neurotoxicity with higher doses of acyclovir have not been observed in neonates and infants under 3 months of age [Kimberlin 2013].

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

• Determination of the blood count every two weeks.
• In high doses or in infusions, monitor the fluid balance, particularly in cases of renal function disorder.
• Dose adjustment is needed for renal function disorders.
• In neonates on high doses of aciclovir, neutropenia and nephrotoxicity must be monitored as these occur in 20% and 6% of cases respectively.
• Determine the creatinine twice weekly. For oral application, valaciclovir is preferred.
• In obese children, dosing based on IBW is preferred (max. dose of 800 mg)[Ross 2015; NHS 2021]

 

Interactions

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

• ANTIINFECTIVES FOR SYSTEMIC USE
• ANTIVIRALS FOR SYSTEMIC USE

DIRECT ACTING ANTIVIRALS

This pages provides a list of drugs from the same ATC class for comparison. This does not necessarily mean that these drugs are interchangeable.

Nucleosides and nucleotides excl. reverse transcriptase inhibitors
	Ribavirin Related Medicines Menu">	J05AB04
	Valaciclovir Related Medicines Menu">	J05AB11
	Valganciclovir Related Medicines Menu">	J05AB14

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

1. Hartwig NC, et al, Vademecum pediatrische antimicrobiele therapie, 2005
2. Rademaker C.M.A. et al, Geneesmiddelen-Formularium voor Kinderen, 2007
3. Nadal D, et al, An investigation of the steady-state pharmacokinetics of oral valacyclovir in immunocompromised children, J Infect Dis, 2002, Oct 15;186 Suppl 1, S123-30
4. Eksborg S, et al, Pharmacokinetics of acyclovir in immunocompromized children with leukopenia and mucositis after chemotherapy: can intravenous acyclovir be substituted by oral valacyclovir?, Med Pediatr Oncol., 2002, 38, 240-6
5. GlaxoSmithKline BV, SPC Zovirax IV (RVG 09696) 09-09-2022, www.geneesmiddeleninformatiebank.nl
6. de Miranda P, et al, Pharmacokinetics of acyclovir after intravenous and oral administration, J Antimicrob Chemother, 1983, Sep;12 Suppl B, 29-37
7. Hintz M, et al, Neonatal acyclovir pharmacokinetics in patients with herpes virus infections., Am J Med, 1982, Jul 20;73(1A), 210-4
8. Kimberlin DW, et al, Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections, Pediatrics, 2001, Aug;108(2), 230-8.
9. Sullender WM, et al, Pharmacokinetics of acyclovir suspension in infants and children, Antimicrob Agents Chemother., 1987, Nov;31(11), 1722-6
10. Enright AM, et al, Antiviral therapy in children with varicella zoster virus and herpes simplex virus infections., Herpes, 2003, Aug;10(2):, 32-7
11. Enright AM, et al, Neonatal herpes infection: diagnosis, treatment and prevention, Semin Neonatol., 2002, Aug;7(4), 283-91
12. Kesson AM, Management of neonatal herpes simplex virus infection, Paediatr Drugs, 2001, 3(2), 81-90
13. Whitley R., Neonatal herpes simplex virus infection., Curr Opin Infect Dis, 2004, Jun;17(3), 243-6
14. Corey L, et al, Maternal and neonatal herpes simplex virus infections., N Engl J Med, 2009, Oct 1;361(14), 1376-85
15. Skoldenberg B, et al., Acyclovir versus vidarabine in herpes simplex encephalitis. Randomised multicentre study in consecutive Swedish patients., Lancet., 1984, Sep 29;2(8405), 707-11
16. Ito Y, et al, Exacerbation of herpes simplex encephalitis after successful treatment with acyclovir., Clin Infect Dis, 2000, Jan;30(1), 185-7
17. Heininger U, et al, Varicella, Lancet, 2006, Oct 14;368(9544), 1365-76
18. Heidl M, et al, Antiviral therapy of varicella-zoster virus infection in immunocompromised children--a prospective randomized study of aciclovir versus brivudin, Infection, 1991, Nov-Dec;19(6), 401-5
19. Shepp DH, et al, Treatment of varicella-zoster virus infection in severely immunocompromised patients. A randomized comparison of acyclovir and vidarabine, N Engl J Med, 1986, Jan 23;314(4), 208-12.
20. Prober CG, et al, Acyclovir therapy of chickenpox in immunosuppressed children--a collaborative study., J Pediatr., 1982, Oct;101(4):622-5, 622-5
21. Whitley RJ, et al, Acyclovir: a decade later, N Engl J Med, 1992, Sep 10;327(11), 782-9
22. Balfour HH, Jr., Intravenous acyclovir therapy for varicella in immunocompromised children, J Pediatr, 1984, Jan;104(1), 134-6
23. HJC de Vries et al, Richtlijn SOA voor de tweede lijn, Nederlandse Vereniging voor Dermatologie en Venereologie (NVDV). , www.huidarts.info, 2012, 114
24. GlaxoSmithKline, SPC Zovirax koortslip (RVG 19078) 10-07-2018, www.geneesmiddeleninformatiebank.nl
25. Werkgroep Neonatale Farmacologie NVK sectie Neonatologie, Expert opinie, 28 maart 2018
26. AVOXA, ABDA-Datenbank Interaktionen (BRD) Aciclovir, accessed 2018-07-12
27. UpToDate®, Pediatric Drug information: Aciclovir Lexicomp® Topic 15938 Version 309.0, accessed 11/2019
28. Hexal, SmPC Acic® Tabletten (30775.00.00), 02/2017
29. Hexal, SmPC Acic® Pulver zur Herstellung einer Infusionslösung (24810.00.00), 02/2018
30. Ratiopharm, SmPC Aciclovir-ratiopharm® 50 mg/g Creme (28080.00.00), 01/2017
31. GlaxoSmithKline, SPC Zovirax oogzalf (RVG 09248) 16-3-2016, www.geneesmiddeleninformatiebank.nl
32. Blum MR et al. 1982 , Overview of acyclovir pharmacokinetic disposition in adults and children., Am J Med. , 1982, Jul 20;73(1A), 186-92
33. Sampson MR et al. , Population pharmacokinetics of intravenous acyclovir in preterm and term infants , Pediatr Infect Dis J, 2014, Jan;33(1), 42-9
34. Ericson JE et al. , Safety of High-dose Acyclovir in Infants With Suspected and Confirmed Neonatal Herpes Simplex Virus Infections. , Pediatr Infect Dis J., 2017, Apr;36(4), 369-373
35. Whitley RJ et al. , The use of antiviral drugs during the neonatal period., Clin Perinatol., 2012, 39(1), 69-81
36. Englund JA et al. , Acyclovir therapy in neonates., J Pediatr., 1991, Jul;119(1 Pt 1), 129-35
37. Zeng L, et al., Population pharmacokinetics of acyclovir in children and young people with malignancy after administration of intravenous acyclovir or oral valacyclovir., Antimicrob Agents Chemother., 2009, Jul;53(7), 2918-27
38. David W. Kimberlin. , Acyclovir Dosing in the Neonatal Period and Beyond, Journal of the Pediatric Infectious Diseases Society, 2013, 2 (2), 179–182
39. National Health Service (NHS), How should medicines be dosed in children who are obese?, Available from: https://www.sps.nhs.uk/articles/how-should-medicines-be-dosed-in-children-who-are-obese/, 2021
40. Maximova N, et al., Population Pharmacokinetics of Intravenous Acyclovir in Oncologic Pediatric Patients., Front Pharmacol., 2022, Apr 14;13, 865871
41. Ross EL,et al., Development of recommendations for dosing of commonly prescribed medications in critically ill obese children., Am J Health Syst Pharm. , 2015, 72(7), 542-56
42. Drugbank., Acyclovir., Available from: https://go.drugbank.com/drugs/DB0078, Accessed June 3, 2024
43. Abdalla S,et al. , Population Pharmacokinetics of Intravenous and Oral Acyclovir and Oral Valacyclovir in Pediatric Population To Optimize Dosing Regimens., Antimicrob Agents Chemother, 2020, Nov 17;64(12), e01426-20
44. Lahat E, et al., Long term neurological outcome of herpes encephalitis. , Arch Dis Child. , 1999, Jan;80(1), 69-71
45. Karli A, et al., Prolonged acyclovir treatment in a child with opercular syndrome related to herpes simplex encephalitis., J Infect Public Health, 2017, Mar-Apr;10(2), 232-234
46. Yalçınkaya R, et al. , Factors associated with acyclovir nephrotoxicity in children: data from 472 pediatric patients from the last 10 years. , Eur J Pediatr., 2021, Aug;180(8), 2521-2527
47. Kuhn N, Landbeck G., Acyclovir-Therapie von Varicella/Zoster-Erkrankungen bei immunsuppressiv behandelten krebskranken Kindern [Acyclovir therapy in varicella/zoster diseases in immunocompromised children with cancer]., Monatsschr Kinderheilkd., 1984, Feb;132(2), 105-9
48. Wade JC, Meyers JD., Neurologic symptoms associated with parenteral acyclovir treatment after marrow transplantation., Ann Intern Med, 1983, Jun;98(6), 921-5
49. Genc G, et al., Acute renal failure with acyclovir treatment in a child with leukemia. , Drug Chem Toxicol., 2010, Apr;33(2), 217-9

Changes

Therapeutic Drug Monitoring

Overdose