Pharmacokinetics in children

There is wide variation between individuals in the pharmacokinetics of amikacin in neonates. The clearance increases most in the first 2 months of life, reaching a plateau at about 2 years of age, after which it slowly increases until 7 years of age.  In contrast, the volume of distribution decreases in the first 2 months, and then remains stable until about 2 years of age, after which the volume of distribution decreases some more until a reading time of 7 years [Treluyer]. The following kinetic parameters were found:

	Premature infants	1-2 days old (n=18)(Vucivecic 2014)	3-28 days old (n=13)(Vucivecic 2014)	> 6 months old
Vd		0.68 l/kg	0.62 l/kg
Cl		65.11 ml/hour/kg	79.98 ml/hour/kg79.98 ml/hour/kg
t½	7-8 hours	6.94 hours	5.64 hours	1.6-2.9 hours

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

Infection in cystic fibrosis
Intravenous 1 month up to 18 years [1] 20 - 30 mg/kg/day in 1 dose Administer over 30 min. Adjust the dose depending on the plasma concentration.

Short-term treatment of severe infections caused by amikacin-sensitive strains of Gram-negative microorganisms, including Pseudomonas species, particularly if they are resistant to other aminoglycosides.

Intravenous Premature infants Postnatal age 0 days up to 14 days and < 1200 g [19] 16 mg/kg per 48 hours in 1 dose Directions for administration: administer over 30 minutes Dose depending on plasma concentration. Determine the trough level before the second dose. Premature infants Postnatal age 0 days up to 14 days and 1200 up to 2800 g [19] 15 mg/kg per 36 hours in 1 dose Directions for administration: Administer over 30 min Dose depending on plasma concentration. Determine the trough level before the second dose. Premature infants Postnatal age 0 days up to 14 days and ≥ 2800 g [19] 15 mg/kg/day in 1 dose Dose depending on plasma concentration. Determine the trough level before the second dose.. Directions for administration: Administer over 30 min. Premature infants Postnatal age 14 days up to 1 month and < 1200 g [19] 20 mg/kg per 36 hours in 1 dose Directions for administration: Administer over 30 min. Dose depending on plasma concentration. Determine the trough level before the second dose. Premature infants Postnatal age 14 days up to 1 month and ≥ 1200 g [19] 18 mg/kg/day in 1 dose Directions for administration: Administer over 30 min. Dose depending on plasma concentration. Determine the trough level before the second dose. Term neonate [4] [11] [15] 15 mg/kg/day in 1 dose Directions for administration: Administer over 30 min Dose depending on plasma concentration. Determine the trough level before the second dose. 1 month up to 18 years [5] [6] [7] [9] [11] [17] 15 mg/kg/day in 1 dose. Max: 1.500 mg/day. Directions for administration: Administer over 30 min Dose depending on plasma concentration. Determine the trough level before the second dose.

Renal impaiment in children > 3 months

Adjustment in renal impairment as specified:

GFR 50-80 ml/min/1.73 m2

Dose reduction and interval lengthening: Depending on the levels (see warnings and precautions)

GFR 30-50 ml/min/1.73 m2

Dose reduction and interval lengthening: Depending on the levels (see warnings and precautions)

GFR 10-30 ml/min/1.73 m2

Dose reduction and interval lengthening: Depending on the levels (see warnings and precautions)

GFR < 10 ml/min/1.73 m2

Dose reduction and interval lengthening: Depending on the levels (see warnings and precautions)

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

Nephrotoxicity, ototoxicity, neuromuscular blockade and allergic reactions.

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

Amikacin doses should be adjusted depending on the plasma concentrations. The length of treatment must be as short as possible, preferably no longer than 7 days and not exceeding 10 days. If the treatment lasts any longer, the risk of ototoxicity and nephrotoxicity increases, as it does for continuous high peak and trough concentrations, renal function disorders, previous use of aminoglycosides, premature infants and neonates. In these cases, good hydration (to reduce the risk of kidney damage) and checks of the renal function and hearing are extremely important.

In premature infants and neonates, the kidney function is not yet fully developed, so the half-life of the drug is extended.
Target concentrations (Dutch Association of Hospital Pharmacists – Therapeutic drug monitoring of amikacin)
Peak concentration: 15-30 mg/l
Trough level: < 5 mg/l

 

 

Interactions

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

• ANTIINFECTIVES FOR SYSTEMIC USE
• ANTIBACTERIALS FOR SYSTEMIC USE

AMINOGLYCOSIDE ANTIBACTERIALS

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

Other aminoglycosides
	Gentamicin Related Medicines Menu">	J01GB03

References

1. Hartwig NC, et al, Vademecum pediatrische antimicrobiele therapie, 2005
2. Wilhelm, B et al, Toegepaste farmokinetiek: Amikacin TDM, www.nvza.nl
3. Allegaert K, et al, Limited predictability of amikacin clearance in extreme premature neonates at birth, Br J Clin Pharmacol, 2005, 61, 39-48
4. Botha JH, et al, Determination of population pharmacokinetic parameters for amikacin in neonates using mixed-effect models, Eur J Clin Pharmacol, 1998, 53, 337-41
5. Bouffet E, et al, Once daily antibiotic regimen in paediatric oncology, Arch Dis Child, 1994, 70, 484-7
6. Forsyth NB, et al, A comparison of two amikacin dosing regimens in paediatric surgical patients, Ann Trop Paediatr, 1997, 17, 253-61
7. Guadalupe Vásquez-Mendoza M, et al, Efficacy and renal toxicity of one daily dose of amikacin versus conventional dosage regime, Am J Perinatol, 2007, 24, 141-6
8. Kenyon CF, et al, Amikacin pharmacokinetics and suggested dosage modifications for the preterm infant., Antimicrob Agents Chemother, 1990, 34, 265-8
9. Krivoy N, et al, Pharmacokinetic analysis of amikacin twice and single daily dosage in immunocompromised pediatric patients, Infection, 1998, 26, 396-8
10. Kotze A, et al, Once versus twice daily amikacin in neonates: prospective study on toxicity, J Paediatr Child Health, 1999, 35, 283-6
11. Langhendries JP, et al, Adaptation in neonatology of the once-daily concept of aminoglycoside administration: evaluation of a dosing chart for amikacin in an intensive care unit., Biol Neonate., 1998, 74, 351-62
12. Langhendries JP, et al, Once-a-day administration of amikacin in neonates: assessment of nephrotoxicity and ototoxicity, Dev Pharmacol Ther, 1993, 20, 220-30
13. Marik PE, et al, The pharmacokinetic of amikacin in critically ill adult and paediatric patients: comparison of once- versus twice-daily dosing regimens, J Antimicrob Chemother, 1991, 27, 81-9
14. Padovani EM, et al, Pharmacokinetics of amikacin in neonates, Dev Pharmacol Ther, 1993, 20, 167-73
15. Sherwin CM, et al, Individualised dosing of amikacin in neonates: a pharmacokinetic/pharmacodynamic analysis., Eur J Clin Pharmacol, 2009, 65, 705-13
16. Tréluyer JM, et al, Nonparametric population pharmacokinetic analysis of amikacin in neonates, infants, and children, Antimicrob Agents Chemother, 2002, 46, 1381-7
17. Vogelstein B, et al, The pharmacokinetics of amikacin in children., J Pediatr., 1977, 91 (2), 333-9
18. Pacifici GM. , Clinical pharmacokinetics of aminoglycosides in the neonate: a review. , Eur J Clin Pharmacol., 2009, Apr:65(4), 419-27
19. Smits A et al., Prospective Evaluation of a Model-Based Dosing Regimen for Amikacin in Preterm and Term Neonates in Clinical Practice. , Antimicrob Agents Chemother. , 2015, Oct;59(10), 6344-6351
20. Sturkenboom MGG et al, Therapeutic drug monitoring: amikacine, www.tdm-monografie.org, 16-10-2014
21. Vucicevic K et al. , Pharmacokinetic variability of amikacin after once-daily and twice-daily dosing regimen in full-term neonates. , J Pharmacol Sci., 2014, 124(2), 138-43

Changes

Therapeutic Drug Monitoring

Overdose