Pharmacokinetics in children

Tobramycin is excreted almost entirely via the kidneys by glomerular filtration. (SmPC Gernebcin)

The elimination half-life in neonates (especially premature infants) is extended. This is the result of the larger volume of distribution and lower clearance of tobramycin in this age category. The average half-lives in the various age groups are as follows: Neonates < 1 week, <2 kg: 8 to 11 hours.
Neonates < 1 week, >2 kg: 5 to 6 hours.
Neonates 1 – 4 weeks, >2 kg: 4 hours.
Children from 6 weeks: 1.5 to 3 hours

Other pharmacokinetic parameters:

GA (weeks)	n	BW (g)	Dose	Cl (ml/min/kg)	Vd (l/kg)
28±2	8	805±105	2.5 mg/kg/18 hours or 3 mg/kg once daily	0.69±0.10	0.59±0.01
29-31	6	1000-1300	2.5 mg/kg every 12 or 18 hours	0.72-1.19	0.74-0.94
?	8	3470±380	5 mg/kg |(IM)	4.9±2.5 ml/min	0.49±2.5

PK in neonates during ECMO receiving Gentamicin is widely studied [Buck 2003, Moffett 2018]. There's only one study investigating Tobramycin during ECMO in an animal model [Moller 1992]. Vd is increased (from 0,3 l/kg to 0,5 l/kg) and t1/2 prolonged (from 1,8 h to 2,7 h). These findings are consistent with data of Gentamicin.

Inhalation
The study by Geller et al. In children older than 6 years shows the serum concentration 1 hour after inhalation of a single dose of 300 mg is approximately 0.95 microg / ml. After 20 weeks of therapy, the median serum concentration of tobramycin 1 hour after dosing was 1.05 microg / ml. The bioavailability is approximately 11.7%.

In children <6 years the serum concentration 1 hour after inhalation of 300 mg tobramycin was approximately 0.6 microg / ml (Rosenfeld et al.).

Elimination: by urine (systemically absorbed tobramycin), and probably by coughed up sputum (unabsorbed tobramycin).

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

Sepsis and severe infections

Intravenous Premature infants Postnatal age 0 days up to 7 days Duration of pregnancy < 32 weeks: 4 mg/kg/48 hours in a single dose Duration of pregnancy 32-37 weeks: 4 mg/kg/36 hours in a single dose Intravenous administration in 20-60 minutes. Adjust the dose depending on the plasma concentration.   Premature infants Postnatal age 1 week up to 4 weeks 4 mg/kg/day in 1 dose Intravenous administration in 20-60 minutes. Adjust the dose depending on the plasma concentration Term neonate 4 mg/kg/day in 1 dose Intravenous administration in 20-60 minutes. Adjust the dose depending on the plasma concentration.

Infections in cystic fibrosis

Inhalation Inhalation powder 6 years up to 18 years (Only in chronic infections) 224 mg/day in 2 doses. Duration of treatment: A cycle should be followed comprising 28 days of tobramycin inhalation treatment and 28 days without tobramycin inhalation treatment. After the first cycle, do a sputum culture to check if the eradication was successful. If not, repeat the cycle. Directions for administration: The time between 2 doses should be 12 hours and may not be less than 6 hours If there are multiple respiratory treatments, apply them in the following order: bronchodilator, mucolytic, sputum expectoration, other inhalation drugs and lastly tobramycin nebulization solution or inhalation powder. 6 years up to 18 years [25] (Only in chronic infections) 224 mg/day in 2 doses. Duration of treatment: A cycle should be followed comprising 28 days of tobramycin inhalation treatment and 28 days without tobramycin inhalation treatment. After the first cycle, do a sputum culture to check if the eradication was successful. If not, repeat the cycle. Directions for administration: The time between 2 doses should be 12 hours and may not be less than 6 hours If there are multiple respiratory treatments, apply them in the following order: bronchodilator, mucolytic, sputum expectoration, other inhalation drugs and lastly tobramycin nebulization solution or inhalation powder.

Pulmonary Pseudomonas infections in non-CF patients

Inhalation 1 month up to 18 years [36] [37] No dosage advice is provide due to very limited evidence. There are signals that nebulization of tobramycin (twice daily 80-300 mg) in non-CF patients leads to a higher systemic absorption and renal dysfunction. Early bloodlevel measurement is recommended. 1 month up to 18 years No dosage advice is provide due to very limited evidence. There are signals that nebulization of tobramycin (twice daily 80-300 mg) in non-CF patients leads to a higher systemic absorption and renal dysfunction. Early bloodlevel measurement is recommended. 1 month up to 18 years No dosage advice is provide due to very limited evidence. There are signals that nebulization of tobramycin (twice daily 80-300 mg) in non-CF patients leads to a higher systemic absorption and renal dysfunction. Early bloodlevel measurement is recommended.

Renal impaiment in children > 3 months

Adjustment in renal impairment as specified:

GFR 50-80 ml/min/1.73 m2

First dose: no adjustment, then adjust dose according to serum concentration. (see warnings and precautions)

GFR 30-50 ml/min/1.73 m2

First dose: no adjustment, then adjust dose according to serum concentration. (see warnings and precautions)

GFR 10-30 ml/min/1.73 m2

First dose: no adjustment, then adjust dose according to serum concentration. (see warnings and precautions)

GFR < 10 ml/min/1.73 m2

A general recommendation for dose adjustment is not given.

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

Intravenous use
Nephrotoxicity and ototoxicity, dizziness, muscular weakness or suppression of respiration by neuromuscular transmission disorder, headaches, nausea, vomiting.

Inhaled use
Voice changes, hoarseness, tinnitus, bronchospasm, increased cough, increased sputum, sputum discoloration, dyspnoea, pharyngitis. Nephrotoxicity and ototoxicity (loss of high tones), especially in young children [Guy 2010].

In children under 13 years of age, inhalation of the inhalation powder is more often associated with coughing than inhalation of the nebuliser solution. Coughing has not been associated with bronchospasm. (SmPC)

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

Intravenous use
Dosage should be determined using the measured serum concentrations. For calculating the dose recommendations, two levels are noted. A level shortly after starting the therapy and a level halfway through or right before the next administration. In haemodialysis it is recommended, if practically feasible, that the peak level should be measured before and after dialysis to determine the clearance during dialysis.
Monitoring concentrations:
- weekly in unchanged renal function
- at least twice weekly in changing renal function, IC patients, septic patients, dialysis patients and neonates.

Be cautious in pediatric patients on ECMO-therapy: pharmacokinetics of aminoglykosides might be changed [Moller 1992, Buck 2003, Moffett 2018].

Usual duration of treatment is 7 to 10 days. Longer treatment may be necessary for persistent and complicated infections. Due to nephrotoxic and ototoxic effects, the kidney, hearing and vestibular  functions should be checked carefully. In general, the nephrotoxicity is lower in once daily doses than in multiple doses per day. Nephrotoxicity is expressed in damage to the proximal tubules; if these symptoms appear, adjust the dosage or cease administration. In renal function disorder, when dosing based on the creatinine clearance the sometimes poor correlation of the elimination with creatinine clearance must also be taken into account.
Caution is needed when using this product in patients with neuromuscular transmission disorders or when using anaesthetics and/or neuromuscular transmission blockers.
Check the calcium, magnesium and sodium levels in the blood during the treatment.

Inhaled use
Caution is needed in patients who are known or suspected to have kidney, hearing, balance or neuromuscular transmission disorders or severe active haemoptysis. In inhalation it is recommended to check the renal function before starting the treatment and after each 6 full cycles. If tinnitus occurs and/or in patients with a known risk because of earlier, lengthy systemic aminoglycoside treatment, consider an auditory examination.
Signs of bronchial spasm can indicate an allergic reaction, when an allergic reaction is suspected the treatment with tobramycin must be stopped. Sometimes administering a bronchodilator prior to tobramycin inhalation can elevate bronchial spasm complaints.

Tobramycin inhalation fluid is registered for administration with the PariLCPlus nebulizer with matching compressor that can generate a flow of 4-6 litres/min and/or a counter-pressure of 110-217 kPa. When deviating from the registered nebulizer on the doctor’s instructions, the dose recommended for that nebulizer must be used and the effectiveness and safety should be monitored carefully. When using vibrating mesh nebulizers for nebulizing tobramycin, it is known that the mesh may clog, which can result in a reduction of the inhalation dose. The mesh must therefore be cleaned carefully and replaced in good time.

 

Interactions

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

Other aminoglycosides
	Amikacin Related Medicines Menu">	J01GB06
	Gentamicin Related Medicines Menu">	J01GB03
	Tobramycin inhalation Related Medicines Menu">	J01GB01

References

1. Hartwig, N.C. et al, Vademecum Pediatrische antimicrobiele therapie, 2005
2. Bragonier R, et al, The pharmacokinetics and toxicity of once-daily tobramycin therapy in children with cystic fibrosis., J Antimicrob Chemother., 1998, Jul;42(1), 103-6
3. de Hoog M, et al, Tobramycin population pharmacokinetics in neonates., Clin Pharmacol Ther., 1997, 62, 392-9
4. Glass S, et al, The effects of intravenous tobramycin on renal tubular function in children with cystic fibrosis., J Cyst Fibros., 2005, 4, 221-5
5. Hennig S, et al, Target concentration intervention is needed for tobramycin dosing in paediatric patients with cystic fibrosis--a population pharmacokinetic study, Br J Clin Pharmacol., 2008, 65, 502-10
6. Massie J, et al, Pharmacokinetic profile of once daily intravenous tobramycin in children with cystic fibrosis., J Paediatr Child Health, 2006, 42, 601-5
7. Nahata MC, et al, Effect of gestational age and birth weight on tobramycin kinetics in newborn infants, J Antimicrob Chemother, 1984, 14, 59-65
8. Nahata MC, et al, Tobramycin pharmacokinetics in very low birth weight infants, Br J Clin Pharmacol, 1986, 21, 325-7
9. Smyth AR, et al, Once-daily versus multiple-daily dosing with intravenous aminoglycosides for cystic fibrosis, Cochrane Database Syst Rev, 2012, Feb 15, CD002009
10. Touw DJ, et al, Population pharmacokinetics of tobramycin administered thrice daily and once daily in children and adults with cystic fibrosis, J Cyst Fibros, 2007, 6, 327-33
11. Vic P, et al, Efficacy, tolerance, and pharmacokinetics of once daily tobramycin for pseudomonas exacerbations in cystic fibrosis, Arch Dis Child, 1998, 78, 536-9
12. Eurocept BV, SmPC Obracin (RVG 08886) 21-09-2018, www.geneesmiddeleninformatiebank.nl
13. CBO, Richtlijn Diagnostiek en behandeling Cystic Fibrosis , www.cbo.nl, 2007
14. Stichting Werkgroep Antibiotica Beleid, Antibioticaboekje_Tobramycine, Geraadpleegd 28 jan 2013, http://customid.duhs.duke.edu/NL/Main/Antibiotic.asp?AntibioticID=205
15. Pacifici GM, Clinical pharmacokinetics of aminoglycosides in the neonate: a review, Eur J Clin Pharmacol, 2009, Apr;65(4), 419-27
16. Bowman CM, The long-term use of inhaled tobramycin in patients with cystic fibrosis, J Cyst Fibros, 2002, Dec;1(Suppl 2), 194-8
17. Novartis Pharma GmbH, SmPC, TOBI® 300 mg/5 ml Lösung für einen Vernebler (49612.00.00), 10/17
18. Novartis Pharma GmbH, SmPC, TOBI® Podhaler® 28 mg Hartkapseln mit Pulver zur Inhalation (EU/1/10/652/001 – 003), 08/18
19. Chiesi GmbH, SmPC, Bramitob® 300 mg/4 ml Lösung für einen Vernebler (65777.00.00), 10/14
20. B.Braun Melsungen AG, SmPC, Tobramycin B. Braun 1 mg/ml 3 mg/ml Infusionslösung (69217.00.00/69218.00.00), 03/11
21. INFECTOPHARM Arzneimittel und Consilium GmbH, SmPC, GERNEBCIN® 40 mg/ml 80 mg/ml Lösung zur Injektion, Infusion und Inhalation (3002159.00.00/3002160.00.00), 06/17
22. INFECTOPHARM Arzneimittel und Consilium GmbH, SmPC, GERNEBCIN® 160 mg/2 ml Lösung zur Injektion, Infusion und Inhalation (65604.00.00), 06/17
23. Uptodate: UpToDate®, Pediatric Drug information: Tobramycin systemic Topic 105135 Version 69.0, accessed 02/19
24. PARI Pharma GmBH, SmPC Vantobra (EU/1/14/932) 19-03-2015
25. Novartis Europharm Limited, SPC TOBI Podhaler (EU 1/10/652/001-003) 20-07-2011
26. Hennig S, et al., Safety of inhaled (Tobi®) and intravenous tobramycin in young children with cystic fibrosis, J Cyst Fibros, 2014, Jul;13(4), 428-34
27. Rosenfeld M, et al, Serum and lower respiratory tract drug concentrations after tobramycin inhalation in young children with cystic fibrosis, J Pediatr, 2001, 139, 572-7
28. Ramsey BW, et al, Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group., N Engl J Med, 1999, 340, 23-30
29. Murphy TD, et al, Treatment with tobramycin solution for inhalation reduces hospitalizations in young CF subjects with mild lung disease, Pediatr Pulmonol, 2004, 38, 314-20
30. Hodson ME, et al, A randomised clinical trial of nebulised tobramycin or colistin in cystic fibrosis., Eur Respir J., 2002, 20, 658-64
31. Gibson RL, et al, Significant microbiological effect of inhaled tobramycin in young children with cystic fibrosis, Am J Respir Crit Care Med., 2003, 167, 841-9
32. Gibson RL, et al, Duration of treatment effect after tobramycin solution for inhalation in young children with cystic fibrosis, Pediatr Pulmonol, 2007, 42, 610-23
33. Geller DE, et al, Pharmacokinetics and bioavailability of aerosolized tobramycin in cystic fibrosis, Chest, 2002, 122, 219-26
34. Novartis Pharma BV., SmPC Tobi (RVG 25484) 8-3-2013., www.geneesmiddeleninformatiebank.nl
35. Guy EL et al., Serum tobramycin levels following delivery of tobramycin (Tobi) via eFlow advanced nebuliser in children with cystic fibrosis., J Cyst Fibros., 2010, Jul;9(4), 292-5
36. De Velde, F et al, High tobramycin serum concentrations after tobramycin inhalation in a child with renal failure., J Antimicrob Chemother, 2014, Nov;69(11):, 3163-4
37. Abdulhamid I. et al, Elevated serum tobramycin concentrations after treatment with tobramycin inhalation in a preterm infant, Pharmacotherapy, 2008, Jul;28(7), 939-44
38. Cheer SM, et al., Inhaled tobramycin (TOBI): a review of its use in the management of Pseudomonas aeruginosa infections in patients with cystic fibrosis, Drugs, 2003, 63, 2501-20
39. Sun Pharmaceuticals Germany, SmPC Tobramycin SUN 300 mg Lösung für einen Vernebler (95878.00.00), 03/2017
40. Buck, ML, et al., Pharmacokinetic changes during extracorporeal membrane oxygenation: implications for drug therapy of neonates, Clin Pharmacokin, 2003, 42(5), 403-17
41. Moffett, BS, et al., Population Pharmacokinetic Analysis of Gentamicin in Pediatric Extracorporeal Membrane Oxygenation, Ther Drug Monit, 2018, 40(5), 581-588
42. Moller, J, et al., Effect of extracorporeal membrane oxygenation on tobramycin pharmacokinetics in sheep, Crit Care Med, 1992, 20, 1454-1458
43. Cohen, P, et al., Gentamicin pharmacokinetics in neonates undergoing extracorporal membrane oxygenation, Pediatr Infect Dis J, 1990, 9, 562–566
44. Bowman CM, The long-term use of inhaled tobramycin in patients with cystic fibrosis, J Cyst Fibros, 2002, Dec;1(Suppl 2), 194-8
45. CBO, Richtlijn Diagnostiek en behandeling Cystic Fibrosis, www.cbo.nl, 2007
46. Hodson ME, et al, A randomised clinical trial of nebulised tobramycin or colistin in cystic fibrosis., Eur Respir J., 2002, 20, 658-64
47. Cheer SM, et al., Inhaled tobramycin (TOBI): a review of its use in the management of Pseudomonas aeruginosa infections in patients with cystic fibrosis, Drugs, 2003, 63, 2501-20

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