Jump to comment:

• Do exicpients have an impact on paracetamol clearance: the jury is still out
  karel allegaert
  Published on: 1 July 2016
• MANNITOL CONTRIBUTION TO IV PARACETAMOL CLEARANCE VARIANCE IN NEONATES
  Jorge Pisapia
  Published on: 24 June 2016

• Published on: 1 July 2016

  Do exicpients have an impact on paracetamol clearance: the jury is still out

  • karel allegaert, MD, PhD

  We support any idea or initiative to try to better understand the covariates of paracetamol PK in neonates, including the potential impact of excipients (propylene glycol, mannitol or none) on paracetamol clearance.

  We have carefully read the e-letter of Pisapia et al., and support the potential impact of mannitol co-administration on paracetamol clearance, however, we do have some relevant additional comments...

  Show More

  We support any idea or initiative to try to better understand the covariates of paracetamol PK in neonates, including the potential impact of excipients (propylene glycol, mannitol or none) on paracetamol clearance.

  We have carefully read the e-letter of Pisapia et al., and support the potential impact of mannitol co-administration on paracetamol clearance, however, we do have some relevant additional comments.

  First, in the initial versions of the paper, we have explored the potential impact of the different study as an indicator for potential differences, including excipients, but this turned out to be negative. This is a common practice for pooled datasets. This does not mean that there is no impact, but it did not reach sufficient impact to be quantified in this cohort of 150 neonates or has been superimposed by other variables;

  Second, if mannitol stimulates diuresis, it is not very likely to affect paracetamol clearance since urinary elimination of paracetamol is a very minor route of elimination in neonates, while sulphation and glucuronidation are the most important contributors (1,2). For drugs eliminated by renal route, the impact may be more relevant.

  Finally, and in order to correct the suggestions made, the estimates should correct for the 'real doses' administered, commonly below 60 mg/kg/24h while the impact of paracetamol administration on hemodynamics in both neonates and healthy adult volunteers have been quantified (3,4).

  References

  1) Allegaert K, de Hoon J, Verbesselt R, Vanhole C, Devlieger H, Tibboel D. Intra- and interindividual variability of glucuronidation of paracetamol during repeated administration of propacetamol in neonates. Acta Paediatr 2005;94:1273-9. 2) Krekels EH, van Ham S, Allegaert K, et al. Developmental changes rather than repeated administration drive paracetamol glucuronidation in neonates and infants. Eur J Clin Pharmacol 2015;71:1075-82. 3) Allegaert K, Naulaers G. Haemodynamics of intravenous paracetamol in neonates. Eur J Clin Pharmacol 2010;66:855-8. 4) Chiam E, Weinberg L, Bailey M, McNicol L, Bellomo R. The haemodynamic effects of intravenous paracetamol (acetaminophen) in healthy volunteers: a double-blind, randomized, triple crossover trial. Br J Clin Pharmacol 2016;81:605-12.

  Conflict of Interest:

  corresponding author of the initial paper

  Show Less

  Conflict of Interest:
  None declared.

  • Back to top
• Published on: 24 June 2016

  MANNITOL CONTRIBUTION TO IV PARACETAMOL CLEARANCE VARIANCE IN NEONATES

  • Jorge Pisapia, Pharmacist

  To the editor:

  We have found very interesting the paper by Dr Allegaert et al. about iv paracetamol pharmacokinetics (1) in which they referred that between- subject variability (BSV) is explained by covariates such as size, weight, disease characteristics or co-administration of drugs. They mentioned that they found an unexplained variance in paracetamol clearance, and that it remained high (39,1 per cent) even a...

  Show More

  To the editor:

  We have found very interesting the paper by Dr Allegaert et al. about iv paracetamol pharmacokinetics (1) in which they referred that between- subject variability (BSV) is explained by covariates such as size, weight, disease characteristics or co-administration of drugs. They mentioned that they found an unexplained variance in paracetamol clearance, and that it remained high (39,1 per cent) even after taking size, age and bilirubin into account.

  Regarding the co-administration of drugs as a covariate, an issue that was not addressed in the paper, we would like to note that the neonates included in the pooled analysis (n: 158) were from different studies and had been administered three different iv paracetamol formulations; one of them (Perfalgan) with a considerable amount of mannitol (3,85g/100ml) as excipient. Thus, the neonates in study 3 (n: 50) were administered every 6 hours a concomitant mannitol dose of 58 mg/Kg with each paracetamol dose of 15 mg/Kg; they received 232 mg/Kg/day of mannitol during 2 to 7 days.

  The amount of mannitol included as excipient in pharmaceutical products licensed for adults and children is considered a non-active ingredient because it is far below the pharmacologically significant dose for them. However, it could be enough to show an osmotic diuretic effect in neonates, especially in low weight preterm infants. This enhanced osmotic effect would be greater in the most immature neonates and would decline logarithmically during the first few weeks of life(2). The osmotic diuretic effect of the same dose of mannitol could be considerably different in accordance with the maturation of the renal function.

  In Argentina iv paracetamol is available only since last year, with mannitol as excipient. In 2006 we had seen that a low amount of mannitol could have some influence on the less oliguria observed with ibuprofen compared to indomethacin for PDA closure.(3) Last year, a new investigation by Chiam et al. showed that the majority of the formulations with 1g iv paracetamol also contain near 4g of mannitol (38-39mg/ml). They explained that this low amount of mannitol was a clinically relevant dose which might cause hypotension in critically ill adults due to its diuretic nature even in low doses.(4)

  The fact that only 1/3 of neonates (50/158) in Allegaert et als study were co-administered a concomitant diuretic dose of mannitol should be considered, as it could have contributed to the extensive variability and the unexplained high variance they found in iv paracetamol clearance.

  Further research is necessary to evaluate the effects of low doses of mannitol in neonates, especially in low birth weight infants, and to determine how iv paracetamol pharmacodynamics and pharmacokinetics are influenced, if so, by the mannitol content of the medication.

  Jorge Pisapia. Matias Lucero. Leonardo Giunta.

  Clinica y Maternidad Suizo Argentina. Department of Pharmacy. SWISS MEDICAL GROUP. Buenos Aires. Argentina.

  REFERENCES 1- Allegaert K, Palmer GM, Anderson BJ. The pharmacokinetics of intravenous paracetamol in neonates: size matters most. Arch Dis Child 2011; 96:575???580.

  2- Kleinman LI, Disney TA. Renal osmotic in the neonatal and adult dog. Am J Physiol Renal Physiol 1984; 247 Issue 3 F396-F402.

  3- Pisapia J, Giunta L, Alonso MR. Mannitol influence on the less renal side effects of ibuprofen vs indomethacin for PDA closure. Arch Dis Child 2003;88:1135.adc.bmj.com/content/88/12/1134.full/reply#archdischild_el_1881 Jan 2006

  4- Chiam E, Weinberg L, Bellomo R. Paracetamol: a review with specific focus on the haemodynamic effects of intravenous administration. Heart Lung Vessel 2015; 7(2):121-32.

  Conflict of Interest:

  None declared

  Show Less

  Conflict of Interest:
  None declared.

  • Back to top