PKPD Explorations Using Paracetamol; 20 years on

Paracetamol (acetaminophen) has served as a useful substrate for population modelling and factors determining dose. This modelling has improved not only PKPD understanding of the drug, but has also been useful to explore models that characterize size (e.g., allometry), clearance maturation, the impact of birth on clearance, the role of fat mass, concentration-response relationships, delayed effects, target concentration strategies, toxicity, and pharmacodynamic interactions with other drugs. Lessons have also included the politics of data sharing and factors influencing translation of PKPD knowledge into clinical practice.

Early studies were designed to determine serum concentration after administration of suppositories. However, data were then required to further explore pharmacokinetics 1, 2 of other formulations in different age groups 3-7 and clearance metabolic pathways involved.The use of allometric theory 9-11 allowed standardization for size, rationalization of dosing 12 and exploration of clearance maturation.13 Rich neonatal data permitted exploration of clearance changes at birth.14 A review of toxicity and its relationship to absorption and clearance in children aged less than 5 years changed treatment recommendations in those presenting with overdose to emergency departments worldwide.15

Target concentration concepts using effect compartment modelling were explored in both children 16-19 and neonates 20. Appraisal of CSF 21, 22 as the effect compartment was reviewed. These studies resulted in rationalization of dose. However dose has been tempered by fears of hepatotoxicity rather than PKPD considerations.  The role of fat for determination of dose 23, 24 has also been explored and paracetamol clearance has been investigated using normal fat mass.25, 26

Paracetamol is commonly used in conjunction with NSAIDs. PD Interaction models 27 were used to explore both diclofenac 28 and ibuprofen 29, 30 interactions. These studies introduced concepts of the hazard of dropping out, placebo effects and disease progression.

Many studies were only possible because data were generously shared by colleagues in other countries. However, data retain usefulness for investigators long after an original publication and the politics of data sharing have become a major sticking point for current investigations.31 The study of paracetamol has been more a journey around PKPD modelling than characterization of the clinical pharmacology of a common analgesic.

  1. Anderson BJ, Holford NH. Rectal acetaminophen pharmacokinetics. Anesthesiology 1998;88: 1131-1133.
  2. Anderson BJ, Woolard GA, Holford NH. Pharmacokinetics of rectal paracetamol after major surgery in children. Paediatr Anaesth 1995; 5: 237-242.
  3. Allegaert K, Anderson BJ, Naulaers G, et al.Intravenous paracetamol (propacetamol) pharmacokinetics in term and preterm neonates. Eur J Clin Pharmacol 2004; 60: 191-197.
  4. Allegaert K, Palmer GM, Anderson BJ. The pharmacokinetics of intravenous paracetamol in neonates: size matters most. Arch Dis Child 2011; 96: 575-580.
  5. Anderson BJ, Allegaert K. Intravenous neonatal paracetamol dosing: the magic of 10 days. Paediatr Anaesth 2009; 19: 289-295.
  6. Anderson BJ, Pons G, Autret-Leca E, et al.Pediatric intravenous paracetamol (propacetamol) pharmacokinetics: a population analysis. Paediatr Anaesth 2005; 15: 282-292.
  7. Anderson BJ, van Lingen RA, Hansen TG, et al.Acetaminophen developmental pharmacokinetics in premature neonates and infants: a pooled population analysis. Anesthesiology 2002; 96: 1336-1345.
  8. van der Marel CD, Anderson BJ, van Lingen RA, et al.Paracetamol and metabolite pharmacokinetics in infants. Eur J Clin Pharmacol 2003; 59: 243-251.
  9. Anderson BJ, Holford NH. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol 2008; 48: 303-332.
  10. Anderson BJ, McKee AD, Holford NH. Size, myths and the clinical pharmacokinetics of analgesia in paediatric patients. Clin Pharmacokinet 1997; 33: 313-327.
  11. Anderson BJ, Meakin GH. Scaling for size: some implications for paediatric anaesthesia dosing. Paediatr Anaesth 2002; 12: 205-219.
  12. Anderson BJ, Holford NH. Understanding dosing: children are small adults, neonates are immature children. Arch Dis Child 2013; 98: 737-744.
  13. Anderson BJ, Holford NH. Mechanistic basis of using body size and maturation to predict clearance in humans. Drug Metab Pharmacokinet 2009; 24: 25-36.
  14. Anderson BJ, Holford NHG. Negligible impact of birth on renal function and drug metabolism. Paediatr Anaesth 2018; 28: 1015-1021.
  15. Anderson BJ, Holford NH, Armishaw JC, et al.Predicting concentrations in children presenting with acetaminophen overdose. J Pediatr 1999; 135: 290-295.
  16. Anderson B, Kanagasundarum S, Woollard G. Analgesic efficacy of paracetamol in children using tonsillectomy as a pain model. Anaesth Intensive Care 1996; 24: 669-673.
  17. Anderson BJ, Holford NH. Rectal paracetamol dosing regimens: determination by computer simulation. Paediatr Anaesth 1997; 7: 451-455.
  18. Anderson BJ, Holford NH, Woollard GA, et al.Perioperative pharmacodynamics of acetaminophen analgesia in children. Anesthesiology1999; 90: 411-421.
  19. Anderson BJ, Woollard GA, Holford NH. Acetaminophen analgesia in children: placebo effect and pain resolution after tonsillectomy. Eur J Clin Pharmacol 2001;57: 559-569.
  20. Allegaert K, Naulaers G, Vanhaesebrouck S, et al.The paracetamol concentration-effect relation in neonates. Paediatr Anaesth 2013; 23: 45-50.
  21. Anderson BJ, Holford NHG, Woollard GA, et al.Paracetamol plasma and cerebrospinal fluid pharmacokinetics in children. Brit J Clin Pharmacol 1998; 46: 237-243.
  22. van der Marel CD, Anderson BJ, Pluim MA, et al.Acetaminophen in cerebrospinal fluid in children. Eur J Clin Pharmacol 2003;59: 297-302.
  23. Holford NHG, Anderson BJ. Allometric size: The scientific theory and extension to normal fat mass. Eur J Pharm Sci 2017; 109S: S59-S64.
  24. Anderson BJ, Holford NH. What is the best size predictor for dose in the obese child? Pediatr Anesth 2017; 27: 1176-1184.
  25. Allegaert K, Olkkola KT, Owens KH, et al.Covariates of intravenous paracetamol pharmacokinetics in adults. BMC Anesthesiol 2014; 14: 77.
  26. Anderson BJ, Holford NH. Getting the dose right for obese children. Arch Dis Child 2017; 102: 54-55.
  27. Hannam JA, Anderson BJ. Pharmacodynamic interaction models in pediatric anesthesia. Paediatr Anaesth 2015; 25: 970-980.
  28. Hannam JA, Anderson BJ, Mahadevan M, et al.Postoperative analgesia using diclofenac and acetaminophen in children. Paediatr Anaesth 2014; 24: 953-961.
  29. Hannam J, Anderson BJ. Explaining the acetaminophen-ibuprofen analgesic interaction using a response surface model. Paediatr Anaesth 2011; 21: 1234-1240.
  30. Hannam JA, Anderson BJ, Potts A. Acetaminophen, ibuprofen, and tramadol analgesic interactions after adenotonsillectomy. Paediatr Anaesth 2018;28: 841-851.
  31. Anderson BJ, Merry AF. Data sharing for pharmacokinetic studies. Paediatr Anaesth2009; 19: 1005-1010.