Brian Anderson
Auckland Children’s Hospital, New Zealand
Growth and development are two major aspects of children not readily apparent in adults. Age is commonly lumped into neonates (<6 weeks age), infants (6 weeks-1 year) and children (>1 year) with age described as postnatal (PNA) or postmenstrual (PMA). Growth and development interact in ways that are not necessarily easy to determine from observations because they are quite highly correlated. (1) Tod has identified three major covariates (size, maturation, organ function) for paediatric PK and suggested standardisation for size before incorporating factors for maturation and organ function.(2) Size can be standardised for clearance in a 70 kg person using the allometric ¾ power model.(3, 4) Remifentanil, a drug cleared by hydrolysis, can be modelled in all age groups by simple application of this model using a standardized clearance of 2800 mL.min-1 for a 70 kg person.(5) Fat mass (6) contributes to overall body size and may have an indirect influence on both metabolic and renal clearance.(7) Allometry alone is insufficient to predict clearance in neonates and infants from adult parameters for most drugs; the addition of a model describing maturation is required. The sigmoid Emax has been found useful for describing this maturation process.(8) Propofol maturation may be described with a mature clearance of 1.83 L.min-1.70kg-1, a maturation half-time (TM50) of 44 weeks PMA and a Hill coefficient of 4.9.(9) Organ function also affects clearance and propofol clearance is reduced in neonates and infants after cardiac surgery.(6)
There are few data describing age-related PD changes. Those described appear to resolve during infancy (6 weeks-1 year PNA). Common examples include an increased sensitivity to the effects of neuromuscular blocking drugs in neonates (10), MAC changes of inhalational anaesthetics (11) and bronchodilator insensitivity (12)
Children are not small adults. Adults are BIG children and children are OLD babies.
References:
[1]. Meibohm B, Laer S, Panetta JC, et al. Population pharmacokinetic studies in pediatrics: issues in design and analysis. AAPS J 2005; 7:E475-87.
[2]. Tod M, Jullien V, Pons G. Facilitation of drug evaluation in children by population methods and modelling. Clin Pharmacokinet 2008; 47:231-43.
[3]. West GB, Brown JH, Enquist BJ. The fourth dimension of life: fractal geometry and allometric scaling of organisms. Science 1999; 284:1677-9.
[4]. Anderson BJ, Holford NH. Mechanistic basis of using body size and maturation to predict clearance in humans. Drug Metab Pharmacokinet 2009.
[5]. Rigby-Jones AE, Priston MJ, Sneyd JR, et al. Remifentanil-midazolam sedation for paediatric patients receiving mechanical ventilation after cardiac surgery. Br J Anaesth 2007; 99:252-61.
[6]. Rigby-Jones AE, Nolan JA, Priston MJ, et al. Pharmacokinetics of propofol infusions in critically ill neonates, infants, and children in an intensive care unit. Anesthesiology 2002; 97:1393-400.
[7]. Rhodin MM, Anderson BJ, Peters AM, et al. Human renal function maturation: a quantitative description using weight and postmenstrual age. Pediatr Nephrol 2009; 24:67-76.
[8]. Anand KJ, Anderson BJ, Holford NH, et al. Morphine pharmacokinetics and pharmacodynamics in preterm and term neonates: secondary results from the NEOPAIN trial. Br J Anaesth 2008; 101:680-9.
[9]. Allegaert K, de Hoon J, Verbesselt R, et al. Maturational pharmacokinetics of single intravenous bolus of propofol. Paediatr Anaesth 2007; 17:1028-34.
[10]. Fisher DM, O'Keeffe C, Stanski DR, et al. Pharmacokinetics and pharmacodynamics of d-tubocurarine in infants, children, and adults. Anesthesiology 1982; 57:203-8.
[11]. LeDez KM, Lerman J. The minimum alveolar concentration (MAC) of isoflurane in preterm neonates. Anesthesiology 1987; 67:301-7.
[12]. Stephenson T. How children's responses to drugs differ from adults. Br J Clin Pharmacol 2005; 59:670-3.
Reference: PAGE 18 (2009) Abstr 1675 [www.page-meeting.org/?abstract=1675]
Poster: Oral Presentation: Pediatrics