Is Morphine Clearance Predictable in Humans?

Objectives: To evaluate pharmacokinetic models for prediction of morphine doses from premature neonates to adults.

Design: External evaluation of published models for morphine clearance by comparison with literature reports of morphine clearance in individual patients and healthy subjects.

Main Outcome Measures: Prediction of morphine dose rate in premature neonates, full term neonates, infants, children and adults.

Results: A previously described theory-based allometric model (1)using weight combined with a sigmoid maturation model using post-menstrual age successfully predicted the morphine dose rate (within 25% of target) in all age groups except infants (predicted dose 30% under target (95% CI 7-46%). Other published models based on empirical allometric scaling all made unacceptable predictions (>100% of target) in at least one age group(2-4).

Conclusions: Theory based allometric scaling combined with a maturation function has been prospectively confirmed to provide a sound basis for describing clearance and predicting doses in humans of all ages.

  1. Anand KJ, Anderson BJ, Holford NH, Hall RW, Young T, Shephard B, et al. Morphine pharmacokinetics and pharmacodynamics in preterm and term neonates: secondary results from the NEOPAIN trial. Br J Anaesth. 2008;101(5):680-9.
  2. Mahmood I. Evaluation of a morphine maturation model for the prediction of morphine clearance in children: How accurate is the predictive performance of the model? Br J Clin Pharmac. 2011;71(1):88-94.
  3. Wang C, Peeters MYM, Allegaert K, Tibboel D, Danhof M, Knibbe CAJ. Scaling clearance of propofol from preterm neonates to adults using an allometric model with a bodyweight-dependent maturational exponent PAGE. 2010;19(Abstr 1818).
  4. Knibbe CA, Krekels EH, van den Anker JN, DeJongh J, Santen GW, van Dijk M, et al. Morphine glucuronidation in preterm neonates, infants and children younger than 3 years. Clin Pharmacokinet. 2009;48(6):371-85.

Nick Holford