2010 - Berlin - Germany

PAGE 2010: Applications- Other topics
Chenguang Wang

Scaling clearance of propofol from preterm neonates to adults using an allometric model with a bodyweight-dependent maturational exponent

C. Wang(1),(2), M.Y.M. Peeters(3), K. Allegaert(4), D. Tibboel(2), M. Danhof(1), C.A.J. Knibbe(1),(2),(3)

(1) Leiden /Amsterdam Center For Drug Research, Division of Pharmacology, Leiden University, Leiden, The Netherlands; (2) Erasmus Medical Centre/Sophia Childrenís Hospital, Department of Paediatric Intensive Care, Rotterdam, The Netherlands; (3) St. Antonius Hospital, Department of Clinical Pharmacy, Nieuwegein, The Netherlands; (4) Neonatal Intensive Care Unit, University Hospitals Leuven, Belgium

Objectives: For propofol clearance, allometric scaling has been applied successfully for between species scaling and for scaling within a certain human weight range [1,2]. However, in neonates and infants, predictions of clearance based on both the 0.75 fixed or 0.78 estimated allometric model are systematically higher and lower than the observed values, respectively [3]. In this study, different covariate models for the influence of bodyweight on clearance of propofol were studied in a full age span from preterm and term neonates, infants, toddlers, adolescents to adults.

Methods: Datasets from six different propofol studies (body weight: 0.68-80kg, age: 0.002-57 yrs) [4,5,6,7,8,9] were included in the analysis using NONMEM VI. The influence of bodyweight on clearance was investigated in 4 ways: i) a single exponent allometric scaling model, ii) a mixture model with different allometric exponents for two subgroups, iii) a bodyweight-cutting-point separated model with two different allometric exponents, iv) an allometric scaling model with a bodyweight-dependent maturational exponent according to equation:

ExponentBW  = Exponent0 - (Exponentmax* BWγ)/( EBW50γ+ BWγ)

in which BW is bodyweight, ExponentBW is the exponent for a bodyweight BW, Exponent0 is the exponent for a bodyweight of 0, Exponentmax is the maximum decrease in exponent with increasing bodyweight, EBW50 is the bodyweight at 50% of the maximum decrease in exponent and γ is the hill coefficient.

Results: The allometric scaling model with a single estimated exponent of 0.7 proved to be inadequate for individuals whose bodyweights were less than 20 kg. The mixture model resulted in a decrease in objective function of 11.5 points (P<0.01) compared to the single exponent allometric model, and comprised of one subpopulation (24.4%) with an estimated exponent of 2.01 and another subpopulation (76.6%) with an estimated exponent of 0.65. The bodyweight-cutting-point separated allometric model further improved the description of the data with a drop in objective function of 14.5 points (p<0.05) compared to the mixture model, and consisted of an exponent of 1.45 for bodyweights lower than 16 kg and an exponent of 0.68 for bodyweights higher than 16 kg. The bodyweight-dependent maturational exponent model best described the data, especially in the younger age range, with a 205 (p<0.001) points drop in objective function. Values for the equation describing the change of the exponent with bodyweight were 1.35, 0.784 and 3.74 for Exponent0, Exponentmax, EBW50, respectively, resulting in a gradual change in exponent from 1.35 in neonates to 0.566 in adults.

Conclusions: Of the studied covariate models, both the mixture model and the bodyweight-cutting-point separated model show that the scaling exponent is larger in neonates and toddlers than in older children and adults. This larger exponent was identified before for morphine glucuronidation in children under the age of three years old [10]. The bodyweight-dependent maturational exponent model was found to best describe the maturation of propofol clearance in a population varying from preterm neonates to adults. The change in the scaling exponent is a potential indicator of the physiological maturation process during ontogeny in children.

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[2] Knibbe CA, Zuideveld KP, Aarts LP, Kuks PF, Danhof M. 2005. Allometric relationships between the pharmacokinetics of propofol in rats, children, and adults. Br J Clin Pharmacol. 99:864-70
[3] Peeters MY, Allegaert K, Blussť van Oud-Alblas HJ, Cella M, Tibboel D, Danhof M, Knibbe CA. 2010. Prediction of Propofol Clearance in Children from an Allometric Model Developed in Rats, Children and Adults versus a 0.75 Fixed-Exponent Allometric Model. Clin Pharmacokinetics 2010, in press
[4] Allegaert K, Peeters MY, Verbesselt R, Tibboel D, Naulaers G, de Hoon JN, Knibbe CA. 2007. Inter-individual variability in propofol pharmacokinetics in preterm and term neonates. Br J Anaesth. 99(6):864-70
[5] Knibbe CA, Melenhorst-de Jong G, Mestrom M, Rademaker CM, Reijnvaan AF, Zuideveld KP, Kuks PF, van Vught H, Danhof M. 2002. Pharmacokinetics and effects of propofol 6% for short-term sedation in paediatric patients following cardiac surgery. Br J Clin Pharmacol. 54(4):415-22
[6] Blussť van Oud-Alblas HJ, Brill MJ, Peeters MY, Tibboel D, Danhof M, Knibbe CA. Population PK-PD model-based dosing optimization of propofol-remifentanil anesthesia in children and adolescents. Anesthesiology 2010, provisionally accepted for publication
[7] Knibbe CA, Voortman HJ, Aarts LP, Kuks PF, Lange R, Langemeijer HJ, Danhof M. 1999. Pharmacokinetics, induction of anaesthesia and safety characteristics of propofol 6% SAZN vs propofol 1% SAZN and Diprivan-10 after bolus injection. Br J Clin Pharmacol 47(6):653-60
[8] Murat I, Billard V, Vernois J, Zaouter M, Marsol P, Souron R, Farinotti R. 1996. Pharmacokinetics of propofol after a single dose in children aged 1-3 years with minor burns. Comparison of three data analysis approaches. Anesthesiology. 84(3):526-32
[9] Peeters MY, Prins SA, Knibbe CA, DeJongh J, van Schaik RH, van Dijk M, van der Heiden IP, Tibboel D, Danhof M. 2006. Propofol pharmacokinetics and pharmacodynamics for depth of sedation in nonventilated infants after major craniofacial surgery. Anesthesiology.104(3):466-74.
[10] Knibbe CA, Krekels EH, van den Anker JN, DeJongh J, Santen GW, van Dijk M, Simons SH, van Lingen RA, Jacqz-Aigrain EM, Danhof M, Tibboel D. 2009 Morphine glucuronidation in preterm neonates, infants and children younger than 3 years. Clin Pharmacokinet. 2009;48(6):371-85.

Reference: PAGE 19 (2010) Abstr 1818 [www.page-meeting.org/?abstract=1818]
Poster: Applications- Other topics