Developmental pharmacokinetics of morphine and its metabolites in neonates, infants and young children N.J. Bouwmeester, B.J. Anderson, D Tibboel, N.H.G.

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Developmental pharmacokinetics of morphine and its metabolites in neonates, infants and young children N.J. Bouwmeester, B.J. Anderson, D Tibboel, N.H.G. Holford British Journal of Anaesthesia Volume 92, Issue 2, Pages 208-217 (February 2004) DOI: 10.1093/bja/aeh042 Copyright © 2004 British Journal of Anaesthesia Terms and Conditions

Fig 1 Pharmacokinetic model. V is the volume of distribution for morphine, CS is morphine serum concentration, CL2M3G is the formation clearance to M3G, CM3G is the serum M3G concentration, CL2M6G is the formation clearance to M6G, CM6G is the serum M6G concentration, CLM3G is the elimination clearance of M3G, CLM6G is the elimination clearance of M6G, VM is the volume of distribution of glucuronide metabolites, CLEX is unaccounted clearance, and Dose is the dose given. British Journal of Anaesthesia 2004 92, 208-217DOI: (10.1093/bja/aeh042) Copyright © 2004 British Journal of Anaesthesia Terms and Conditions

Fig 2 Volume of distribution change with postnatal age. Individual predicted volumes, standardized to a 70-kg person, from the NONMEM post hoc step, are plotted against age. The solid line represents the non-linear relation between volume of distribution and age. British Journal of Anaesthesia 2004 92, 208-217DOI: (10.1093/bja/aeh042) Copyright © 2004 British Journal of Anaesthesia Terms and Conditions

Fig 3 (a) Individual predicted formation clearances to M3G, standardized to a 70-kg person, from the NONMEM post hoc step, are plotted against age. The solid line represents the non-linear relation between clearance and age. (b) Individual predicted formation clearances to M6G, standardized to a 70-kg person, from the NONMEM post hoc step, are plotted against age. British Journal of Anaesthesia 2004 92, 208-217DOI: (10.1093/bja/aeh042) Copyright © 2004 British Journal of Anaesthesia Terms and Conditions

Fig 4 Individual a posteriori Bayesian estimates for CL2M3G corrected for size and age plotted against serum bilirubin. Formation clearance decreases as serum bilirubin increases. British Journal of Anaesthesia 2004 92, 208-217DOI: (10.1093/bja/aeh042) Copyright © 2004 British Journal of Anaesthesia Terms and Conditions

Fig 5 Individual a posteriori Bayesian estimates of CLM3G (a) are plotted against postnatal age. The dashed line represents the maturation of glomerular filtration rate (GFR; ml min−1 per 1.73 m2), scaled to overlie CLM3G maturation (data from Bergstein).25 (b) Individual a posteriori Bayesian estimates of CLM6G are plotted against postnatal age. British Journal of Anaesthesia 2004 92, 208-217DOI: (10.1093/bja/aeh042) Copyright © 2004 British Journal of Anaesthesia Terms and Conditions

Fig 6 The relationship of creatinine clearance to metabolite elimination clearance of M3G, corrected for size and age. Changes in creatinine clearance are accounted for by maturation of M3G clearance. British Journal of Anaesthesia 2004 92, 208-217DOI: (10.1093/bja/aeh042) Copyright © 2004 British Journal of Anaesthesia Terms and Conditions

Fig 7 Quality of fit for pharmacokinetic data over the study time period. A line connects each subject's data. The individual a posteriori Bayesian predictions for serum concentration of morphine (a), M3G (b) and M6G (c) are compared with those observed. These predictions are based on maximum a posteriori Bayesian estimates of the parameters for each specific individual using their observed data. British Journal of Anaesthesia 2004 92, 208-217DOI: (10.1093/bja/aeh042) Copyright © 2004 British Journal of Anaesthesia Terms and Conditions