Aspects of Theophylline Clearance in Children

Michaelis-Menten pharmacokinetic parameters for theophylline were estimated in a three-month infant following an accidental overdose of intravenous aminophylline. Fitting of time-concentration data was performed using nonlinear regression with MKMODEL. A mixed order elimination model was superior to a first order model. Parameter estimates were standardized to a 70 kg human using an allometric power model. Parameter estimates (SE) were: maximum rate of metabolism (Vmax) 71 (42) mg.h-1, Michaelis-Menten constant (Km) 32.3 (33.5) mg.l-1, volume of distribution (Vd) 46.9 (2.6)l. This Michaelis-Menten constant is lower than that reported for adults and consequently non-linear elimination will occur at lower plasma concentrations in infants than in adults. Theophylline clearance has traditionally been reported as directly proportional to body weight. This per kilogram model gives an erroneous impression that clearance is greatest in early childhood and then decreases with age until adult rates are reached in late adolescence. Age-related clearance values reported in the literature were reviewed using an allometric 3/4 power model. This size model demonstrates that clearance increases in infancy and reaches adult rates in the first one to two years of life.