A Bodyweight-Dependent Allometric Exponent for Scaling Clearance Across the Human Life-Span

Purpose To explore different allometric equations for scaling clearance across the human life-span using propofol as a model drug. Methods Data from seven previously published propofol studies ((pre)term neonates, infants, toddlers, children, adolescents and adults) were analysed using NONMEM VI. To scale clearance, a bodyweight-based exponential equation with four different struc-tures for the exponent was used: (I) 3/4 allometric scaling model; (II) mixture model; (III) bodyweight-cut-point separated model; (IV) bodyweight-dependent exponent model. Results Model I adequately described clearance in adults and older children, but overestimated clearance of neonates and underestimated clearance of infants. Use of two different expo-nents in Model II and Model III showed significantly improved performance, but yielded ambiguities on the boundaries of the two subpopulations. This discontinuity was overcome in Model IV, in which the exponent changed sigmoidally from 1.35 at a hypothetical bodyweight of 0 kg to a value of 0.56 from 10 kg onwards, thereby describing clearance of all individuals best. Conclusions A model was developed for scaling clearance over the entire human life-span with a single continuous equation, in which the exponent of the bodyweight-based exponential equation varied with bodyweight. KEY WORDS allometric. clearance. life-span. pharmacokinetics. propofol ABBREVIATIONS BDE bodyweight-dependent exponent EDTA ethylenediaminetetraacetic acid NPDE normalized prediction distribution errors RMSE root mean square erro