Details of allometry and maturation on model parameters for the design with adults and children

CL/Fpop and V/Fpop represent the typical oral clearance value and apparent volume of distribution value for the adult population, and weightpop represents a typical weight for the adult population. CL/F for an infant was also allowed to mature to an allometrically scaled adult value according to age (months) to reach the population value CL/Fpop, hence kmat is a first-order rate constant that determines the rate at which an infant’s clearance approaches the allometrically scaled value of CL/Fpop [28]. This oral clearance maturation calculation assumes that the ontological maturation process reflects the same rate as that of the kidneys, however, DHA is cleared hepatically, with UDP-glucuronosyltransferase (UGT) 1A9 and 2B7 being the predominant isoforms involved in the clearance of DHA in humans [29]. Although DHA is not renally cleared, the expression above is a conservative assumption on the rate of maturation and others have made similar assumptions about hepatically cleared drugs [30]. In POPT, CL/Fpop and V/Fpop were set to the values determined in the analysis of the nonpregnant adults (Table 1) and the population weight (weightpop) was set to the median weight of the non-pregnant adults, 51 kg. kmat was set to 0.082, which assumes CL/F maturates at the same rate that the glomerular filtration rate (GFR) matures. The age/weight combinations that were used were based on the linear model mentioned in the methods section, and ranges of these combinations were considered for each age group. The resulting values for CL/F and V/F considered for the designs are displayed in Figure S2 (see the Figures and Tables section).