Growth and development can be investigated using readily observable demographic factors such as weight and age. Size is the primary covariate and can be referenced to a 70-kg person with allometry using a coefficient of 0.75 for clearance and 1 for volume. The use of these coefficients is supported by fractal geometric concepts and observations from diverse areas in biology. Fat free mass (FFM) might be expected to do better than total body weight when there are wide variations in fat affecting body composition. Clearance pathways develop in the fetus before birth. The use of postnatal age as a descriptor of maturation is unsatisfactory because birth may occur prematurely; therefore postmenstrual age is a superior predictor of elimination function. A sigmoid E_maxmodel (Hill equation) describes gradual maturation of clearance in early life leading to a mature adult clearance achieved at a later age.

Growth and development are two major aspects of children not readily apparent in adults. Clearance in the paediatric population should be investigated using models that describe size, maturation and organ function influences. Size is the primary covariate and although lean body weight is argued as a better measure than total body weight, the use of different fractions of fat mass to explain how pharmacokinetic parameters vary with body composition has been proposed. Allometric scaling using an empiric power exponent of 3/4 is superior to scaling using body surface area. The sigmoid hyperbolic model has proven useful to describe maturation. An extra parameter that describes asymmetry can be incorporated into this model. These descriptors are used to illustrate creatinine, morphine and paracetamol clearance in children. Simultaneous investigation of pooled GFR, paracetamol and morphine data enabled testing for shared common features of maturation processes. Results suggest that GFR matures before paracetamol or morphine clearance, consistent with phase II conjugation processes that convert xenobiotics to water soluble forms that can subsequently be eliminated from the body through the renal system. The use of such mechanistic approaches improves understanding of paediatric pharmacokinetics; improving dosing predictions and allowing projection in exploratory drug development.

Descriptions of the pharmacokinetics and metabolism of morphine and its metabolites in young children are scant. Previous studies have not differentiated the effects of size from those related to age during infancy. Postoperative children 0-3 yr old were given an intravenous loading dose of morphine hydrochloride (100 micro g kg(-1) in 2 min) followed by either an intravenous morphine infusion of 10 micro g h(-1) kg(-1) (n=92) or 3-hourly intravenous morphine boluses of 30 micro g kg(-1) (n=92). Additional morphine (5 micro g kg(-1)) every 10 min was given if the visual analogue (VAS, 0-10) pain score was >/=4. Arterial blood (1.4 ml) was sampled within 5 min of the loading dose and at 6, 12 and 24 h for morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). The disposition of morphine and formation clearances of morphine base to its glucuronide metabolites and their elimination clearances were estimated using non-linear mixed effects models. The analysis used 1856 concentration observations from 184 subjects. Population parameter estimates and their variability (%) for a one-compartment, first-order elimination model were as follows: volume of distribution 136 (59.3) litres, formation clearance to M3G 64.3 (58.8) litres h(-1), formation clearance to M6G 3.63 (82.2) litres h(-1), morphine clearance by other routes 3.12 litres h(-1) per 70 kg, elimination clearance of M3G 17.4 (43.0) litres h(-1), elimination clearance of M6G 5.8 (73.8) litres h(-1). All parameters are standardized to a 70 kg person using allometric 3/4 power models and reflect fully mature adult values. The volume of distribution increased exponentially with a maturation half-life of 26 days from 83 litres per 70 kg at birth; formation clearance to M3G and M6G increased with a maturation half-life of 88.3 days from 10.8 and 0.61 litres h(-1) per 70 kg respectively at birth. Metabolite formation decreased with increased serum bilirubin concentration. Metabolite clearance increased with age (maturation half-life 129 days), and appeared to be similar to that described for glomerular filtration rate maturation in infants. M3G is the predominant metabolite of morphine in young children and total body morphine clearance is 80% that of adult values by 6 months. A mean steady-state serum concentration of 10 ng ml(-1) can be achieved in children after non-cardiac surgery in an intensive care unit with a morphine hydrochloride infusion of 5 micro g h(-1) kg(-1) at birth (term neonates), 8.5 micro g h(-1) kg(-1) at 1 month, 13.5 micro g h(-1) kg(-1) at 3 months and 18 micro g h(-1) kg(-1) at 1 year and 16 micro g h(-1) kg(-1) for 1- to 3-yr-old children.

Computer simulation of clinical trials has evolved over the past two decades from a simple instructive game to “full” simulation models yielding pharmacologically sound, realistic trial outcomes. The need to make drug development more efficient and informative and the awareness that many industries make extensive use of simulation in product development have advanced considerably the use of simulation of clinical trials in pharmaceutical product development over the past decade. The structural and stochastic components of trial simulation models are explained as a prelude to a listing of representative simulation projects, reflecting investigative applications of statistical methods, trial design comparisons, and full simulation of new drugs being developed. Lessons learned from these projects are reviewed in the context of their current impact and potential for influencing the future of drug development.