A developmental comparison can change when a quantity is expressed for an entire organ or per gram of tissue. A 2018 midazolam study illustrates that distinction in physiological population pharmacokinetic modeling of children undergoing surgery.
Investigators analyzed midazolam and 1-hydroxymidazolam data from 264 children aged one to eighteen after oral administration. The model represented intestinal and hepatic handling separately. Physiological information and scaling assumptions supplemented the concentration measurements.
Estimated intrinsic clearance for the whole gut wall and whole liver increased with body weight. When expressed per gram of organ, however, gut-wall intrinsic clearance increased with weight while hepatic intrinsic clearance decreased. Organ growth and clearance per unit tissue therefore contributed differently to the whole-organ values.
The model’s total oral bioavailability showed substantial variability without a parallel age trend. That overall result did not require gut and liver development to follow identical patterns. The authors also discussed assumptions about blood flow, distribution, and metabolite formation, with sensitivity analyses examining their effects. These were model-derived organ estimates, distinct from directly measuring enzyme activity in tissue. For forensic toxicologists reviewing a pediatric extrapolation, identify whether a cited clearance is systemic, whole-organ intrinsic, or normalized to organ mass. Carrying a number between those definitions can change its meaning. An individual estimate additionally needs the child’s relevant characteristics and the uncertainty in applying the model.
Read the full scientific paper. DOI 10.1007/s11095-018-2458-6.