BACKGROUND: Physiological-based pharmacokinetic models have been used to describe midazolam clearance (CL) maturation. There are no maturation descriptors of CL from neonate to adulthood based on reported estimates at different ages.METHODS: Published CL estimates after intravenous administration from time-concentration profiles were used to construct a maturation model based on size and age. Curve fitting was performed using nonlinear mixed effects models.RESULTS: There were 16 publications reporting an estimate of CL after intravenous administration in children, although few estimates were available from 44-80 weeks postmenstrual age (PMA). CL maturation, standardized to a 70 -kg person was described using the Hill equation. Mature CL was 523 (CV 32%, 95%CI 469, 597) ml·min(-1) ·70 kg(-1) . The maturation half-time was 73.6 (95%CI 59.4, 80.0) weeks PMA and the Hill coefficient 3 (95%CI 2.2, 4.1). Predicted CL changes with age based on this model were in close agreement with physiologically based pharmacokinetic (PBPK) models. A comparison with a published PBPK model predictions revealed a root mean squared prediction error (precision) of 4.0% (95%CI 1.1, 5.8) and bias was -0.9% (95%CI -4.3, 2.6).CONCLUSIONS: Previously published pharmacokinetic parameters can be used to develop maturation models that address gaps in current knowledge regarding the influence of age on a drug's disposition. If a midazolam sedation target concentration of 0.1 mg·l(-1) , similar to that given to adults, is assumed, then we might anticipate steady-state infusion rates of 0.014 mg·kg(-1) ·h(-1) in neonates, 0.05 mg·kg(-1) ·h(-1) in a 1-year-old, 0.06 mg·kg(-1) ·h(-1) in a 5-year-old and 0.05 mg·kg(-1) ·h(-1) in a 12-year-old child. Age-related pharmacodynamic differences that will affect dose and the impact of active metabolites on response are not yet quantified.
Adolescent Aging