Population PK modeling of Midazolam in Children; The effect of age versus other covariates
I. Ince(1,2), S.N. de Wildt(1), M.Y.M. Peeters(3), N.J. Vet(1), D. Tibboel(1), M. Danhof(2), C.A. Knibbe(1,2,3)
(1)ErasmusMC Sophia Children’s Hospital, Departments of Paediatric Surgery and Paediatrics, Rotterdam, The Netherlands, (2)Leiden/Amsterdam Center For Drug Research, Department of Pharmacology, Leiden, The Netherlands, (3)St. Antonius Hospital, Department of Clinical Pharmacy, Nieuwegein, The Netherlands
Objectives: In order to develop rational dosing schemes for drugs in children, we investigate the influence of age-related changes on the PK and PD of drugs. For the ontogeny of the CYP3A subfamily, we use midazolam as an in vivo probe to describe the clearance of CYP3A substrates in different patient populations, ranging from neonates to adolescents. The aim of the current analysis is to study, among other covariates, the influence of age-related changes on the clearance of midazolam in two paediatric populations.
Methods: Midazolam data from two different studies were used; 21 critically ill pediatric patients (2 days - 17 years) received midazolam for sedation [1] and 23, previously healthy children (3 months - 25 months) received midazolam postoperatively after elective craniofacial surgery [2]. The two datasets were merged in R and population PK modeling was performed using NONMEM 6.2. During the covariate analysis step, the influence of the study population (study factor), postnatal age, bodyweight, gender, and severity of illness (PELOD score) on clearance were investigated.
Results: Using a 2 compartment PK model the simple model of the combined dataset without covariates showed remarkable differences in clearance between the postoperative [1] and critically ill [2] children. The influence of bodyweight on clearance seemed to vary considerably between the two study populations. In the covariate analysis, a study factor added to clearance, as well as bodyweight as a covariate for clearance of midazolam for each of the two patient groups, all proved to significantly improve the model. Clearance of midazolam was found to be reduced by 93% in critically ill children compared to postoperative children. The influence of bodyweight was linear in postoperative children, whereas an exponential scaling factor of 0.48 was found in critically ill children. Age and PELOD score were less predictive covariates for clearance compared to study factor and bodyweight.
Conclusions: In pediatric pharmacology, the emphasis is usually on the age-related influence on PK parameters. We show here that, similar to the adult population, other covariates (e.g. health state) should be quantified as well. More datasets including metabolites will be added to the PK and PD analysis, which will be followed by validation procedures, after which specific dosing guidelines will be developed.
References:
[1] Peeters, M.Y. et al. (2006) Propofol pharmacokinetics and pharmacodynamics for depth of sedation in nonventilated infants after major craniofacial surgery. Anesthesiology 104 (3), 466-474
[2] de Wildt, S.N. et al. (2003) Population pharmacokinetics and metabolism of midazolam in pediatric intensive care patients. Crit Care Med 31 (7), 1952-1958
