Use of developmental Midazolam and 1-hydroxymidazolam data with pediatric physiologically based modelling to assess CYP3A4 and UGT2B4 ontogeny in vivo.

Pediatric physiologically based pharmacokinetics modeling in drug development has grown in the past decade but uncertainty remains regarding ontogeny of some drug metabolizing enzymes. In this study a midazolam and 1-hydroxymidazolam PBPK model was developed and used to define the ontogeny for hepatic CYP3A4 and UGT2B4. Data for model development and pharmacokinetic studies on iv midazolam in adults and pediatrics, were collated from the literature. The PBPK model was verified in the adult population and then used to compare the performance of two ontogeny profiles for CYP3A4 in terms of parent drug elimination in pediatrics. Four studies also published data on the 1-hydroxymidazolam and this was used to evaluate the known ontogeny for UGT2B4. For midazolam elimination the Upreti CYP3A4 ontogeny performed better than Salem, mean error and mean squared error were 0.14 and 0.064 compared to 0.69 and 1.21. For 1-hydroxymidazolam elimination, the Simcyp default ontogeny of UGT2B4 appeared to perform best for studies covering the age range 0.5 to 15.7 years whilst for a study in younger ages 0 to 1 years it was the Badee UGT2B4 ontogeny. In preterm neonates overall expression of UGT appeared to be around 10% of that in adults. Identifying the optimal model of CYP3A4 ontogeny is important for the regulatory use of PBPK. The results for midazolam are conclusive but research about other CYP3A4 metabolized compounds will underpin generalizability of the CYP3A4 ontogeny. UGT2B4 ontogeny is less certain, but this study indicates the most likely scenarios. Significance Statement A PBPK model for midazolam and 1-hydroxymidazolam was developed to test various ontogeny scenarios for CYP3A4 and UGT2B4. The CYP3A4 ontogeny of Upreti resulted in more accurate prediction of midazolam PK across 9 clinical studies, age range birth to 18 years. 1-hydroxy midazolam was used as a marker of UGT, the Simcyp default 'no ontogeny' profiles for UGT2B4 performed the best, however for < 1 year of age there was some evidence of over-activity of this enzyme compared to adults.