PII-121 - CONTRIBUTION OF INFLAMMATION AND OBESITY TO VARIABILITY IN MIDAZOLAM PHARMACOKINETICS IN CHILDREN.
Thursday, March 23, 2023
5:00 PM – 6:30 PM EDT
N. Ahmed1, Y. Chhonker1, D. Murry1, J. Leeder2, R. Selvarangan3, A. Sasidharan3, S. Chan2,4, N. Artz3, V. Williams3, C. Friesen3, A. Gaedigk3, V. Shakhnovich3,4,5; 1University of Nebraska Medical Center, Omaha, NE, USA, 2Children's Mercy Kansas City, Kansas City, MO, USA, 3Children's Mercy Kansas City, Kansas City, MO, USA, 4University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA, 5Center for Children's Healthy Lifestyles and Nutrition, Kansas City, MO, USA.
PhD Student University of Nebraska Medical Center, United States
Background: Understanding the relative contribution of body habitus, organ physiology and inflammation to pharmacokinetics (PK) is critical for predictive models of drug dose individualization in obesity. We explored this for midazolam (MDZ) in children. Methods: After administering 2mg intravenous MDZ, plasma concentrations of MDZ and 1-hydroxy (1-OH) MDZ were quantitated using LC-MS/MS in 22 children with a CYP3A4*1/*1 genotype. PK parameters were generated by non-compartmental analysis (Pheonix 6.4) and compared across weight groups based on body mass index (BMI). Liver fat (%) was quantified by magnetic resonance imaging, and plasma inflammatory cytokines using the 21-plex MILLIPLEX Human Cytokine/Chemokine Bead Panel (MilliporeSigma). Nonparametric tests and bivariate plots were used for statistical comparisons and correlations explored in JMPv16; data are presented as median (range) or r2, α=0.05. Results: MDZ CL (L/hr/kg) and Vd (L/kg) ranged from 0.12-0.49 (median 0.26) and 1.36-6.05 (median 2.23) respectively. Compared to MDZ Vd (L/kg) in normal weight children (1.62 (1.24-1.83), differences were most pronounced in morbid obesity [2.26(1.34-3.36)] and obesity [2.3 (1.38-3.22)]. Positive correlations were observed for free 1-OH MDZ and MDZ Vd and total body weight, BMI z-score and liver fat (p < 0.05). In obesity, MDZ Cmax and AUClast correlated inversely with IL-1B and IL-6, while Vd increased (r2≥0.5, p< 0.05). Conclusion: Vd of MDZ and 1-OH MDZ was increased in obesity as previously reported. Our data suggest that interindividual variability may be explained by obesity-related inflammation in IL-1B and IL-6, known to downregulate hepatic CYP3A4 activity. Integration of additional data through population PK methods is in progress.
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