Midazolam Dosing During CRRT: A Combined Ex Vivo and Physiologically-Based Pharmacokinetic Approach

Children supported with continuous renal replacement therapy have high mortality rates ranging from 30% to 70%. The cause of this high mortality is multifactorial and includes ineffective drug dosing and altered drug pharmacokinetics. Changes in drug exposure can result from (1) underlying disease; and (2) direct drug interaction and/or clearance by the circuit. The extent to which these effects interact and modify drug pharmacokinetics is currently unknown for most drugs. As a result, there is little guidance on drug dosing in this population. We have developed a combined ex vivo and physiologically-based pharmacokinetic modeling approach to mechanistically model midazolam concentrations in pediatric patients on continuous renal replacement therapy. Published models were scaled to children and modified to incorporate patient-specific physiological changes due to critical illness including residual renal function, hematocrit, albumin levels, and inflammation-induced downregulation of drug metabolizing enzymes. A compartment representing the dialysis circuit was created, parameterized using ex vivo data, and added to the full child physiological based pharmacokinetic model. The child model was then used to predict drug exposure in children undergoing continuous renal replacement therapy. Observed data from an ongoing opportunistic pharmacokinetic study were used to validate the models. The midazolam continuous renal replacement therapy models accurately represented drug concentrations and were used to predict optimal drug dosing. Model informed dosing for all age groups fell within the standard dosing range suggesting no changes are needed during continuous renal replacement therapy.