107: A Combined Ex Vivo & Physiologically-based Pharmacokinetic Approach to Determine Fentanyl Dosing in Children on Continuous Renal Replacement Therapy

Statement of Purpose: Critically ill pediatric patients on continuous renal replacement therapy (CRRT) have high mortality rates ranging from 30-70%, due in part to altered and ineffective drug dosing. Changes in drug exposure can result from 1) underlying disease and 2) direct drug interaction with and/or clearance by the CRRT circuit. The extent to which these effects interact and modify drug pharmacokinetics (PK) is currently unknown for most drugs. To address this issue, we developed a fentanyl physiologically based PK (PBPK) model to translate results from ex vivo drug-circuit interaction studies into bedside dosing recommendations for children on CRRT.

Description of Methods & Materials: Fentanyl was injected at therapeutic concentration into ex vivo CRRT circuits and concentrations measured over a 6-hour period. A control was paired with each circuit to determine the amount of drug degradation. A previously published adult PBPK fentanyl model was modified in PK Sim and scaled to children, incorporating ontogeny. Data from the ex vivo experiments were used to parameterize a new PBPK model compartment in MoBi representing the CRRT circuit. The fentanyl pediatric CRRT-PBPK model was used to simulate drug exposure in a 6 year old patient undergoing CRRT. The CRRT-PBPK model was validated using observed data from this individual as part of an ongoing opportunistic PK study of drugs in children on CRRT. Hematocrit, albumin and GFR were all adjusted in the full CRRT-PBPK model to represent critical illness in the individual used for model validation. Lab values for hematocrit and albumin were averaged across the modeled time period. GFR was calculated based on lab values immediately prior to CRRT initiation. The model was then run with and without the CRRT compartment. Average fold error (AFE), absolute average fold error (AAFE) and percent of observed data within the 90% confidence interval were used to determine model bias and precision.

Data & Results: Fentanyl ex vivo mean circuit recovery was 22% (20.6 – 22.8%) at 6 hours with no degradation present in the control. The initial CRRT model underpredicted concentrations. Adding low albumin and hematocrit, which are common in critically ill patients undergoing CRRT, improved model simulations. The CRRT model simulation was significantly lower (P = 2.2 x 10-16) compared to no CRRT (Figure 1). Final model performance is good with all patient samples within the 90% confidence interval and AFE values of 0.89, and AAFE of 1.29.

Interpretation, Conclusion or Significance: The fentanyl CRRT-PBPK model accurately represented drug concentrations in critically ill pediatric patients undergoing CRRT. This is the first PBPK model method to incorporate a CRRT specific compartment and accurately predict drug concentrations in this patient population. Differences between no CRRT and CRRT model simulations suggest a change in dosing may be required for pediatric patients on CRRT. This combined ex vivo and PBPK modeling approach can be used for other drugs to predict concentrations in children on CRRT and guide dosing.

Disclosures: