PT-011 - PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELING WITH PAIRED PLASMA AND CEREBROSPINAL FLUID CONCENTRATIONS OF LEVETIRACETAM IN PATIENTS WITH EXTERNAL VENTRICULAR DRAINS.

P. Hunt¹, K. Ampofo², R. Iyer¹, D. Green¹, A. Whelan¹, S. Tanner¹, J. Kestle¹, V. Yellepeddi¹, K. Watt³; ¹University of Utah, Salt Lake City, UT, USA, ²University of Utah, Salt Lake City, UT, United States, ³Division of Clinical Pharmacology, Department of Pediatrics, Spencer Fox Eccles School of Medicine, University of Utah, Salt Lake City, Utah, USA.

Background: Despite the advantages of new anti-epileptic drugs including levetiracetam (LEV), epilepsy remains resistant to treatment in up to 20% of patients. The extent to which treatment resistance results from inadequate drug exposure in the central nervous system (CNS) is not well understood because of the difficulty in obtaining representative pharmacokinetic (PK) samples. External ventricular drains therapeutically remove cerebrospinal fluid (CSF) from the patient and enable non-invasive PK sampling to parameterize physiologically based pharmacokinetic (PBPK) models and optimize treatment based on CSF exposure.

Methods: We developed a whole-body CNS-PBPK model of LEV in children. The model included blood-brain barrier permeability, ventricular and spinal CSF compartments, and CSF production and flow. The CNS-PBPK model provided predictions of plasma vs. CSF exposure to LEV. We compared these model predictions with rich plasma and CSF observed data from an ongoing, prospective PK study of LEV (10-13 mg/kg twice daily) in children with external ventricular drains. We refined CNS-PBPK model parameters and assessed model performance using average fold error (AFE) and absolute average fold error (AAFE). We used the final model to compare exposure in plasma vs. CSF by calculating ratios for Cmin, Cmax, and AUC0-τ. Finally, we calculated the percentage of time that plasma and CSF concentrations in a virtual adolescent population remained above a therapeutic target of 10 mg/L at doses of 10, 15, and 20 mg/kg twice daily.

Results: The validated CNS-PBPK model accurately captured the 28 observed paired plasma and CSF concentrations from three adolescent patients. Plasma and CSF AFE were 1.04 and 1.10, and AAFE were 1.08 and 1.18, respectively. The model predicted comparable exposure between plasma and CSF, with a plasma to CSF AUC0-τ of 1.0 (Figure 1). At simulated doses of 10, 15, and 20 mg/kg, 95% of plasma (CSF) concentration predictions remained above 10 mg/L for 46% (49%), 84% (94%), and 100% (100%) of the dosing interval, respectively.

Conclusion: CSF exposure to LEV is reflected by plasma exposure, and plasma exposure may effectively guide optimal therapy. A dose of 20 mg/kg twice daily should achieve steady-state plasma and CSF levels of 10 mg/L for 100% of the dosing interval for epilepsy in adolescents.