Pediatric pharmacokinetics and pharmacodynamics of guanabenz for the treatment of vanishing white matter

Vanishing White Matter (VWM) is a leukodystrophy with cystic cerebral white matter degeneration, resulting in neurological decline and premature death. There is currently no treatment. Guanabenz, a central α 2 -adrenergic receptor agonist, ameliorates the disease in VWM mouse models. We aimed to evaluate the validity of a translational guanabenz pediatric pharmacokinetic model, to explore the concentration-toxicity association, and to estimate brain guanabenz concentrations using a biomarker of biological effect and toxicity. Translational modelling was performed to determine the potentially effective guanabenz dose. During a phase 1/2 clinical trial for pediatric VWM patients, this model was evaluated and the correlation between guanabenz concentrations and side-effects was explored. Translating rodent PK/PD models and adult PK models, the estimated pediatric target dose of guanabenz was 2 mg/kg/d, with a minimum effective dose of 1 mg/kg/d and a maximum of 10 mg/kg/d. PK modelling was performed with 32 trial participants, aged 2.4–12.9 years. Evaluation of the translational model showed an underprediction with a median prediction error of -50% with oral doses between 1.04 and 1.68 mg/kg/d. Hallucinations were an unexpected side-effect. A trend was seen in the correlation between the decrease in mean arterial blood pressure and hallucinations. The developed translational model was able to predict plasma concentrations within acceptable range of 2-fold prediction error. The plasma concentrations reached were above the predicted minimal effective dose. Hallucinations were a dose limiting adverse event and the predicted optimal dose may have been underestimated. Blood pressure may be useful as a non-invasive biomarker in future studies. This clinical trial was registered under number: 2017-001438-25 on 28/11/2018.