Dissertation for Pharmacy Doctoral degree at Sahlgrenska Academy, Institute of Neuroscience and Physiology, Department of Pharmacology
Opponent: Associate Professor Irena Loryan, Department of Pharmacy, Uppsala University, Uppsala
Examining committee: Professor Elisabet Jerlhag Holm (chair), Associate Professor Urban Fagerholm (Prosilico/UU) and Professor Hans Lennernäs (UU)
The disputation is held in English
Chairperson of the disputation: Professor Lars Westberg
Cannabidiol (CBD) oral oil solution is approved as add-on treatment for severe childhood epileptic syndromes, but clinical pharmacokinetic knowledge remains limited, especially in pediatric patients. CBD shows dose-dependent oral absorption, high pharmacokinetic variability, and therapeutic concentrations are not yet well established. In addition, potential drug-drug interactions with antiseizure medications require further investigation. Better methods for predicting CBD exposure under different dosing regimens could support treatment optimization, particularly in children.
This thesis addressed these questions through several complementary studies. First, a rapid and sensitive HPLC-MS/MS assay was developed and validated for quantification of CBD and its metabolites 7-OH-CBD and 7-COOH-CBD. Second, the effects of concomitant antiseizure medications on CBD intrinsic clearance were examined in vitro in pooled human liver microsomes. Third, effective and neurotoxic CBD concentrations were explored in human iPSC-derived neuronal culture models using microelectrode array techniques. Finally, a physiologically based pharmacokinetic (PBPK) model was developed for CBD and its active metabolite 7-OH-CBD and evaluated against available clinical literature data.
The results showed that most tested antiseizure medication combinations had marginal to moderate effects on CBD hepatic intrinsic clearance, while stiripentol caused a marked reduction. CYP3A4 substrates also reduced the metabolism of 7-OH-CBD. The in vitro neuronal models provided preliminary estimates of effective antiseizure and neurotoxic CBD concentrations. The PBPK model showed good predictive performance in adults and fair performance in children, and was used to simulate CBD exposure in children of different ages and during combination treatment.
Overall, the thesis contributes new knowledge on CBD metabolism, effects, and exposure prediction, with relevance for improved dosing and treatment optimization in pediatric epilepsy.