Predictive PBPK modeling as a tool in the formulation of the drug candidate TMP-001

Abstract Since many drugs in the therapy scheme of multiple sclerosis (MS) are applied parenterally with significant side effects, oral treatment is the most accepted therapy option for chronic diseases like MS. The drug candidate TMP-001, which has disease-modifying properties, can be applied orally. Beside other symptoms, swallowing disorders have a major impact not only on the health status and quality of life of MS patients, but also impede reliable drug therapy. Consequently, the development of an easy-to-swallow liquid oral dosage form supported by a combined PBPK-IVIVC model was approached. In this context, the impact of formulation parameters was studied. Biorelevant in vitro drug release studies resulted in an almost complete release of 96.91% ± 1.00% in the intestine which was translated to rapidly increasing in silico plasma profiles. The predictions were compared to the outcome of a phase I clinical trial. A partial parameter sensitivity analysis of the in silico model deepened our understanding of the physiological processes underlying human pharmacokinetics.