Toward Therapeutic Control of Circadian Rhythms: Optimisation of Pharmaceutical Administration Models for Circadian Entrainment via Nonlinear Model Predictive Control

Abstract

The ability to shift circadian phase in vivo has the potential to offer substantial health benefits, and constructing an appropriate model — from therapeutic administration to phase response — will enable this possibility. The blood-brain barrier (BBB), however, prevents the absorption of essentially all large and many small molecules, posing a challenge to neurological pharmaceutical development. Motivated by the presence of the circadian molecule KL001, which is capable of causing phase shifts in a circadian oscillator, this work explores the effect of two passive and three active transport mechanisms on the dynamics of circadian phase. Specifically, this thesis investigates the effect of melatonin, which passively diffuses across the BBB, triiodothyronine (T3), amine, and neutral amino acid carrier mediated transport (CMT), and polymeric nanoparticle adsorptive transcytosis administration mechanics. The pharmacokinetic/pharmacodynamic (PK/PD) modeling approach has been considered to describe the physiological dynamic behavior in response to such delivery mechanisms and provides an accurate estimate of the cerebrospinal fluid (CSF) concentration curves. The introduction of the PK/PD models achieves a physiologically accurate prediction of the phase response curve of the circadian oscillator and informs a constrained, infinitesimal parametric phase response curve (ipPRC)-defined, nonlinear model predictive controller (MPC) to compute appropriate dosing for clock re-entrainment. The phase-resetting capacity of these models is investigated through the real-world scenario of jet lag.