Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Boston, MA 02134, USA.
Sansum Diabetes Research Institute, Santa Barbara, CA 93105, USA.
Int J Mol Sci. 2023 Oct 2;24(19):14830. doi: 10.3390/ijms241914830.
The ability to shift circadian phase in vivo has the potential to offer substantial health benefits. However, the blood-brain barrier prevents the absorption of the majority of 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, we investigated the pharmacokinetics of different neurological pharmaceuticals on the dynamics of circadian phase. Specifically, we developed and validated five different transport models that describe drug concentration profiles of a circadian pharmaceutical at the brain level under oral administration and designed a nonlinear model predictive control (MPC)-based framework for phase resetting. Performance of the novel control algorithm based on the identified pharmacokinetic models was demonstrated through simulations of real-world misalignment scenarios due to jet lag. The time to achieve a complete phase reset for 11-h phase delay ranged between 48 and 72 h, while a 5-h phase advance was compensated in 30 to 60 h. This approach provides mechanistic insight into the underlying structure of the circadian oscillatory system and thus leads to a better understanding of the feasibility of therapeutic manipulations of the system.
体内生物钟相位移动的能力具有带来重大健康益处的潜力。然而，血脑屏障阻止了大多数大分子和许多小分子的吸收，这对神经药物的开发构成了挑战。受昼夜节律分子 KL001 的存在的启发，KL001 能够引起生物钟振荡器的相位移动，我们研究了不同神经药物对生物钟相位动力学的药代动力学。具体来说，我们开发并验证了五个不同的转运模型，这些模型描述了口服给药时生物钟药物在大脑水平上的药物浓度曲线，并设计了基于非线性模型预测控制（MPC）的相位重置框架。通过模拟因时差导致的现实世界中的失准情况，证明了基于所识别的药代动力学模型的新型控制算法的性能。对于 11 小时的相位延迟，完全相位重置的时间范围在 48 到 72 小时之间，而 5 小时的相位提前则在 30 到 60 小时内得到补偿。该方法为生物钟振荡系统的底层结构提供了机理上的见解，从而更好地理解了对系统进行治疗干预的可行性。
