Mathematical model could help boost drug efficacy by getting dosing in rhythm with circadian clocks

Researchers at the University of Michigan have developed a mathematical model that reveals how our circadian rhythms can have dramatic impacts on how our bodies interact with medicines.

This could help doctors prescribe medicines to have the best intended effect by syncing the dosing up with the natural clocks of their patients.

“These findings provide a mechanistic basis for chronotherapeutics—optimizing drug efficacy by considering circadian timing,” said the new study’s author Tianyong Yao, an undergraduate researcher in the U-M Department of Mathematics. “This could improve treatment for conditions such as ADHD, depression and fatigue.”

The study, published in the journal PLOS Computational Biology, focused on a class of drugs called dopamine reuptake inhibitors—DRIs for short—which are used to treat narcolepsy and depression. But the model could be generalized to related drugs that are used to help regulate dopamine, a chemical that helps neurons communicate with each other. Such drugs can be used to help manage addiction and Parkinson’s disease, in addition to the conditions Yao mentioned.

“Our mathematical model suggests that taking DRIs a few hours before your body’s natural rise in dopamine can help prolong the treatment’s effects,” said senior author Ruby Kim, a postdoctoral research fellow with Michigan Medicine.

Kim and Yao constructed the model using data from a DRI known as modafinil, used to treat narcolepsy. Having taken that step, doctors could now turn to the model to help predict the impact of the dose and timing of drugs with similar modes of action, Yao said.

“We can examine some more generalized cases and consider a lot of different combinations of dose timing and concentration,” Yao said. “The model could thus help doctors zero in on the most promising regimens for their patients.”

Kim said their model doesn’t replace experiments or clinical trials, but can be used to help guide them.

“Dopamine can vary a lot throughout the day, but there haven’t been many experimental studies looking at time-of-day effects,” she said. “Our study shows that it’s important to take these effects into account.”

Our bodies’ dopamine levels vary naturally throughout the day, which is tied to the activity of certain proteins, which, in turn, is connected to our circadian rhythms. The team showed that the effects of modafinil can vary markedly depending on whether a person takes the drug in rhythm or not.

“Taking modafinil at the wrong time of day can trigger sharp spikes and crashes in dopamine levels, while dosing at the right circadian window sustains dopamine levels much longer,” Yao said.

The model also enabled the duo to go a step further and probe interactions between modafinil and another natural clock that also impacts dopamine levels. This clock, which cycles several times a day rather than just once, is a type of rhythm known as an ultradian rhythm.

This ultradian rhythm for dopamine was discovered in mammals within the last 10 to 15 years, Yao said. How it works isn’t fully understood, but the team’s model, which showed how DRIs lengthened each cycle of this ultradian rhythm, could also help provide information to solve this question of fundamental biology, he said.

“People didn’t really understand the circadian rhythm 100 years ago, but they gathered evidence and came up with a hypothesis,” Yao said. “That’s sort of where we are with this ultradian rhythm.”

Researchers at the University of Michigan have developed a mathematical model that reveals how our circadian rhythms can have dramatic impacts on how our bodies interact with medicines.

This could help doctors prescribe medicines to have the best intended effect by syncing the dosing up with the natural clocks of their patients.

“These findings provide a mechanistic basis for chronotherapeutics—optimizing drug efficacy by considering circadian timing,” said the new study’s author Tianyong Yao, an undergraduate researcher in the U-M Department of Mathematics. “This could improve treatment for conditions such as ADHD, depression and fatigue.”

The study, published in the journal PLOS Computational Biology, focused on a class of drugs called dopamine reuptake inhibitors—DRIs for short—which are used to treat narcolepsy and depression. But the model could be generalized to related drugs that are used to help regulate dopamine, a chemical that helps neurons communicate with each other. Such drugs can be used to help manage addiction and Parkinson’s disease, in addition to the conditions Yao mentioned.

“Our mathematical model suggests that taking DRIs a few hours before your body’s natural rise in dopamine can help prolong the treatment’s effects,” said senior author Ruby Kim, a postdoctoral research fellow with Michigan Medicine.

Kim and Yao constructed the model using data from a DRI known as modafinil, used to treat narcolepsy. Having taken that step, doctors could now turn to the model to help predict the impact of the dose and timing of drugs with similar modes of action, Yao said.

“We can examine some more generalized cases and consider a lot of different combinations of dose timing and concentration,” Yao said. “The model could thus help doctors zero in on the most promising regimens for their patients.”

Kim said their model doesn’t replace experiments or clinical trials, but can be used to help guide them.

“Dopamine can vary a lot throughout the day, but there haven’t been many experimental studies looking at time-of-day effects,” she said. “Our study shows that it’s important to take these effects into account.”

Our bodies’ dopamine levels vary naturally throughout the day, which is tied to the activity of certain proteins, which, in turn, is connected to our circadian rhythms. The team showed that the effects of modafinil can vary markedly depending on whether a person takes the drug in rhythm or not.

“Taking modafinil at the wrong time of day can trigger sharp spikes and crashes in dopamine levels, while dosing at the right circadian window sustains dopamine levels much longer,” Yao said.

The model also enabled the duo to go a step further and probe interactions between modafinil and another natural clock that also impacts dopamine levels. This clock, which cycles several times a day rather than just once, is a type of rhythm known as an ultradian rhythm.

This ultradian rhythm for dopamine was discovered in mammals within the last 10 to 15 years, Yao said. How it works isn’t fully understood, but the team’s model, which showed how DRIs lengthened each cycle of this ultradian rhythm, could also help provide information to solve this question of fundamental biology, he said.

“People didn’t really understand the circadian rhythm 100 years ago, but they gathered evidence and came up with a hypothesis,” Yao said. “That’s sort of where we are with this ultradian rhythm.”