Figure EV6. Two types of adaptive chronotherapeutics.

• A
  Detailed diagram describing an adaptive chronotherapeutics which identifies a precise dosing regimen by solely adjusting dosing time. Step 1: 10 mpk at ZT3 is recommended so that the following dosing time can be flexibly advanced or delayed depending on current drug effect with a low probability of leading to an accumulating or an alternating phase shift (Fig EV4B–D). Step 2: Single daily dosing is performed until a stable phase delay is observed (i.e., the phase delays at two consecutive days, i−1 and i, are similar, $|P_i-P_{i-1}|$ < 0.2 h). However, if a larger phase delay than the desired one is achieved before the stable phase delay is obtained (i.e., $\overline{P}-P_i$ > 0.5 h), the dosing is immediately stopped. Step 3: Depending on the drug effect observed in Step 2, the dosing regimen is modified (Fig 5A). If the induced phase delay is smaller than the desired phase delay (i.e., $P_i-\overline{P}$ > 0.5 h), the dosing time is delayed by 1 h. Otherwise ($\overline{P}-P_i$ > 0.5 h), the dosing time is advanced by 1 h. Step 2 and Step 3 are repeated until a constant stable phase delay similar to the desired one ($|P_i-\overline{P}|\le$ 0.5 h) is achieved.
• B
  Modification of the adaptive chronotherapeutics (A) to adjust dose level as well as dosing time simultaneously: If the induced phase delay is smaller than the desired phase delay (i.e., $P_i-\overline{P}$ > 0.5 h), the dose level is increased by 1 mpk and the dosing time is delayed by 1 h. Otherwise ($\overline{P}-P_i$ > 0.5 h), the dose level is decreased by 1 mpk and the dosing time is advanced by 1 h.
• C–F
  Due to the simultaneous change in dose level and dosing time (B), the precise dosing regimen can be more rapidly achieved with a lower dose level than the adaptive chronotherapeutics solely adjusting the dosing time (Fig 5B–E).