TABLE 1.
Plasma exposure data for AZD3965 in the rat studies
| Day 1 μmol·L−1 | Day 4 μmol·L−1 | Day 6 μmol·L−1 | |
|---|---|---|---|
| Han Wistar rats (visual acuity; M&F) | |||
| 200 mg·kg−1 p.o. | 19.5 ± 9.1 | ||
| 500 mg·kg−1 p.o. | 22.8 ± 6.4 | ||
| 1,000 mg·kg−1 p.o. | 30.8 ± 11.2 | ||
| Long Evans rats (visual acuity; M&F) | |||
| 1,000 mg·kg−1 p.o. | 52.9 ± 7.2 | 63.5 ± 9.8 | |
| Long Evans rats (ERG; M) | |||
| 10 mg·kg−1 p.o. | 1.5 ± 0.4 | ||
| 50 mg·kg−1 p.o. | 7.7 ± 2.2 | ||
| 200 mg·kg−1 p.o. | 22.9 ± 4.4 | ||
| 1,000 mg·kg−1 p.o. | 48.0 ± 7.3 |
Note: Data presented are total plasma concentrations (mean ± SD) at 1 h 20 min post‐dose (2 h post‐dose for Day 4 of the repeat‐dose visual acuity study in Long Evans rats). M male; F female. There were no sex differences in exposures (data not shown). Note that there is a small difference in exposure between the two strains of rat and no change in exposure on repeated dosing. Exposure data presented in bold were associated with statistically significant effects on visual acuity or electroretinogram (ERG) in their respective studies. Note that detectable effects on the ERG were observed at approximately threefold lower plasma concentrations than were effects on visual acuity. AZD3965 is approximately 64% unbound in plasma in the rat; therefore, the threshold total plasma exposure of 7.7 μmol·L−1 corresponds to a free plasma concentration of ~3 μmol·L−1. The free concentration reaching the retina is unknown, but the expectation is that it would be at concentrations inhibiting MCT1 (nanomolar range) rather than MCT4 (inactive at 10 μM).