Mean peak induction of MX1 and OAS1 gene expression in healthy human volunteers, cynomolgus monkeys, and mice after a single dose of GS-9620
| Species Dose | HEDa | ISG Induction without Detectable Serum IFN-α, mean ± S.D.b | ISG Induction with Detectable Serum IFN-α, mean ± S.D.b | |||||
|---|---|---|---|---|---|---|---|---|
| Total | MX1 Fold Increase | OAS1 Fold Increase | Total | IFN-α | MX1 Fold Increase | OAS1 Fold Increase | ||
| mg | n | n | n | n | pg/ml (n) | n | n | |
| Human | ||||||||
| 8 mg | N/A | 5 | 21.7 ± 13.2 (5) | 10.9 ± 5.0 (5) | 1 | 19 | 27.8 | 12.4 |
| 12 mg | N/A | 2 | 28.2 (2) | 11.8 (2) | 4 | 132 ± 201 (4) | 31.6 ± 17.0 (4) | 13.7 ± 5.2 (4) |
| Cynomolgus monkey | ||||||||
| 0.05 mg/kg | 1 | 13 | 5.6 ± 3.3 (5) | 12.2 (2) | 1 | 1792 (1) | 25.6 (1) | 70.4 (1) |
| 0.15 mg/kg | 2.9 | 13 | 16.1 ± 7.1 (11) | 30.4 ± 25.8 (10) | 6 | 457 ± 259 (6) | 19.4 ± 23.2 (6) | 19.6 ± 30.9 (6) |
| 0.5 mg/kg | 9.6 | 5 | 23.8 ± 17.2 (5) | 41.3 ± 32.7 (3) | 23 | 6052 ± 7551 (23) | 38.5 ± 15.9 (23) | 87.5 ± 62.1 (23) |
| 1.5 mg/kg | 29 | 0 | N/A | N/A | 13 | 28186 ± 23788 (13) | 33.2 ± 15.0 (13) | 70.2 ± 50.6 (13) |
| Mouse | ||||||||
| 0.3 mg/kg | 1.4 | N/A | 17.6 ± 7.8 (4) | 3.4 ± 0.5 (4) | N/A | N/A | N/A | N/A |
HED, human equivalent dose; N/A, not applicable.
↵a HED was calculated by multiplying the animal dose in milligrams per kilogram by 0.32 and 0.08 conversion factors for cynomolgus monkey and mouse, respectively, and then converted to a total human dose (milligrams) by multiplying by a standard human body weight of 60 kg ( U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research, 2005).
↵b Animals were included in the calculation if ISG induction was ≥3-fold. Fold increases in MX1 and OAS1 were determined by comparison of pre- and post-treatment levels or comparison with control groups.