Table 1.
Mean Plasma Concentrations and Exposure Margins Relative to Predicted Human Clinical Exposures Across in vivo Studies.
| Dose (mg/kg per dose) | Cmaxa (μg/mL) (total) | AUC24a (μg/h/mL) (total) | Exposure margin (Cmax) (total)b | Exposure margin (AUC24) (total)b |
|---|---|---|---|---|
| Nervous system and pulmonary safety pharmacology GLP studies in male rats (n = 6)c | ||||
| 60 (q.d.) | 11.0 | 25.0 | 2.7 | 0.4 |
| 1000 (q.d.) | 72.4 | 961.0 | 17.0 | 14.0 |
| Cardiovascular safety pharmacology GLP studies in male cynomolgus monkeys (n = 8) | ||||
| 20 (b.i.d.) | ND | ND | –– | –– |
| 75 (b.i.d.) | 14.7 | 131.0 | 3.6 | 1.9 |
| 14-Day oral GLP toxicity study in rats (n = 15) | ||||
| 60 (q.d.) | 13.3 | 17.2 | 3.2 | 0.25 |
| 200 (q.d.) | 27.1 | 80.5 | 6.5 | 1.2 |
| 1000 (q.d.) (NOAEL) | 51.5 | 292.0 | 12 | 4.3 |
| 1-Month oral GLP toxicity study in rats (n = 15) | ||||
| 60 (q.d.) | 12.8 | 19.2 | 3.1 | 0.28 |
| 200 (q.d.) | 26.0 | 94.9 | 6.3 | 1.4 |
| 1000 (q.d.) (NOAEL) | 44.5 | 548.0 | 11.0 | 8.0 |
| 15-Day oral GLP toxicity study in cynomolgus monkeys (n = 3) | ||||
| 20 (b.i.d.) | 2.4 | 9.6 | 0.6 | 0.1 |
| 50 (b.i.d.) | 11.8 | 52.6 | 2.9 | 0.8 |
| 300 (b.i.d.) (NOAEL) | 106.0 | 1220.0 | 26.0 | 18.0 |
| 1-Month oral GLP toxicity study in cynomolgus monkeys (n = 3) | ||||
| 20 (b.i.d.) | 1.4 | 5.6 | 0.3 | 0.1 |
| 50 (b.i.d.) | 7.8 | 45.9 | 1.9 | 0.7 |
| 300 (b.i.d.) (NOAEL) | 87.5 | 991.0 | 21.0 | 14.0 |
aAUC24 and Cmax values indicate mean plasma exposure concentrations and reported values were obtained near termination, or as specified.
bExposure margins calculated using mean animal exposures relative to predicted human total nirmatrelvir Cmax of 4.14 μg/mL and AUC24 of 68.6 μg/h/mL at a b.i.d. dose of 300/100 mg of nirmatrelvir/ritonavir.
cExposures are based on Day 1 males from the 14-day toxicity study in rats.
ND, not determined; NOAEL, no observed adverse event level.