Adequate Sensitivity Ramifications of the UF Adjustment to the AET Applied to a Drug Product. Is Method Sensitivity Adequate to Achieve the Adjusted AET?a
| Maximum Daily Dose Vol. (mL) | AET, µg/mL | LoD (µg/mL)b | Is the LoD ≤ the Adjusted AET? | |||
|---|---|---|---|---|---|---|
| No UF | UF = 2 | UF = 5 | UF = 10 | |||
| Acute Drug Product, AET is based on a Toxicological Dose Threshold (TDT) of 5 µg/day | ||||||
| 1 | 5 | 0.05 | Yes | Yes | Yes | Yes |
| 10 | 0.5 | 0.05 | Yes | Yes | Yes | Yes |
| 100 | 0.05 | 0.05 | Yes | No | No | No |
| Critical Daily Dose Volumec | 100 | 50 | 20 | 10 | ||
| Chronic Drug Product, AET is based on a Toxocological Dose Threshold (TDT) of 1.5 µg/day | ||||||
| 1 | 1.5 | 0.05 | Yes | Yes | Yes | Yes |
| 10 | 0.15 | 0.05 | Yes | Yes | No | No |
| 100 | 0.015 | 0.05 | No | No | No | No |
| Critical Daily Dose Volume | 30d | 15 | 6 | 3 | ||
↵a Abbreviations: UF, uncertainty factor; AET, analytical evaluation threshold; LoD, limit of detection.
↵b Taken as 0.05 µg/mL, within the capability of many optimized chromatographic screening methods.
↵c That daily dose volume above which the LOD is greater than the AET. When this occurs, the analytical method is no longer protoective as it cannot repond to compounds at levels of the AET.
↵d For example, AET = LOD = 0.05 µg/mL = (1.5 µg/day) ÷ Critical Daily Dose Volume. Critical Daily Dose Volume = 30 mL.