Use of low-dose clinical pharmacodynamic and pharmacokinetic data to establish an occupational exposure limit for dapagliflozin, a potent inhibitor of the renal sodium glucose co-transporter 2

- The initial occupational exposure limit (OEL) for dapagliflozin used a standard approach and uncertainty factors.
- Since this initial OEL, data from low-dose pharmacodynamic and pharmacokinetic studies were developed.
- Dose-related exposures of dapagliflozin were measured at doses ⩾0.1 mg, and glucosuria was observed at doses ⩾0.3 mg.
- The human No Observed Effect Level (NOEL) for glucosuria, the most sensitive effect, was 0.1 mg.
- A refined OEL based on the identified NOEL for dapagliflozin was calculated to be 0.01 mg/m3.

Classical risk assessment models for setting safe occupational exposure limits (OEL) have used multiple uncertainty factors (UF) applied to a point of departure (POD), e.g., a No Observed Effect Level (NOEL), which in some cases is the pharmacological effect. Dapagliflozin promotes glucosuria by inhibiting the renal sodium-glucose cotransporter-2 transporter. The initial OEL for dapagliflozin (0.002 mg/m3) was calculated when low dose clinical data was not available to identify a NOEL resulting in the need to use excessive UFs. To reduce the UFs from the OEL, a clinical pharmacodynamic [glucosuria and urinary glucose dipstick (UGD)] and pharmacokinetic study was conducted with single oral doses of 0.001, 0.01, 0.1, 0.3, 1.0 or 2.5 mg administered to 36 healthy subjects. Dose-related dapagliflozin systemic exposures were observed at doses ⩾0.1 mg and glucosuria was observed at doses ⩾0.3 mg and corroborated by UGD. The NOEL was therefore 0.1 mg for glucosuria. For setting the new OEL, no UFs were required. Dividing the POD by 10 m3 (the volume of air an adult inhales in a workday), the resulting OEL was 0.01 mg/m3. In conclusion, low-dose clinical pharmacodynamic and pharmacokinetic data can allow the OEL to be adjusted to the highest safe level.