SUN-460 Anticipating Hypokalemia in Patients With ACTH-Dependent Cushing Syndrome Treated With Mifepristone: Utilization of Cortisol and ACTH Levels to Identify At-Risk Patients

Background: Hypokalemia (K+ level <3.5 mEq/L) is common in patients with hypercortisolism. Treatment with mifepristone, a glucocorticoid receptor antagonist, can exacerbate hypokalemia due to the mineralocorticoid effects produced by the rapid and significant increase in cortisol levels that result from the loss of negative feedback of the HPA axis. Correction of hypokalemia is required prior to initiating mifepristone and K+ levels must be closely monitored during treatment. However, there is little guidance to help clinicians identify patients who may be at a greater risk for developing hypokalemia during mifepristone therapy and who may benefit from prophylactic treatment (eg, mineralocorticoid antagonists, potassium replacement). Method: Using data from the 24-week, open-label, phase 3 SEISMIC study, this report investigated associations between cortisol and adrenocorticotropic hormone (ACTH) levels and the development of hypokalemia in patients with ACTH-dependent Cushing syndrome treated with mifepristone. Data from 47 patients were retrospectively analyzed using logistic regressions and receiver operating characteristic (ROC) curves. Analyses were performed to identify factors associated with early-onset hypokalemia (occurring within the first 2 weeks of mifepristone treatment during doses of 300 mg/day) and late-onset hypokalemia (occurring after 2 weeks of mifepristone treatment during dose escalation). Results: Nineteen patients (40.4%) developed hypokalemia at least once during mifepristone treatment. Of these 19 patients, 10 (52.6%) developed hypokalemia by day 14. Early-onset hypokalemia was significantly related to baseline serum cortisol levels (P=.0155). Baseline serum cortisol levels >27 µg/dL (>750 nmol/L) were associated with a 6.8-fold increase in the occurrence of early-onset hypokalemia vs patients with cortisol ≤27 µg/dL (≤750 nmol/L) (58.3% vs 8.6%, P<.0011). Late-onset hypokalemia was significantly related to the 2-week ACTH levels (P=.0032). At 2 weeks, ACTH levels >112 pg/mL (>25 pmol/L) were associated with a 5.64-fold higher risk of late-onset hypokalemia vs patients with ACTH ≤112 pg/mL (≤25 pmol/L) (75% vs 13.3%; P<.0001). ACTH levels >112 pg/mL (>25 pmol/L) at 2 weeks were also associated with a greater risk of severe (K+ ≤2.5 mEq/L) or recurrent hypokalemia. Conclusions: Serum cortisol and ACTH levels may be useful in identifying patients at risk for developing hypokalemia while being treated with mifepristone. Patients with serum cortisol levels >27 µg/dL (>750 nmol/L) assessed before mifepristone initiation had a 6.8-fold increase in occurrence of early-onset hypokalemia. Patients with ACTH levels >112 pg/mL (>25 pmol/L) at 2 weeks after initiation of mifepristone (prior to dose escalation) had a 5.64-fold higher risk of late-onset hypokalemia.