Immediate versus modified release hydrocortisone in mitotane-treated patients with adrenocortical cancer

Objective: Mitotane induces hepatic CYP3A4 activity, resulting in accelerated cortisol inactivation, and also increases cortisol binding globulin (CBG). Therefore, higher hydrocortisone doses are required in patients with adrenocortical cancer (ACC) on mitotane treatment. Modified release hydrocortisone has not been used in mitotane-treated ACC patients yet.

Aim: Case series to compare serum cortisol, calculated free serum cortisol and ACTH levels in ACC patients on mitotane treatment with immediate and modified release hydrocortisone.

Design: Pharmacokinetics of immediate and modified release hydrocortisone, each administered at a dose of 40-20-0mg, in 9 patients with ACC and adjuvant mitotane treatment. For comparison, ten patients with secondary adrenal insufficiency (SAI) on three different hydrocortisone regimens, and ten healthy males were included.

Methods: Serum cortisol and plasma ACTH were measured by chemiluminescent enzyme immunoassay, and CBG by RIA, followed by calculation of free cortisol.

Results: Calculated free serum cortisol levels after 40mg immediate release hydrocortisone in ACC patients (46±14nmol/l) were similar to those after 10mg immediate release hydrocortisone intake in men with SAI (64±16nmol/l) or to the physiological morning free cortisol levels in healthy subjects (31±5nmol/l), Compared to immediate release hydrocortisone, free cortisol levels after 40mg modified release hydrocortisone in ACC patients were significantly lower (12±3nmol/l; p=0.03) resulting in a generally lower AUC (98±21 vs 149±37 nmol*h/l; p=0.02).

Conclusions: 40-20-0mg immediate release, but not modified release hydrocortisone, resulted in sufficient glucocorticoid coverage in patients with ACC under mitotane treatment. The use of equivalent doses of modified release hydrocortisone preparation should be avoided in patients on mitotane treatment.