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Pharmacokinetics and Pharmacodynamics of Drospirenone-Estradiol Combination Hormone Therapy Product Coadministered With Hydrochlorothiazide in Hypertensive Postmenopausal Women

From Berlex Pharmaceuticals, Inc, Montville, New Jersey (Dr Karara, Dr Hanes, Dr Ni, Dr Poola, Ms Silang); Division of Clinical Pharmacology and Pharmacokinetics Clinical Research Center, Department of Medicine, Miller School of Medicine, University of Miami, Florida (Dr Alonso, Dr Preston); and Bayer Schering Pharma AG, Clinical Pharmacokinetics, Berlin, Germany (Dr Blode).

The effects of combination hormone therapy of drospirenone (DRSP), a novel progestin with antialdosterone properties, and 17ß-estradiol (E2) on hydrochlorothiazide (HCTZ) pharmacokinetics/pharmacodynamics versus placebo were investigated in a double-blind, placebo-controlled, crossover study. Thirty-six postmenopausal women with stage 1 hypertension maintained on 25 mg of HCTZ once daily were randomized to receive either 3 mg of DRSP/1 mg of E2 or placebo once daily for 4 weeks. Plasma HCTZ, serum DRSP, E2, potassium, aldosterone, and plasma renin activity were determined at baseline and after 4 weeks. Results showed that the combination of DRSP/E2 plus 25 mg of HCTZ is safe and well tolerated in hypertensive postmenopausal women. The pharmacokinetics of HCTZ were not affected by coadministration of DRSP/E2. The geometric mean ratios and 90% confidence intervals ([HCTZ + DRSP/E2]/[HCTZ + placebo]) for HCTZ (a) area under the serum/plasma concentration-time curve from 0 to 24 hours and (b) maximum plasma concentration were 101 (90.7, 112) and 103 (92.8, 115), respectively. In the HCTZ + DRSP/E2 group, serum potassium, aldosterone, and plasma renin activity all increased in a manner marginally consistent with a beneficial antialdosterone effect, counteracting the HCTZ-induced potassium loss and lowering both systolic and diastolic blood pressure. No dose adjustment is required when DRSP/E2 is added to antihypertensive therapy with HCTZ in hypertensive postmenopausal women.

Key Words: Hormone therapy • hypertension • estradiol • drospirenone • aldosterone • aldosterone antagonists • progesterone • progestogens • hydrochlorothiazide • potassium • diuretics • drug interactions

Address for correspondence: Dr. A. Karara, Clinical Pharmacology at Hoffmann-La Roche, 340 Kingsland Street, Nutley, NJ 07110-1199.

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