UNDULY ENHANCED RESPONSE TO TOLVAPTAN IN A WOMAN SHOWING SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION: AN INVESTIGATION OF POSSIBLE CAUSES

Objective: To investigate possible causes of an excessive response to tolvaptan in a woman with syndrome of inappropriate antidiuretic hormone secretion (SIADH). Methods: A 32-year-old woman was admitted to our cardiologic unit 3 months after delivery for hypertension and severe hyponatremia (120 mEq/L). Two hyponatremic episodes had already been documented in her medical history. SIADH was diagnosed and treatment with tolvaptan, an arginine vasopressin (AVP) antagonist, was instituted. After the first 15-mg dose, excessive polyuria (1 L/ hour) and a rapid increase in serum sodium (13 mEq/L in 8 hours) occurred, so that therapy was stopped and restarted 2 days later at a reduced dose (5 mg). This level was effective and well tolerated. To explore the possible pharmacokinetic and pharmacodynamic mechanisms underlying the patient’s hyperresponsiveness, the following tests were carried out: (1) in vivo phenotyping of CYP3A4 activity, the cytochrome responsible for tolvaptan metabolism, with two probe drugs (omeprazole and dextromethorphan); and (2) search for mutations in genes involved in AVP signaling (AVP, V2R, AQP2, OXT).