Tolvaptan pharmacokinetics and pharmacodynamics in adolescents with autosomal dominant polycystic kidney disease
Abstract
Tolvaptan, an oral selective antagonist of the vasopressin V2 receptor, is the only medication for autosomal dominant polycystic kidney disease (ADPKD) with disease-modifying properties in adults at risk of rapid progression. The pharmacokinetics (PK) and pharmacodynamics (PD) of tolvaptan have been well characterized in adults with ADPKD, but data are lacking for adolescents. We assessed prespecified PK/PD endpoints from a randomized clinical trial of tolvaptan in adolescents (ages 12-17 years) with ADPKD (NCT02964273). Dense 24-h PK and PD sampling was conducted in a subgroup of 20 trial participants after a minimum of 1 month on treatment. Endpoints included standard PK parameters and PD endpoints of urine volume, fluid intake, fluid balance, and clearance of sodium, creatinine, and free water. The analysis population (12 tolvaptan; 8 placebo) had well-preserved kidney function. Total daily tolvaptan doses ranged from 22.5-60.0 mg dependent on tolerability. All tolvaptan-treated adolescents had a tolvaptan maximum plasma concentration > 100 ng/mL, urine osmolality in each collection interval of < 215 mOsm/kg, and positive 24-h free water clearance values. In the placebo group, median 12- to 24-h urine osmolality was 507 mOsm/kg, and free water clearance values were close to zero. There was wide interindividual variability in response to tolvaptan, with no correlation between exposure and 24-h urine output or free water clearance. Tolvaptan did not affect sodium excretion.…
How strong is the evidence?
Evidence Hub reads this as a randomized trial, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence. Reported size: 20 participants or records.
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