Tolvaptan for Pediatric ADPKD

Results of previous studies have shown that tolvaptan slows expansion of kidney volume and decline in kidney function in adults with autosomal dominant polycystic kidney disease (ADPKD). According to Djalila Mekahli, MD, PhD, and colleagues, there are few data available on the efficacy and safety of treatment with tolvaptan in children and adolescents with ADPKD.

The researchers reported results of a 1-year, randomized, double-blind portion of a phase 3b two-part trial being conducted at 20 academic pediatric nephrology centers [Clinical Journal of the American Society of Nephrology. 2023;18(1):36-46].

Eligibility criteria included ADPKD and estimated glomerular filtration rate ≥60 mL/min/1.73 m2. The target group was patients 12 to 17 years of age (group 1, enrollment goal >60); patients 4 to 11 years of age could additionally enroll (group 2, anticipated enrollment approximately 40).

Participants received either tolvaptan or placebo titrated by body weight and tolerability. The primary end points of interest were change from baseline in spot urine osmolality and specific gravity at week 1, and assessed inhibition of antidiuretic hormone activity. Secondary end points included change in height-adjusted total kidney volume (htTKV) to month 12 in group 1, safety and tolerability, and quality of life. Statistical comparisons were exploratory and post hoc.

The total cohort included 91 participants; of those, 66 were in group 1 and 25 were in group 2. Least squares mean reduction in spot urine osmolality at week 1 was greater with tolvaptan than placenbo (–390 mOsm/kg vs –90 mOsm/kg, respectively; P<.001). Least squares mean reduction in specific gravity was also greater with tolvaptan than with placebo (–0.009 vs –0.002, respectively; P<.001).

In group 1, the 12-month increase in htTKV was 2.6% with tolvaptan and 5.8% with placebo (P<.05). In the tolvaptan group, 65% experienced aquaretic adverse events and 2% experienced hypernatremia. The corresponding percentages in the placebo group were 16% and 0%. There were no elevated transaminases or drug-induced liver injuries in either group. Four participants in the tolvaptan group discontinued the study drug and three in the placebo group discontinued placebo. Assessments of quality-of-life remained stable in both groups.

In summary, the authors said, “Tolvaptan exhibited pharmacodynamic activity in pediatric ADPKD. Aquaretic effects were manageable, with few discontinuations.”

Clinical Trial registry and registration number: Safety, Pharmacokinetics, Tolerability and Efficacy of Tolvaptan in Children with Adolescents with ADPKD (Autosomal Dominant Polycystic Kidney Disease). NCT02964273.