In the TEMPO clinical trial of tolvaptan among patients with autosomal dominant polycystic kidney disease (ADPKD), researchers observed a hepatic safety signal for tolvaptan; the one to 18 month treatment period was the time of greatest susceptibility. Researchers led by Vicente E. Torres, MD, PhD, conducted a phase 3b, open-label extension study (NCT02251275) to evaluate long-term safety of tolvaptan in patients with ADPKD. Liver enzyme level was monitored every month for the initial 18 months of treatment and every three months thereafter.
The researchers reported results of the extension study during a poster session at Kidney Week 2019 in a poster titled Long-Term Safety and Tolerability of Tolvaptan (TLV) in Later-Stage ADPKD.
The cohort included patients from the REPRISE trial (n=570 placebo/506 tolvaptan), TEMPO 4:4 (n=718), and nine from prior trials. The tolvaptan exposure prior to inclusion in the extension study was <5 years for patients from TEMPO 4:4 and approximately 1 year for patients randomized to tolvaptan in REPRISE. In patients with tolvaptan exposure of <18 months, hepatic safety was monitored every month; then every 3 months thereafter. The starting tolvaptan dose depended on the prior trial; maintenance regimens in the extension study were daily split doses 45/15 mg, and 90/30 mg, with down-titration allowed for tolerability.
Of the 1803 participants, 1800 received one or more doses of tolvaptan. The duration of tolvaptan exposure in this extension study ranged from 1 to 1435 days; median exposure was 651 days.
The percentages of treatment-emergent adverse events (TEAEs) were similar across the three subgroups; however, the REPRISE placebo cohort reported more TEAEs (3678) than the REPRISE tolvaptan group (2965) and the TEMPO 4:4 cohort (3297). Overall, the most common TEAEs were thirst (23%), renal pain (20%), polyuria (20%), hypertension (17%), nasopharyngitis (15%), and nocturia (15%). Patients in the REPRISE placebo group experienced aquaretic AEs most frequently, including thirst, 32%; polyuria, 32%; and nocturia, 22%. There were no Hy’s Law cases.
TEAE alanine transaminase (ALT) increased 2.8%; median time to ALT increase was 245 days. TEAE aspartate aminotransferase (AST) increased 0.6%; median time to AST increase was 251 days.
In conclusion, the researchers said, “Aquaretic AEs and discontinuations due to AEs were less frequent in patients with longer tolvaptan exposure. [There were] no new Hy’s Law cases with monthly monitoring during the first 18 months of treatment, nor in previously tolvaptan treated patients, nor in the 570 patients who started tolvaptan in the present study.”
Source: Torres VE, Chapman AB, Devuyst O, et al. Long-term safety and tolerability of tolvaptan (TLV) in later-stage ADPKD. Abstract of a poster presented at the American Society of Nephrology Kidney Week 2019 (Abstract TH-PO834), November 7, 2019,Washington, DC.