Safety Profile of Tolvaptan in the Treatment of Autosomal Dominant Polycystic Kidney Disease

Abstract

Autosomal dominant polycystic kidney disease constitutes the most prevalent hereditary kidney disease, associated with high rates of morbidity leading eventually to end-stage renal disease. Tolvaptan is a selective vasopressin antagonist and has emerged as a promising therapeutic option for patients with autosomal dominant polycystic kidney disease. The present review summarized current evidence regarding the safety profile of tolvaptan in patients with the disease. Consistent with its pharmacological action, aquaretic adverse events represent the most common side effects of tolvaptan, consisting of polyuria, pollakiuria and polydipsia. Gradual dose titration based on urinary osmolality, as well as dietary interventions aiming to reduce solute excretion, have been proposed as potential strategies to mitigate polyuria. In addition, tolvaptan administration may be complicated by liver injury, characterized by alanine aminotransferase and bilirubin elevations. Hepatotoxicity has been suggested to be triggered by impaired biliary clearance, activation of innate immunity and increased oxidative stress. Frequent monitoring of liver function tests has been shown to be effective in preventing Hy’s Law and liver failure cases. Uric acid elevation due to reduced renal excretion may lead to hyperuricemia and gout, although no drug discontinuations have been linked to these events. Future studies should confirm the safety profile of tolvaptan in large-scale real-world studies, clarify the pathogenetic pathways leading to hepatotoxicity and define its role in special populations, especially pediatric patients.

Inhibition of Centrosome Clustering Reduces Cystogenesis and Improves Kidney Function in Autosomal Dominant Polycystic Kidney Disease

“…In parallel, Pkd1 RC/RC mice were given Tolvaptan, a selective vasopressin receptor 2 (V2) antagonist that is currently the only FDA approved drug for treatment of ADPKD ( 53, 54 ) and has a different mechanism of action than centrosome clustering inhibitors. Similar to the 2-month treatment plan, the mice showed no adverse effects to CCB02, whereas Tolvaptan-treated animals showed significant weight loss over that 5-month period (Figure 5B), which has been previously reported as a significant side effect of this compound ( 54, 55 ). Treatment with CCB02 resulted in preservation of kidney size, reduced cyst index and cyst number compared to control Pkd1 RC/RC , and better than the Tolvaptan treated group (Figure 5C-G and Supplemental Figure 5, A and B).…”

“…The copyright holder for this preprint this version posted November 17, 2022. ; https://doi.org/10.1101/2022.11.16.516801 doi: bioRxiv preprint receptor 2 (V2) antagonist that is currently the only FDA approved drug for treatment of ADPKD (53,54) and has a different mechanism of action than centrosome clustering inhibitors. Similar to the 2-month treatment plan, the mice showed no adverse effects to CCB02, whereas Tolvaptan-treated animals showed significant weight loss over that 5-month period (Figure 5B), which has been previously reported as a significant side effect of this compound (54,55).…”

“…These compounds were well tolerated by the animals, who showed better weight management, feeding behavior and urination that those treated with Tolvaptan (Figure 5). This is not surprising since Tolvaptan has been reported to cause changes in water retention, fluid secretion, urination and weight maintenance ( 54, 55 ). Importantly, treatment with the centrosome clustering inhibitors, followed by a washout period where no drug was administered for two months, showed that the observed improvement in kidney morphology and function were maintained well after the cells with CA are eliminated.…”

The role of tolvaptan in pulmonary hypertension: A retrospective study

“…[ 20 – 22 ] Some studies have demonstrated that TLV increases the serum UA level by decreasing its renal clearance. [ 23 ] Furthermore, water intake increased in these studies, which effectively reduced urinary UA supersaturation. [ 24 ] However, our results demonstrated that adding TLV to targeted drug and traditional diuretic therapies decreased the serum UA level, perhaps because the patients’ water intake increased.…”

Can tolvaptan usage cause cytotoxicity? An in vitro study

“…At all those trials, the doses of tolvaptan were approximately between 15 mg and 60 mg in a day. Above this dosage and also prolonged usage were reported to cause liver dysfunction via toxicity because tolvaptan is mainly metabolized by CYP3A4 [11,37]. All these trials were conducted with higher concentrations of tolvaptan treatment in patients; therefore, our results of cellular toxicity cannot be compared with these trials because our results are more meaningful for very small dosages of tolvaptan which could be measured in the cell culture system.…”