Influence of vasopressin receptor antagonists on triple-whammy acute kidney injury: A VigiBase analysis.

Although diuretics play an important role in triple-whammy acute kidney injury (AKI), it is unclear whether the type of diuretic influences the risk of triple-whammy AKI. The aim of this study was to evaluate whether vasopressin receptor antagonists affect triple-whammy AKI. This cross-sectional study used disproportionality analysis of VigiBase data to assess the risk of AKI with various diuretics. Although multiple logistic regression analysis showed that aldosterone antagonists (odds ratio [OR] 2.19, 95% CI 2.01-2.37), loop diuretics (OR 4.40, 95% CI 4.07-4.76) and thiazide diuretics (OR 1.98, 95% CI 1.83-2.15) increased the risk of AKI in patients who received non-steroidal anti-inflammatory drugs (NSAIDs) and renin-angiotensin system inhibitors (RASi), vasopressin receptor antagonists did not increase the risk of AKI in those patients. Vasopressin receptor antagonists might not influence the development of triple-whammy AKI.

Estimating risk of rapid disease progression in pediatric patients with autosomal dominant polycystic kidney disease: a randomized trial of tolvaptan.

BACKGROUND: Tolvaptan preserves kidney function in adults with autosomal dominant polycystic kidney disease (ADPKD) at elevated risk of rapid progression. A trial (NCT02964273) evaluated tolvaptan safety and pharmacodynamics in children (5-17 years). However, progression risk was not part of study eligibility criteria due to lack of validated criteria for risk assessment in children. As risk estimation is important to guide clinical management, baseline characteristics of the study participants were retrospectively evaluated to determine whether risk of rapid disease progression in pediatric ADPKD can be assessed and to identify parameters relevant for risk estimation. METHODS: Four academic pediatric nephrologists reviewed baseline data and rated participant risk from 1 (lowest) to 5 (highest) based on clinical judgement and the literature. Three primary reviewers independently scored all cases, with each case reviewed by two primary reviewers. For cases with discordant ratings (≥ 2-point difference), the fourth reviewer provided a secondary rating blinded to the primary evaluations. Study participants with discordant ratings and/or for whom data were lacking were later discussed to clarify parameters relevant to risk estimation. RESULTS: Of 90 evaluable subjects, primary reviews of 69 (77%) were concordant. The proportion considered at risk of rapid progression (final mean rating ≥ 3.5) by age group was: 15-17 years, 27/34 (79%); 12- < 15, 9/32 (28%); 4- < 12, 8/24 (33%). The panelists agreed on characteristics important for risk determination: age, kidney imaging, kidney function, blood pressure, urine protein, and genetics. CONCLUSIONS: High ratings concordance and agreement among reviewers on relevant clinical characteristics support the feasibility of pediatric risk assessment.

Long-Term Effects of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease: Predictors of Treatment Response and Safety over 6 Years of Continuous Therapy.

Tolvaptan, an oral vasopressin V2 receptor antagonist, reduces renal volume expansion and loss of renal function in patients with autosomal dominant polycystic kidney disease (ADPKD). Data for predictive factors indicating patients more likely to benefit from long-term tolvaptan are lacking. Data were retrospectively collected from 55 patients on tolvaptan for 6 years. Changes in renal function, progression of renal dysfunction (estimated glomerular filtration rate [eGFR], 1-year change in eGFR [ΔeGFR/year]), and renal volume (total kidney volume [TKV], percentage 1-year change in TKV [ΔTKV%/year]) were evaluated at 3-years pre-tolvaptan, at baseline, and at 6 years. In 76.4% of patients, ΔeGFR/year improved at 6 years. The average 6-year ΔeGFR/year (range) minus baseline ΔeGFR/year: 3.024 (-8.77-20.58 mL/min/1.73 m2). The increase in TKV was reduced for the first 3 years. A higher BMI was associated with less of an improvement in ΔeGFR (p = 0.027), and family history was associated with more of an improvement in ΔeGFR (p = 0.044). Hypernatremia was generally mild; 3 patients had moderate-to-severe hyponatremia due to prolonged, excessive water intake in response to water diuresis-a side effect of tolvaptan. Family history of ADPKD and baseline BMI were contributing factors for ΔeGFR/year improvement on tolvaptan. Hyponatremia should be monitored with long-term tolvaptan administration.

Drug repurposing in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease is characterized by progressive kidney cyst formation that leads to kidney failure. Tolvaptan, a vasopressin 2 receptor antagonist, is the only drug approved to treat patients with autosomal dominant polycystic kidney disease who have rapid disease progression. The use of tolvaptan is limited by reduced tolerability from aquaretic effects and potential hepatotoxicity. Thus, the search for more effective drugs to slow down the progression of autosomal dominant polycystic kidney disease is urgent and challenging. Drug repurposing is a strategy for identifying new clinical indications for approved or investigational medications. Drug repurposing is increasingly becoming an attractive proposition because of its cost-efficiency and time-efficiency and known pharmacokinetic and safety profiles. In this review, we focus on the repurposing approaches to identify suitable drug candidates to treat autosomal dominant polycystic kidney disease and prioritization and implementation of candidates with high probability of success. Identification of drug candidates through understanding of disease pathogenesis and signaling pathways is highlighted.

Tolvaptan's Association with Low Risk of Acute Kidney Injury in Patients with Advanced Chronic Kidney Disease and Acute Decompensated Heart Failure.

INTRODUCTION: Furosemide, a loop diuretic, is often empirically used to treat acute decompensated heart failure (ADHF) initially. Conversely, decongestion using tolvaptan, an aquaretic, is thought to maintain renal function compared to furosemide. However, it has not been investigated in patients with advanced chronic kidney disease (CKD) at high risk of developing acute kidney injury (AKI). This study aimed to investigate AKI incidence using tolvaptan add-on treatment, compared to increased furosemide treatment for patients with ADHF complicated by advanced CKD. METHODS: We retrospectively studied patients with advanced CKD (estimated glomerular filtration rate [eGFR] <45 mL/min/1.73 m2) who developed ADHF under outpatient furosemide treatment. The exposure was set to tolvaptan add-on treatment, and the control was set to increased furosemide treatment. RESULTS: Of the 163 patients enrolled, 79 were in the tolvaptan group and 84 in the furosemide group. The mean age was 71.6 years, the percentage of males was 63.8%, the mean eGFR was 15.7 mL/min/1.73 m2, and patients with CKD stage G5 were 61.9%. AKI incidence was 17.7% in the tolvaptan group and 42.9% in the furosemide group (odds ratio [95% confidence interval]: 0.34 [0.13-0.86], p = 0.023 in multivariate logistic regression analysis). Persistent AKI incidence was 11.8% in the tolvaptan group and 32.9% in the furosemide group (odds ratio [95% confidence interval]: 0.34 [0.10-1.06], p = 0.066 in the multinomial logit analysis). CONCLUSION: This study suggests that tolvaptan may be better than furosemide in patients with ADHF experiencing complicated advanced CKD.

Efficacy of tolvaptan in postoperative volume therapy for acute Stanford type A aortic dissection.

BACKGROUND: Despite the increasing application of tolvaptan in cardiac surgery, there is no information on the use of tolvaptan in Stanford patients with type A aortic dissection. This study aimed to evaluate the postoperative clinical effects of tolvaptan in patients with type A aortic dissection  after tafter surgery. METHODS: A retrospective analysis was performed on 45 patients treated for type A aortic dissection in our hospital from 2018 to 2020. These included 21 patients who were treated with tolvaptan (Group T) and 24 patients who received traditional diuretics (Group L). The hospital's electronic health records were used to obtain perioperative data. RESULTS: Group T did not differ significantly from Group L in terms of the duration of mechanical ventilation, postoperative blood required, length of catecholamine use, or the amount of intravenous diuretic drugs administered (all P > 0.05). The development of postoperative atrial fibrillation was significantly less in the tolvaptan group (P = 0.023). The urine volumes and change in body weight loss were slightly higher in group T than in group L but the differences were non-significant (P > 0.05). Serum potassium, creatinine, and urea nitrogen levels did not differ between the groups in the week after surgery, At the same time, sodium was significantly higher in the Group T group on day 7 after transfer from the ICU (P = 0.001). In Group L, sodium levels were also elevated by day 7 (P = 0.001). On days 3 and 7, serum creatinine and urea nitrogen levels increased in both groups (both P < 0.05). CONCLUSIONS: Both tolvaptan and traditional diuretics were found to be effective and safe for patients with acute Stanford type A aortic dissection. Moreover, tolvaptan may be associated with reducing the incidence of postoperative atrial fibrillation.

Trends in tolvaptan prescription and the association between hypernatremia and aging in tolvaptan-treated patients in Japan: Real-world data mining using Japanese databases.

OBJECTIVE: To identify the trends in tolvaptan prescription and the association between aging and tolvaptan-induced hypernatremia. MATERIALS AND METHODS: A health insurance claims database and a spontaneous adverse drug reaction database were used. RESULTS: Of all patients who had been prescribed tolvaptan, the proportion of patients aged 60 - 79 years and ≥ 80 years was consistent at ~ 40%. Moreover, the prescription frequency of tolvaptan increased over time for patients in the same age groups. The adjusted reporting odds ratio of tolvaptan-induced hypernatremia was 5.54 (95% confidence interval, 3.31 - 9.25) in patients aged ≥ 60 years from among all patients and 2.09 (95% confidence interval, 1.59 - 2.75) in those aged ≥ 80 years from among those aged ≥ 60 years. CONCLUSION: It may be necessary to be aware of hypernatremia in elderly patients who are expected to have increased prescriptions of tolvaptan.

Efficacy and safety of postoperative preemptive use of tolvaptan for patients with cirrhosis undergoing hepatectomy for hepatocellular carcinoma.

PURPOSE: Optimal choice of diuretics in perioperative management remains unclear in enhanced recovery after liver surgery. This study investigated the efficacy and safety of tolvaptan (oral vasopressin V2-receptor antagonist) in postoperative management of patients with liver injury and hepatocellular carcinoma. METHODS: The patients clinically diagnosed with liver cirrhosis were included in this study. Clinical outcomes of 51 prospective cohort managed with a modified postoperative protocol using tolvaptan (validation group) were compared with 83 patients treated with a conventional management protocol (control group). RESULTS: Postoperative urine output were significantly larger and excessive body weight increase were reduced with no impairment in renal function or serum sodium levels in the validation group. Although the total amount of discharge and trend of serum albumin level were not significantly different among the groups, global incidence of postoperative morbidity was less frequent (19.6% vs. 44.6%, P=0.005) and postoperative stay was significantly shorter (8 days vs.10 days, P=0.008) in the validation group compared with the control group. CONCLUSIONS: Tolvaptan could be safely used for the patients with injured liver in postoperative management after hepatectomy and potentially advantageous in the era of enhanced recovery after surgery with its strong diuretic effect and better fluid management.

Effects of tolvaptan discontinuation in patients with autosomal dominant polycystic kidney disease: a post hoc pooled analysis.

BACKGROUND: Tolvaptan slows kidney function decline in patients with autosomal dominant polycystic kidney disease (ADPKD) who are at risk of rapid progression. Given that treatment requires commitment to long-term use, we evaluated the effects of tolvaptan discontinuation on the trajectory of ADPKD progression. METHODS: This was a post hoc analysis of pooled data from two clinical trials of tolvaptan (TEMPO 2:4 [NCT00413777] and TEMPO 3:4 [NCT00428948]), an extension trial (TEMPO 4:4 [NCT01214421]), and an observational study (OVERTURE [NCT01430494]) that enrolled patients from the other trials. Individual subject data were linked longitudinally across trials to construct analysis cohorts of subjects with a tolvaptan treatment duration > 180 days followed by an off-treatment observation period of > 180 days. For inclusion in Cohort 1, subjects were required have ≥ 2 outcome assessments during the tolvaptan treatment period and ≥ 2 assessments during the follow-up period. For Cohort 2, subjects were required to have ≥ 1 assessment during the tolvaptan treatment period and ≥ 1 assessment during the follow-up period. Outcomes were rates of change in estimated glomerular filtration rate (eGFR) and total kidney volume (TKV). Piecewise-mixed models compared changes in eGFR or TKV in the on-treatment and post-treatment periods. RESULTS: In the Cohort 1 eGFR population (n = 20), the annual rate of eGFR change (in mL/min/1.73 m2) was -3.18 on treatment and -4.33 post-treatment, a difference that was not significant (P = 0.16), whereas in Cohort 2 (n = 82), the difference between on treatment (-1.89) and post-treatment (-4.94) was significant (P < 0.001). In the Cohort 1 TKV population (n = 11), TKV increased annually by 5.18% on treatment and 11.69% post-treatment (P = 0.06). In Cohort 2 (n = 88), the annual TKV growth rates were 5.15% on treatment and 8.16% post-treatment (P = 0.001). CONCLUSIONS: Although limited by small sample sizes, these analyses showed directionally consistent acceleration in measures of ADPKD progression following the discontinuation of tolvaptan.

Design of two ongoing clinical trials of tolvaptan in the treatment of pediatric patients with autosomal recessive polycystic kidney disease.

PURPOSE: Autosomal recessive polycystic kidney disease (ARPKD) is a hereditary condition characterized by massive kidney enlargement and developmental liver defects. Potential consequences during childhood include the need for kidney replacement therapy (KRT). We report the design of 2 ongoing clinical trials (Study 204, Study 307) to evaluate safety, tolerability, and efficacy of tolvaptan in children with ARPKD. METHODS: Both trials are of multinational, multicenter, open-label design. Age range at enrollment is 28 days to < 12 weeks in Study 204 and 28 days to < 18 years in Study 307. Subjects in both studies must have a clinical diagnosis of ARPKD, and those in Study 204 must additionally have signs indicative of risk of rapid progression to KRT, namely, all of: nephromegaly, multiple kidney cysts or increased kidney echogenicity suggesting microcysts, and oligohydramnios or anhydramnios. Target enrollment is 20 subjects for Study 204 and ≥ 10 subjects for Study 307. RESULTS: Follow-up is 24 months in Study 204 (with optional additional treatment up to 36 months) and 18 months in Study 307. Outcomes include safety, tolerability, change in kidney function, and percentage of subjects requiring KRT relative to historical data. Regular safety assessments monitor for possible adverse effects of treatment on parameters such as liver function, kidney function, fluid balance, electrolyte levels, and growth trajectory, with increased frequency of monitoring following tolvaptan initiation or dose escalation. CONCLUSIONS: These trials will provide data on tolvaptan safety and efficacy in a population without disease-specific treatment options. TRIAL REGISTRATION: Study 204: EudraCT 2020-005991-36; Study 307: EudraCT 2020-005992-10.

Effectiveness and safety of Tolvaptan in infants with congenital heart disease.

BACKGROUND: Tolvaptan (TLV) is a selective vasopressin receptor 2 antagonist administered for congestive heart failure (CHF) after inadequate response to other diuretics. The effectiveness and safety of TLV have been evaluated well in adult patients. However, reports on its use in pediatric patients, especially infants, are scarce. METHODS: We retrospectively evaluated 41 children younger than 1 year of age who received TLV for CHF for congenital heart disease (CHD) between January 2010 and August 2021. We monitored the occurrence of adverse events, including acute kidney injury and hypernatremia, as well as laboratory data trends. RESULTS: Of the 41 infants included, 51.2% were male. The median age when TLV was initiated was 2 months, interquartile range (IQR) 1-4 months, and all infants had been administered other diuretics previously. The median dose of TLV was 0.1 mg/kg/day (IQR, 0.1-0.1). Urine output increased significantly after 48 h of treatment: baseline, 315 mL/day (IQR, 243-394); 48 h, 381 mL/day (IQR, 262-518) , p = 0.0004; 72 h, 385 mL/day (IQR, 301-569), p = 0.0013; 96 h, 425 mL/day (IQR, 272-524), p = 0.0006; and 144 h, 396 mL/day (IQR, 305-477), p = 0.0036. No adverse events were observed. CONCLUSIONS: Tolvaptan can be used safely and efficiently in infants with CHD. From the perspective of adverse effects, initiating administration at a lower dosage is preferable because this was found to be sufficiently effective.

Vaptans for oedematous and hyponatraemic disorders in childhood: A systematic literature review.

AIMS: The aim of this study was to systematically review the use of vaptans (nonpeptide vasopressin receptor antagonists) in children. METHODS: Through a database search (Web of Science, the National Library of Medicine, Excerpta Medica), we identified case series and case reports and extracted clinical and laboratory data. RESULTS: Twenty-six articles, published since 2008, reported on 226 patients. Among 115 children with hyponatraemic (n = 63) and oedematous disorders (n = 52), a 48 hour course of tolvaptan with an initial dose of 0.38 ± 0.27 mg/kg was administered in 106 cases, while intravenous conivaptan was reported in nine cases. An increase (P < .02) in urine output was shown in both oedematous (from 3.2 ± 2.0 to 5.3 ± 6.7 mL/kg/day) and hyponatraemic (from 3.0 ± 1.5 to 4.4 ± 2.3 mL/kg/day) patients. In these latter, sodium increased from 125 ± 6 to 133 ± 6 mmol/L (P < .0001). The increase in sodium level correlated with its basal value, but not with the administered vaptan dose. Among 111 children undergoing cardiac surgery, after tolvaptan 0.21 ± 0.01 mg/kg/day, mostly combined with conventional diuretics, an increase in diuresis by 41 ± 4% was seen within 24 hours (P < .0001). Similarly, a single add-on dose of tolvaptan 0.45 mg/kg allowed a reduced additional intravenous furosemide administration (0.26 ± 0.23 vs 0.62 ± 0.48 mg/kg, P < .005). Side effects were rarely reported, and included excessive thirst and xerostomia in seven, skin rash in one and elevated aminotransferases in one patient(s). CONCLUSION: Vaptans appear to be safe for oedematous and hyponatraemic disorders also in children. Although they increase diuresis and natraemia, no superiority to traditional diuretics and sodium supplements has been demonstrated. Reported side effects are rare and non-serious.

Tolerability of the Intravenously Administered Tolvaptan Prodrug, OPC-61815, in Patients With Congestive Heart Failure Who Have Difficulty With, or Are Incapable of, Oral Intake (TRITON-HF)　- A Phase III, Multicenter, Open-Label Trial.

BACKGROUND: OPC-61815, a prodrug of tolvaptan, is an injectable aquaretic drug. This study evaluated the tolerability of OPC-61815 in patients with congestive heart failure (CHF) who had difficulty with, or were incapable of, oral intake in a multicenter, uncontrolled, open-label Phase III study.Methods and Results: Forty-five patients were enrolled at 30 Japanese sites. OPC-61815 infusion was administered once daily; the 8 mg initial dose could be increased to 16 mg if the dose escalation criteria were met. Patients were treated for up to 5 days. Thirty-eight patients maintained the 8-mg dose and 7 had a dose increase to 16 mg; 41 completed the trial (34 completed early). One patient had mild hypernatremia. No significant safety concerns were observed with OPC-61815 administration at a starting dose of 8 mg and with dose escalation in accordance with the protocol-specified criteria. Treatment resulted in weight decrease (-3.01 kg); improvement or disappearance rates for other CHF symptoms (including edema, dyspnea, orthopnea, pulmonary congestion, and rales) indicated that treatment was effective. Urine excretion was increased 0-1 h after OPC-61815 administration and reached a maximum level at 1-2 h. CONCLUSIONS: The tolerability of once daily (up to 5 days) intravenous OPC-61815 (8 mg or 16 mg) was confirmed in patients with CHF who had difficulty with, or were incapable of, oral intake.

Pharmacokinetics, Pharmacodynamics, Efficacy, and Safety of OPC-61815, a Prodrug of Tolvaptan for Intravenous Administration, in Patients With Congestive Heart Failure　- A Phase II, Multicenter, Double-Blind, Randomized, Active-Controlled Trial.

BACKGROUND: Tolvaptan is an orally administered aquaretic drug indicated for patients with congestive heart failure (CHF) to remove excess fluid. OPC-61815, a prodrug of tolvaptan with improved water solubility, is considered suitable for intravenous (IV) administration. This Phase II study investigated the OPC-61815 dose that would result in an exposure equivalent to tolvaptan 15 mg.Methods and Results:We conducted a multicenter, randomized study in Japanese patients aged 20-85 years with CHF and volume overload despite treatment with diuretics other than vasopressin antagonists. Patients received IV OPC-61815 2 mg (n=13), 4 mg (n=12), 8 mg (n=12), 16 mg (n=11), or oral tolvaptan 15 mg (n=12). The primary endpoint was tolvaptan exposure on treatment Day 1; efficacy and safety were also assessed. Tolvaptan exposure increased in a dose-dependent manner following a single IV administration of OPC-61815; the exposure following an IV dose of OPC-61815 16 mg was similar to that of a tolvaptan 15-mg tablet, with no marked differences in safety or tolerability. OPC-61815 increased urine volume from baseline, resulting in decreased body weight and improved lower limb edema. No notable safety concerns were observed. CONCLUSIONS: In this first study of OPC-61815 in patients with CHF, exposure following a single IV administration of OPC-61815 16 mg was comparable with a single oral administration of tolvaptan 15 mg, with no safety concerns.

Early initiation of tolvaptan is associated with early discharge in patients with heart failure regardless of age.

BACKGROUND: Elderly patients with heart failure (HF) have been observed to decrease activities of daily living (ADL) during hospitalization. Prevention of ADL decline from shortening of hospital stays is especially important in the elderly, because decreasing ADL is associated with poor prognosis. We investigated the relationship between the early initiation of tolvaptan (TLV) after hospitalization and the length of hospital stay in patients with HF aged younger than 80 years and aged 80 years and older. METHODS: We analyzed 146 patients younger than 80 years (< 80) and 101 patients aged 80 years and older (≥ 80) who were hospitalized with HF from February 2011 to June 2016 and had initiated TLV. The relationship between the time until commencement of TLV and the length of hospital stay was assessed. Additionally, a comparison made between the TLV early start group (within the median) and the delayed start group (over the median) for both groups. Multivariate analysis was also performed on factors that required hospital stays below the median. RESULTS: A significant correlation was observed between time to TLV initiation and the length of hospital stay (< 80: r = 0.382, P < 0.001; ≥ 80: r = 0.395, P < 0.001). The length of hospital stay in the early group was significantly longer than that in the delayed group for both groups (< 80: early 21.0 ± 13.0 days and 33.0 ± 22.7 days, respectively, P < 0.001; ≥ 80: early 21.3 ± 12.5 days and 32.9 ± 17.9 days, respectively, P < 0.001). Conversely, no statistically significant difference found in the length of hospital stay after initiation of TLV. Moreover, no increase in adverse events in the elderly observed. A multivariate analysis revealed that a predictive factor for short-term hospitalization was early administration of TLV regardless of age. CONCLUSIONS: The early initiation of TLV after hospitalization was associated with a shorter length of hospital stay in patients with HF regardless of age.

Efficacy of tolvaptan on advanced chronic kidney disease with heart failure: a randomized controlled trial.

BACKGROUND: Tolvaptan (TLV) is reported to improve diuretic effects in patients with chronic kidney disease (CKD) when furosemide (FUR) is not sufficiently effective. However, it is not clear whether TLV addition is effective for advanced CKD patients with heart failure. METHODS: An open-label, parallel-group randomized trial was performed. The subjects were 33 patients with CKD stage G3-G5 who had fluid overload despite taking 20-100 mg/day FUR. They were divided into two groups: a group administered 15 mg/day TLV plus their original FUR dose for 7 days (TLV group), and a group administered 120-200 mg/day FUR (i.e., 100 mg/day over their previous dose) for 7 days (FUR group). RESULTS: The mean change in urine volume was significantly higher in the TLV group compared to the FUR group (637 ml vs 119 ml; p < 0.05). The difference was greater when the urine osmolality before treatment was high. Serum creatinine was increased only in the FUR group. The incidence of worsening renal function (WRF) was significantly lower in the TLV group (18.8% vs 58.8%; p < 0.05). Serum sodium decreased significantly in the FUR group, but did not change in the TLV group. CONCLUSIONS: In patients with advanced CKD with fluid overload, the addition of TLV achieved a significantly higher urine volume with less adverse effects on renal function compared with increasing the dose of FUR. The efficacy and safety of TLV were higher in patients who had higher urine osmolality and lower serum sodium before treatment. CLINICAL TRIAL REGISTRATION: UMIN000014763.

Efficacy and safety of tolvaptan in patients with malignant ascites: a phase 2, multicenter, open-label, dose-escalation study.

OBJECTIVE: This phase 2 study examined the efficacy and safety of tolvaptan, an aquaretic drug, in the treatment of ascites associated with cancer. METHODS: In the dose-escalation phase, oral tolvaptan was initiated at a dose of 3.75 mg/day, and the dose was increased daily to 7.5, 15 and 30 mg/day. Dose escalation was terminated once the increase from baseline in the daily urine volume reached 500 ml, at which point the patient proceeded to the maintenance phase of 5-7 days. Improvement of ascites was determined primarily by reduction in body weight and ascitic fluid volume. RESULTS: The mean change from baseline in body weight was maintained below 0 kg throughout the study. The mean change (±standard deviation) from baseline in ascitic fluid volume at the end of treatment (EOT) was 237.45 ± 868.14 ml in 33 evaluable patients. Although an increase from baseline in ascitic fluid volume at the EOT was observed in 23 of 33 patients (maximum: 1589.3 ml, minimum: 3.83 ml), a reduction in ascitic fluid volume was observed in the remaining 10 patients (maximum: -2304.3 ml, minimum: -27.5 ml). The common treatment-emergent adverse events included vomiting (5 of 43 patients, 11.6%), abdominal distension, constipation, thirst, blood osmolarity increased and renal impairment (3 of 43 patients, 7.0% each). CONCLUSIONS: Tolvaptan seemed to have no definitive effect on reducing ascites; however, it might be effective in at least some cancer patients. No new safety concerns were identified at doses of 3.75-30 mg/day.

Effect of tolvaptan in Japanese patients with autosomal dominant polycystic kidney disease: a post hoc analysis of TEMPO 3:4 and TEMPO Extension Japan.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a progressive condition that eventually leads to end-stage renal disease. A phase 3 trial of tolvaptan (TEMPO 3:4; NCT00428948) and its open-label extension (TEMPO Extension Japan: TEMPO-EXTJ; NCT01280721) were conducted in patients with ADPKD. In this post hoc analysis, effects on renal function and the safety profile of tolvaptan were assessed over a long-term period that included the 3-year TEMPO 3:4 and the approximately 3-year TEMPO-EXTJ trials. METHODS: Patients from Japanese trial sites who completed TEMPO 3:4 were offered participation in TEMPO-EXTJ. Patients whose efficacy parameters were measured at year 2 in TEMPO-EXTJ for efficacy evaluation were included. The annual slope of the estimated glomerular filtration rate (eGFR) and growth in total kidney volume (TKV) were analyzed. RESULTS: In patients who received tolvaptan in TEMPO 3:4 and TEMPO-EXTJ, the annual slope of eGFR (mL/min/1.73 m2) was - 3.480 in TEMPO 3:4 and - 3.417 in TEMPO-EXTJ, with no apparent effect of an approximately 3.6-month off-treatment interval between the two trials. In patients who received a placebo in TEMPO 3:4 before initiating tolvaptan in TEMPO-EXTJ, the slope of eGFR was significantly less steep from TEMPO 3:4 (- 4.287) to TEMPO-EXTJ (- 3.364), a difference of 0.923 (P = 0.0441). CONCLUSION: The TEMPO-EXTJ trial supports a sustained beneficial effect of tolvaptan on eGFR. In patients who received a placebo in TEMPO 3:4, initiation of tolvaptan in TEMPO-EXTJ was associated with a significant slowing of eGFR decline.

Safety and efficacy of Tolvaptan in real-world patients with autosomal dominant polycystic kidney disease- interim results of SLOW-PKD surveillance.

BACKGROUND: Tolvaptan is a vasopressin type 2 receptor antagonist and has been used to treat autosomal dominant polycystic kidney disease (ADPKD) since 2014. There has been limited real-world data on the safety and efficacy of tolvaptan. METHODS: This post-marketing surveillance was conducted to evaluate the long-term safety and the efficacy of tolvaptan in Japanese patients with ADPKD in real-world clinical settings. The baseline characteristics of 1630 patients treated with tolvaptan are reported. Safety analysis comprises evaluation of adverse drug reactions (ADRs). The efficacy evaluation includes percent change in total kidney volume (TKV) and change in estimated glomerular filtration rate (eGFR) before and after tolvaptan treatment. RESULTS: Mean age was 49.7 ± 11.2 years and 843 (51.7%) patients were male. Baseline TKV was 2158 ± 1346 mL and eGFR was 44.4 ± 21.7 mL/min/1.73 m2. The majority of CKD patients were stage G3b (27.0%) and G4 (30.1%). Frequently reported ADRs were hepatic function abnormal (8.3%), thirst (8.2%), and hyperuricaemia (6.9%). The frequency of ALT elevation (> 30 and > 90 IU/L) was slightly high (32.9 and 8.3%) to previous studies. After tolvaptan treatment, the annual rate of percentage change in TKV reduced from 11.68%/year to 2.73%/year (P < 0.0001). Similar results were also obtained for the effect on change in eGFR from - 3.31 to - 2.28 mL/min/1.73 m2/year after initiation of tolvaptan treatment (P = 0.0403). CONCLUSION: There were no major problems with safety of tolvaptan treatment and comparable efficacy for TKV and eGFR was observed in relation to the previous pivotal two randomized control trials in this post-marketing surveillance.

Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: In a previous trial involving patients with early autosomal dominant polycystic kidney disease (ADPKD; estimated creatinine clearance, ≥60 ml per minute), the vasopressin V2-receptor antagonist tolvaptan slowed the growth in total kidney volume and the decline in the estimated glomerular filtration rate (GFR) but also caused more elevations in aminotransferase and bilirubin levels. The efficacy and safety of tolvaptan in patients with later-stage ADPKD are unknown. METHODS: We conducted a phase 3, randomized withdrawal, multicenter, placebo-controlled, double-blind trial. After an 8-week prerandomization period that included sequential placebo and tolvaptan run-in phases, during which each patient's ability to take tolvaptan without dose-limiting side effects was assessed, 1370 patients with ADPKD who were either 18 to 55 years of age with an estimated GFR of 25 to 65 ml per minute per 1.73 m2 of body-surface area or 56 to 65 years of age with an estimated GFR of 25 to 44 ml per minute per 1.73 m2 were randomly assigned in a 1:1 ratio to receive tolvaptan or placebo for 12 months. The primary end point was the change in the estimated GFR from baseline to follow-up, with adjustment for the exact duration that each patient participated (interpolated to 1 year). Safety assessments were conducted monthly. RESULTS: The change from baseline in the estimated GFR was -2.34 ml per minute per 1.73 m2 (95% confidence interval [CI], -2.81 to -1.87) in the tolvaptan group, as compared with -3.61 ml per minute per 1.73 m2 (95% CI, -4.08 to -3.14) in the placebo group (difference, 1.27 ml per minute per 1.73 m2; 95% CI, 0.86 to 1.68; P<0.001). Elevations in the alanine aminotransferase level (to >3 times the upper limit of the normal range) occurred in 38 of 681 patients (5.6%) in the tolvaptan group and in 8 of 685 (1.2%) in the placebo group. Elevations in the aminotransferase level were reversible after stopping tolvaptan. No elevations in the bilirubin level of more than twice the upper limit of the normal range were detected. CONCLUSIONS: Tolvaptan resulted in a slower decline than placebo in the estimated GFR over a 1-year period in patients with later-stage ADPKD. (Funded by Otsuka Pharmaceuticals and Otsuka Pharmaceutical Development and Commercialization; REPRISE ClinicalTrials.gov number, NCT02160145 .).