Tolvaptan Sodium Phosphate

Intravenous tolvaptan sodium phosphate (IV-tolvaptan) is a novel aquaretic agent for acute decompensated heart failure (ADHF). This study evaluated its short-term effects and prognostic implications in clinical practice.

In this retrospective cohort of 169 consecutive ADHF patients receiving IV-tolvaptan for the first time (mean age 76.0 ± 12.7 years; 50.9% female), we measured hourly urine output over 6 h and assessed clinical and biochemical parameters at baseline and 24 h post-dose. The primary endpoint was a composite of all-cause mortality and heart failure rehospitalization. At 24 h, IV-tolvaptan significantly reduced body weight (mean difference: −1.1 ± 2.3 kg, P < 0.001), NT-proBNP (median change: −1704 pg/mL; P < 0.001), and urinary osmolality (mean change: −71.4 ± 169.4 mOsm/kg; P = 0.015), while raising serum sodium (mean change: 1.7 ± 2.9 mEq/L; P < 0.001). Six-hour urine output correlated with baseline estimated glomerular filtration rate (eGFR) (r = 0.34; P < 0.001), urinary osmolality (r = 0.28; P = 0.003), and the change in serum sodium (r = 0.21; P = 0.005). In multivariable logistic regression, renal impairment (eGFR < 60 mL/min/1.73m2) [odds ratio (OR) 0.2; 95% confidence interval (CI) 0.1–0.4; P < 0.001] and higher furosemide doses (>20 mg) (OR 0.3; 95% CI 0.2–0.6; P = 0.01) predicted reduced responsiveness, whereas first hospitalization (OR 2.2; 95% CI 1.1–4.5; P = 0.04) and high urinary osmolality (OR 2.3; 95% CI 1.0–5.4; P = 0.05) predicted favourable response. Kaplan–Meier analysis demonstrated a lower incidence of the primary endpoint in patients achieving ≥ 1000 mL urine output (log-rank P = 0.032).

Intravenous tolvaptan sodium phosphate enhances decongestion and short-term outcomes in ADHF without worsening renal function. Early diuretic responsiveness is a robust prognostic marker.

OPC-61815 is an intravenous formulation vasopressin antagonist designed to treat heart failure patients, especially who have difficulty in oral intake. Tolvaptan together with DM-4103 and DM-4107 are considered as the major metabolites of OPC-61815 biotransformed in the liver via cytochrome P450 (CYP) 3A. An efficient and robust ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for quantification of OPC-61815 and its three metabolites in human plasma was developed and fully validated. To our best knowledge, it was the first published method that simultaneously quantified all of these four analytes in only one run. Simple and rapid sample preparation procedure and very short UPLC-MS/MS run time (3.5 min) offered OPC-61815 and its metabolites relatively high throughput detection, which was greatly beneficial to further clinical bio-sample analysis. The method showed good linearity and sufficient sensitivity in the range of 2.00-1000 ng/mL with a low limit of quantitation (2.00 ng/mL) for each analyte. For samples with concentrations above 1000 ng/mL, 100-fold dilution with blank plasma before sample preparation was accepted. High precision and accuracy, high selectivity and satisfactory recovery of this method were demonstrated. For all of the four analytes, no significant matrix effect or carry-over was observed. The stability of analytes and internal standards under different conditions were evaluated to ensure they were stable during the whole period of storage, preparation and detection. Also, re-injection reproducibility was investigated. In addition, the conversion test showed that almost no OPC-61815 converted into DM-4103 and DM-4107 during sample processing, while attention should be paid to the concentration difference between OPC-61815 and tolvaptan in bioanalysis. The developed UPLC-MS/MS method was successfully applied to an open, single and multiple dose administration phase I trial for monitoring the pharmacokinetics of OPC-61815. This work provided a promising way for further pharmacokinetic study of OPC-61815.