Ipragliflozin does not prolong QTc interval in healthy male and female subjects: a phase I study.

BACKGROUND: Ipragliflozin, a potent, selective sodium glucose cotransporter 2 inhibitor, is in development for the treatment of type 2 diabetes mellitus. The International Conference on Harmonisation recommends that the safety investigation of new drugs include characterization of each agent's effects on the QT/QTc interval. OBJECTIVE: The goal of this study was to assess the effect on cardiac repolarization (QTc interval) of repeated oral dosing of ipragliflozin at therapeutic (100 mg/d) and supratherapeutic (600 mg/d) levels in healthy subjects. METHODS: This was a double-blind, placebo- and active-controlled, 4-way crossover study. Subjects were randomized to 1 of 4 treatment sequences each including the following 4 treatments: placebo for 7 days; ipragliflozin 100 mg/d for 7 days; ipragliflozin 600 mg/d for 7 days; and active control moxifloxacin 400 mg on day 7 only. The primary assessment of QTc was based on Fridericia's correction for heart rate (QTcF). Continuous 12-lead ECG interval extraction assessments were conducted on day 7. The least squares mean treatment difference from placebo and corresponding 2-sided 90% CIs were calculated for QTcF up to 14 hours postdose on treatment day 7. Ipragliflozin was deemed unlikely to have a clinically relevant effect on QTcF if the upper bound of the maximum treatment difference from placebo for ipragliflozin across all time points was < 10 ms. Assay sensitivity for QTcF interval prolongation was confirmed if the lower bound of the 2-sided 90% CIs for the mean moxifloxacin QTcF difference from placebo, determined at sampling time closest to average Tmax, was > 5 ms. RESULTS: A total of 88 subjects were randomized to treatment (n = 22 per sequence; 10 males and 12 females). The largest upper bounds of the 90% CIs of mean treatment differences from placebo were 4.44 and 3.39 ms for ipragliflozin 600 and 100 mg, respectively, in all subjects, indicating no clinically relevant effect on QTcF interval. No specific effects were observed when the data were analyzed according to sex. No subject showed outlier QTcF intervals > 480 ms or a time-matched change from baseline > 60 ms. Moxifloxacin confirmed assay sensitivity for QTcF interval prolongation; the lower bound of the 2-sided 90% CIs at 3 hours postdose was 11.7 ms (> 5 ms). CONCLUSIONS: No clinically meaningful QTc interval prolongation was observed in these healthy subjects who received ipragliflozin doses up to 600 mg/d for 7 days. ClinicalTrials.gov identifier: NCT01232413.

Pharmacokinetics of intravenous conivaptan in subjects with hepatic or renal impairment.

BACKGROUND: Conivaptan is a non-peptide dual antagonist of vasopressin V1A and V2 receptors that is approved in the United States as an intravenous formulation for the treatment of euvolemic and hypervolemic hyponatremia in hospitalized patients. The pharmacokinetics of intravenous conivaptan had not been studied in patients with hepatic or renal impairment. OBJECTIVE: The objective of this study was to assess the pharmacokinetics and tolerability of intravenous conivaptan in subjects with mild or moderate hepatic or renal impairment compared with subjects with normal function. STUDY DESIGN: These studies were phase I, open-label pharmacokinetic studies conducted at two sites in the US. PATIENTS: Men and non-pregnant women 30-70 years of age were allocated to the mild (Child-Pugh classification score of 5-6) or moderate (Child-Pugh classification score of 7-9) hepatically impaired groups (n = 8-9 per group) based on their liver function assessed at screening. For the renal study, men and non-pregnant women between 18 and 70 years of age were assigned to renal function groups (n = 8-9 per group) based on estimated glomerular filtration rate (eGFR) assessed at screening. Normal renal function was defined as an eGFR >80 ml/min, mild renal impairment as 50-80 ml/min, and moderate renal impairment as 30-49 ml/min. Subjects with normal hepatic or renal function were selected to match the race, sex, age, and body mass index of subjects enrolled in the impaired groups. INTERVENTION: Subjects were administered a 20-mg/30-min intravenous loading dose of conivaptan on day 1, followed by a 20-mg/23.5-h continuous conivaptan infusion. On day 2, immediately following the end of the day 1 infusion, a 20-mg/24-h continuous conivaptan infusion was administered. MAIN OUTCOME MEASURE: Primary pharmacokinetic parameters estimated were the area under the plasma conivaptan concentration-time curve from time 0 to infinity (AUC∞), plasma conivaptan concentrations at the end of the 20-mg loading dose (C LD), and plasma conivaptan concentrations at the end of the second day 20-mg/24-h continuous infusion (C 48). RESULTS: For each of C LD, C 48, and AUC∞, the mean values were similar for subjects with mild hepatic impairment and subjects with normal hepatic function. Subjects with moderate hepatic impairment had a 73 % higher C 48 and an 80 % higher AUC∞ compared with subjects with normal hepatic function. There were no clinically relevant changes in conivaptan exposure in the mild and moderate renal impairment groups compared with subjects with normal renal function. Intravenous conivaptan was generally well tolerated in subjects with mild or moderate hepatic or renal impairment. Infusion-site reaction was the most commonly reported adverse event. CONCLUSION: Overall exposure to conivaptan increased in subjects with moderate hepatic impairment compared with subjects with normal hepatic function. Therefore, in patients with moderate hepatic impairment, conivaptan should be initiated with a loading dose of 10 mg over 30 min followed by 10 mg per day as a continuous infusion for 2-4 days, which is half the approved dose. No dose adjustment is necessary in patients with mild or moderate renal impairment and in patients with mild hepatic impairment.

Effect of loading dose and formulation on safety and efficacy of conivaptan in treatment of euvolemic and hypervolemic hyponatremia.

PURPOSE: The effect of loading dose and formulation on the safety and efficacy of conivaptan in the treatment of euvolemic and hypervolemic hyponatremia was studied. METHODS: This parallel-group study randomized 121 hospitalized patients with euvolemic or hypervolemic hyponatremia to one of four treatment regimens: placebo loading dose followed by conivaptan continuous i.v. infusion using the ampul formulation (regimen 1), conivaptan loading dose followed by continuous i.v. infusion using the ampul formulation (regimen 2), placebo loading dose followed by conivaptan continuous i.v. infusion using the premixed formulation (regimen 3), or conivaptan loading dose followed by continuous i.v. infusion using the premixed formulation (regimen 4). The primary variable was the incidence and severity of injection-site reactions (ISRs), as evaluated using the ISR modified 5-point scale (ISRMS). Secondary outcomes included effects on serum sodium concentration (SSC), duration of effect, and safety and tolerability. RESULTS: All four dosing regimens were efficacious, safe, and well tolerated. No significant differences in ISRMS scores or differences in changes from baseline SSC or in the duration of effects on SSC were observed between the regimens. Overly rapid SSC increases occurred in 7%, 7%, 3%, and 21% of patients treated with regimens 1, 2, 3, and 4, respectively. Overall, adverse events related to general disorders and ISRs occurred in 39%, 43%, 53%, and 55% of patients receiving regimens 1, 2, 3, and 4, respectively. CONCLUSION: Intravenous conivaptan regimens with or without a loading dose, whether using the ampul or a premixed formulation, had similar safety, tolerability, and efficacy in patients with euvolemic or hypervolemic hyponatremia. The pre-mixed formulation used with a loading dose may be associated with an increased frequency of overly rapid increase in SSC compared with the other regimens studied.

Efficacy and safety of 30-minute infusions of conivaptan in euvolemic and hypervolemic hyponatremia.

PURPOSE: The efficacy and safety of conivaptan administered via 30-minute i.v. infusion to patients with euvolemic or hypervolemic hyponatremia were evaluated. METHODS: Hospitalized adults with a baseline serum sodium concentration (SSC) of 115-130 meq/L and euvolemia or hypervolemia on clinical evaluation were randomized to receive conivaptan hydrochloride 20 mg once or twice daily or placebo via 30-minute i.v. infusion. The primary efficacy measure was the change in SSC from baseline to 48 hours. RESULTS: A total of 49 patients received one of the three treatment regimens. Conivaptan once and twice daily produced significant least-squares mean changes from baseline in SSC at 48 hours of 3.46 meq/L (95% confidence interval [CI], 1.75-5.18 meq/L) and 6.22 meq/L (95% CI, 4.34-8.10 meq/L), respectively (p = 0.028 between conivaptan-treated groups). These changes were significantly greater compared with those in the placebo group at hour 4 (p = 0.049) and at all time points onward of hour 28 (p ≤ 0.019) for the once-daily regimen and at all time points for the twice-daily regimen (p = 0.045 at hour 4, then p ≤ 0.010). Both conivaptan regimens were more efficacious than placebo in all secondary efficacy outcomes. Conivaptan was generally well tolerated, with infusion-site reactions being the most common adverse effects (AEs). CONCLUSION: Conivaptan hydrochloride 20 mg, administered once or twice daily via 30-minute i.v. infusion, significantly increased SSCs over 48 hours in patients with euvolemic or hypervolemic hyponatremia when compared with placebo. Common AEs were similar to those seen with continuous conivaptan infusions.