Safety Of Single Intravenous Doses Research Articles

Pharmacokinetics and Safety of Single Intravenous Doses of JNJ-54452840, an Anti-β1-Adrenergic Receptor Antibody Cyclopeptide, in Healthy Male Japanese and Caucasian Participants.

To evaluate the pharmacokinetics and safety of single intravenous doses of JNJ-54452840 infused over 1 minute in healthy male Japanese and Caucasian participants. JNJ-54452840 is a novel peptide for the treatment of chronic heart failure, with a proposed mechanism of action of binding interference and decreased production of anti-β1-adrenergic receptor (anti-β1-AR) antibodies, which stimulate the cardiac β1-AR. In this randomized, single-centre, double-blind, placebo-controlled, four-way crossover study, 32 male Japanese and Caucasian participants (16 in each group) received single intravenous doses of JNJ-54452840 20, 80 and 240mg, and placebo, each separated by a≥7-day washout period. Pharmacokinetics and safety were assessed predose and at specified timepoints for 24h. Anti-β1-AR antibodies were monitored. The mean JNJ-54452840 maximum observed plasma concentration (C max) and area under the concentration-time curve from time zero to infinity with extrapolation of the terminal phase (AUCinf) values increased linearly with dose, with rapid elimination in both groups. Dose proportionality criteria were not met between the 20 and 240mg doses for both study cohorts. The median time to reach C max (T max) ranged from 1 to 5 minutes. The mean total systemic clearance after intravenous administration (CL), volume of distribution at steady state (V ss), mean residence time (MRT) and terminal half-life (T ½) values were similar for both groups. The mean T ½ values ranged from 5.9 to 26.1 min in a dose-dependent manner. The overall prevalence of antibodies was 9.4% at baseline; antibodies not present at baseline developed in five Caucasians (15.6%) but not in Japanese participants. One participant in each group experienced a serious thromboembolic event (pulmonary embolism, ischaemic stroke). JNJ-54452840 demonstrated similar pharmacokinetics in both groups. JNJ-54452840 was possibly immunogenic, and two participants reported thromboembolic serious adverse events. The relationship between these events and antibody formation is not known.

A double-blind, randomised comparison of the anti-emetic efficacy of two intravenous doses of dolasetron mesilate and granisetron in patients receiving high dose cisplatin chemotherapy

This multicentre, double-blind, double-dummy, randomised trial was designed to compare the efficacy and safety of single intravenous doses of dolasetron mesilate and granisetron in the prevention of acute emesis and nausea due to high-dose (⩾ 80 mg/m 2) cisplatin. Single intravenous doses of 1.8 or 2.4 mg/kg of dolasetron mesilate or 3 mg of granisetron hydrochloride were administered in a volume of 50 ml over a 5-min period, beginning 30 min prior to cisplatin (⩾ 80 mg/m 2) administration. The number and timing of emetic episodes, time to administration of escape anti-emetic medication, severity of nausea by visual analogue scale (VAS), and safety were monitored for 24 h after the start of cisplatin-containing chemotherapy. Investigators' evaluations of overall efficacy and patients' satisfaction with therapy were recorded at the end of the 24-h study period. Of the 474 patients evaluable for efficacy, complete responses were achieved by 54, 47 and 48% of patients given dolasetron mesilate 1.8 mg/kg, dolasetron mesilate 2.4 mg/kg and granisetron, respectively. Statistically, treatment groups had comparable complete and complete plus major responses, times to first emesis, and use of escape medication; patient maximum nausea severity and treatment satisfaction ratings; and physician nausea severity and overall efficacy assessments. For the majority of efficacy endpoints, 1.8 mg/kg dolasetron mesilate produced numerically superior responses compared with the 2.4 mg/kg dose. Gender and prior chemotherapy were significant predictors of complete response; males and chemotherapy-naive patients had higher responses. The overall incidences of adverse events were comparable among the treatment groups; headache and diarrhoea were most common. In conclusion, 1.8 and 2.4 mg/kg of dolasetron mesilate and granisetron (3 mg) were equally effective in preventing nausea and vomiting induced by highly emetogenic cisplatin-containing chemotherapy. In addition, because no additional benefit was observed with 2.4 mg/kg of dolasetron mesilate and numerically greater responses were observed with the 1.8 mg/kg dose, the lower dose of 1.8 mg/kg is optimal for further clinical development.