Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement
The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.
A Clinical Study to Assess the Effect of Tocilizumab at a Therapeutic Dose & a Supra-Therapeutic Dose of Tocilizumab On QT/QTc Interval After a Single Dose in Healthy Subjects
Grange1, Susan, Schmitt1, Christophe, Georgy2, Angela, Ludger1, Banken, Kuhn1, Barbara, Zhang2, Xiaoping
Tocilizumab (TCZ) is a humanized IL-6 receptor inhibitor that has demonstrated significant improvements in the signs and symptoms of moderate-to-severe rheumatoid arthritis (RA). This study was designed to evaluate the threshold pharmacological effect on cardiac repolarization, as detected by changes in the QT/QTc interval on 12-lead ECGs in healthy volunteers.
This was a multi-center, double-blind, placebo- and active-controlled, parallel group study. A total of 121 healthy male & female subjects received either an intravenous infusion of TCZ 10 mg/kg (N=30) or 20 mg/kg (N=31), oral moxifloxacin 400 mg (MOX, N=31), or placebo (N=29). Triplicate ECGs were obtained at predose and 2 hr post dose on Day 1 and Days 8, 15 and 29 to cover entire TCZ serum concentration-time profile. Time-matched ECGs were taken on Day -1 for baseline corrections. All ECGs were centrally read by a blinded cardiologist. Study-specific corrected QT (QTcS) was derived from linear regression of individual mean QT on individual mean RR interval data obtained at baseline (Day -1). The change from time-matched baseline in QTcS was determined at each time point. An analysis of variance with the fixed factors treatment and day and their interaction and the random factor subject was applied to time-matched change from baseline in QTcS to estimate the placebo-corrected mean change from baseline together with one-sided upper 95% confidence intervals (CI). Blood samples for pharmacokinetic analyses were collected at predose and up to 28 days post dose.
Of 121 subjects dosed, 67 were female and 54 male. Mean age varied from 29 to 37 years with an age range of 18 to 64 across groups. The majority of subjects were white. For TCZ at both 10 and 20 mg/kg doses, the estimated placebo-corrected mean change from time-matched baseline was negative at all time points and ranged from -5.4 msec to -1.0 msec. The associated upper one-sided 95% confidence limit was below 10 msec. Similar results were obtained for QTcF (Fridericia correction). The estimated placebo-corrected mean change from time-matched baseline for MOX was around 6.8 msec (95% CI: 0.8 to 12.7 msec). The upper bound of the 2-sided 95% CI is comparable to the literature reported value for MOX, establishing study assay sensitivity. There were no clinically significant abnormalities for other ECG parameters (QRS, PR, heart rate, RR, T-wave and U-wave morphology). There were no ECG abnormalities that constituted an adverse event. Following 10 and 20 mg/kg TCZ dosing, the time to reach maximum serum concentration was 2 hours post dose and the mean half-life was 9.3 days for 10 mg/kg and 12 days for 20 mg/kg. Both doses of TCZ were well tolerated and no unexpected safety findings were observed.
Analysis of the 12-lead ECG data obtained from this study indicates that there is no QT prolonging effect of clinical concern by TCZ at both the low (10mg/kg) & high (20mg/kg) dose.
To cite this abstract, please use the following information:
Grange, Susan, Schmitt, Christophe, Georgy, Angela, Ludger, Banken, Kuhn, Barbara, Zhang, Xiaoping; A Clinical Study to Assess the Effect of Tocilizumab at a Therapeutic Dose & a Supra-Therapeutic Dose of Tocilizumab On QT/QTc Interval After a Single Dose in Healthy Subjects [abstract]. Arthritis Rheum 2009;60 Suppl 10 :1614