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Effects of cladribine tablets on heart rate, atrio-ventricular conduction and cardiac repolarization in patients with relapsing multiple sclerosis
Cr Appliance, Heinrich Vingerhut Weg 3, D-63571 Gelnhausen, Germany.
WCG Clin, Princeton, NJ USA.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.ORCID iD: 0000-0002-2979-679X
EMD Serono Inc, Billerica, MA USA.
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2019 (English)In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 85, no 7, p. 1484-1494Article in journal (Refereed) Published
Abstract [en]

Aims Cladribine tablets have shown significant efficacy for the treatment of relapsing multiple sclerosis, a chronic and debilitating immune-mediated disorder. This study was conducted to examine acute and/or cumulative effects of cladribine tablets 10 mg (3.5 or 5.25 mg/kg cumulative dose over 2 years) on heart rate, AV conduction and cardiac repolarization in patients with relapsing-remitting multiple sclerosis (RRMS). Methods CLARITY was a 96-week, double-blind, placebo-controlled, multicentre trial which evaluated the safety and efficacy of cladribine tablets 3.5 and 5.25 mg/kg body weight in patients with RRMS. A total of 135 patients were included in the ECG substudy, providing a total of 1534 post-dose ECGs. ECG data were collected 15 minutes pre-dose and between 0.5 and 3 hours post-dose at pre-study evaluation, study Day 1 and Weeks 5, 9, 13, 48 and 52. Results For cladribine tablets 3.5 mg/kg, the maximum change in placebo-adjusted post-dose QTcF vs. visit-baseline (BL) was -0.42 ms (90% CI: -3.61-4.44) at Week 1 (acute effects), and 3.20 ms (90% CI: -0.08-6.33) for cladribine tablets 5.25 mg/kg. The greatest observed differences in post-dose QTcF vs. study BL occurred at Week 48 for both the 3.5 and 5.25 mg/kg doses of cladribine tablets with 5.99 ms (90% CI: 0.53-11.44) and 8.74 ms (90% CI: 3.18-14.31), respectively. No significant changes were observed in T-wave morphology in either treatment group. Conclusions Cladribine tablets 3.5 mg/kg (approved dose in Europe/other regions) did not confer clinically meaningful effects on heart rate, AV conduction and ventricular repolarization.

Place, publisher, year, edition, pages
WILEY , 2019. Vol. 85, no 7, p. 1484-1494
Keywords [en]
cardiac safety, cladribine, modelling, multiple sclerosis, QT, QTc interval
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-390805DOI: 10.1111/bcp.13919ISI: 000473090600015PubMedID: 30883839OAI: oai:DiVA.org:uu-390805DiVA, id: diva2:1343742
Available from: 2019-08-19 Created: 2019-08-19 Last updated: 2019-08-19Bibliographically approved

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Friberg, Lena E.

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