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Effects of cladribine tablets on heart rate, atrio-ventricular conduction and cardiac repolarization in patients with relapsing multiple sclerosis.

ABSTRACT: 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.

SUBMITTER: Hermann R

PROVIDER: S-EPMC6595470 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Effects of cladribine tablets on heart rate, atrio-ventricular conduction and cardiac repolarization in patients with relapsing multiple sclerosis.

Hermann Robert R Litwin Jeffrey S JS Friberg Lena E LE Dangond Fernando F Munafo Alain A

British journal of clinical pharmacology 20190506 7

<h4>Aims</h4>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).<h4>Methods</h4>CLARITY was a 96-week, double-blind, placebo-control ...[more]

PMID: 30883839

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Project description:Cladribine Tablets (MAVENCLAD®) are used to treat relapsing multiple sclerosis (MS). The recommended dose is 3.5 mg/kg, consisting of 2 annual courses, each comprising 2 treatment weeks 1 month apart. We reviewed the clinical pharmacology of Cladribine Tablets in patients with MS, including pharmacokinetic and pharmacometric data. Cladribine Tablets are rapidly absorbed, with a median time to reach maximum concentration (Tmax) of 0.5 h (range 0.5-1.5 h) in fasted patients. When administered with food, absorption is delayed (median Tmax 1.5 h, range 1-3 h), and maximum concentration (Cmax) is reduced by 29% (based on geometric mean). Area under the concentration-time curve (AUC) is essentially unchanged. Oral bioavailability of cladribine is approximately 40%, pharmacokinetics are linear and time-independent, and volume of distribution is 480-490 L. Plasma protein binding is 20%, independent of cladribine plasma concentration. Cladribine is rapidly distributed to lymphocytes and retained (either as parent drug or its phosphorylated metabolites), resulting in approximately 30- to 40-fold intracellular accumulation versus extracellular concentrations as early as 1 h after cladribine exposure. Cytochrome P450-mediated biotransformation of cladribine is of minor importance. Cladribine elimination is equally dependent on renal and non-renal routes. In vitro studies indicate that cladribine efflux is minimally P-glycoprotein (P-gp)-related, and clinically relevant interactions with P-gp inhibitors are not expected. Cladribine distribution across membranes is primarily facilitated by equilibrative nucleoside transporter (ENT) 1, concentrative nucleoside transporter (CNT) 3 and breast cancer resistance protein (BCRP), and there is no evidence of any cladribine-related effect on heart rate, atrioventricular conduction or cardiac repolarisation (QTc interval prolongation). Cladribine Tablets are associated with targeted lymphocyte reduction and durable efficacy, with the exposure-effect relationship showing the recommended dose is appropriate in reducing relapse risk.

Project description:BackgroundCladribine tablets have recently become available in The Netherlands for patients with relapsing-remitting multiple sclerosis (RRMS) as a disease-modifying agent that reduces the frequency and severity of relapses and delays disability progression.ObjectiveThe aim of this study was to evaluate the cost effectiveness of cladribine tablets, compared with alternative options, in the treatment of RRMS patients with high disease activity (HDA) and patients with rapidly evolving severe (RES) MS in The Netherlands.MethodsA Markov model was developed simulating the costs and effects of RRMS treatment. For HDA, alemtuzumab and fingolimod were used as comparators; natalizumab was used for the RES subpopulation. The analysis included a societal perspective and a value-of-information (VOI) analysis.ResultsFor the HDA subpopulation, treatment with cladribine tablets was the cost-effective (dominant) strategy compared with alemtuzumab and fingolimod, with 50.9% and 98.2%, respectively, probability of being cost effective at a threshold of €50,000/QALY gained and a net monetary benefit (NMB) of €10,866 and €151,115, respectively. For the RES subpopulation, treatment with cladribine tablets dominated treatment with natalizumab, with 94.1% probability of being cost effective at a threshold of €50,000/QALY gained and an NMB of €122,986. Note that these outcomes are driven by the lower costs of cladribine tablets. Efficacy differences were small, very uncertain, and likely not clinically meaningful. The probabilistic sensitivity analyses showed significant overlap in the credible intervals for total lifetime QALY outcomes and costs of cladribine tablets and all relevant comparators. The population-level VOI amounted to €19,295,441.ConclusionsThe base-case analysis shows that treatment of RRMS with cladribine tablets is cost effective versus alemtuzumab and fingolimod in HDA patients, and cost effective versus natalizumab in RES patients, at a threshold of €50,000. Driven by the lower costs, cladribine tablets were cost effective (dominant) in all base-case analyses. However, given that outcomes are based on indirect comparisons and post hoc subgroup analysis, as well as the uncertainty surrounding the outcomes, the results presented in this paper should be interpreted with caution.

Dataset Information

Effects of cladribine tablets on heart rate, atrio-ventricular conduction and cardiac repolarization in patients with relapsing multiple sclerosis.

Publications

Effects of cladribine tablets on heart rate, atrio-ventricular conduction and cardiac repolarization in patients with relapsing multiple sclerosis.

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