To review the pharmacology, pharmacokinetics, efficacy, and safety of cladribine, a purine analog undergoing Phase III trials for approval of its use in the treatment of multiple sclerosis (MS).
Data Sources:
A MEDLINE search (1966–September 2006) was conducted using the key words cladribine and multiple sclerosis. No limits were placed on the search.
Study Selection and Data Extraction:
Studies and review articles related to cladribine and MS were reviewed. The trials examining the role of cladribine in MS were analyzed.
Data Synthesis:
Cladribine is a purine analog that demonstrates lymphocytotoxic activity. Recent data suggest that cladribine may have a role in the treatment of relapsing–remitting and the progressive forms of MS. In these studies, cladribine has shown mixed results in decreasing neurologic disability, as measured by various rating scales, but has consistently shown positive results in reducing the number of enhancing lesions, which reflects a measure of disease activity. To date, there is one ongoing study examining the role of oral cladribine in the treatment of relapsing–remitting MS. The incidence of adverse effects with cladribine has been significantly greater than with placebo, with the most common being myelosuppression.
Conclusions:
While data do not support its use as a first-line MS treatment, cladribine may be a promising agent for refractory patients with secondary progressive MS. Further studies are warranted.
LucchinettiCF, RodriguezM.The controversy surrounding the pathogenesis of the multiple sclerosis lesions. Mayo Clin Proc1997; 72: 665–78.
4.
SobelRA. The pathology of multiple sclerosis. Neurol Clin1995; 13: 1–16.
5.
WeinshenkerBG. Natural history of multiple sclerosis. Ann Neurol1994; 36:S6–S11.
6.
GoodwinDS, FrohmanEM, GarmanyGPDisease-modifying therapies in muttiple sclerosis: report of the therapeutics and technology assessment subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology2002; 58: 169–78.
7.
JohnsonKP, BrooksBR, CohenJAExtended use of glatiramir acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Neurology1998; 50: 701–8.
8.
PeriniP, ClabreseM, BiasiGThe clinical impact of interferon beta antibodies in relapsing–remitting MS. J Neurol2004; 251: 305–9.
CarsonDA, WassonDB, TaetleR, YuA.Specific toxicity of 2-chlorodeoxyadenosine toward resting and proliferating human lymphocytes. Blood1983; 62: 737–43.
14.
BeutlerE, KoziolJA, McMillanR, SipeJC, RomineJS, CarreraCJ. Marrow suppression produced by repeated doses of cladribine. Acta Haematol1994; 91: 10–5.
15.
SelbyR, BrandweinJ, O'ConnorP.Safety and tolerability of subcutaneous cladribine therapy in progressive multiple sclerosis. Can J Neurol Sci1998; 25: 295–9.
16.
RiceGP, FilippiM, ComiG.Cladribine and progressive MS: clinical and MRI outcomes of a multicenter controlled trial. Neurology2000; 54: 1145–55.
17.
AlbertoniF, JuliussonG, LiliemarkJ.On the bioavailability of 2-chloro-2′-deoxyadenosine (CdA): the influence of food and omeprazole. Eur J Clin Pharmacol1993; 44: 579–82.
18.
LiliemarkJ, AlbertoniF, HassanMOn the bioavailability of oral and subcutaneous 2-chloro-2′-deoxyadenosine in humans; alternative routes of administration. J Clin Oncol1992; 10: 1514–8.
19.
SavenA, CheungWK, SmithIPharmacokinetic study of oral and bolus intravenous 2-chlorodeoxyadenosine in patients with malignancy. J Clin Oncol1996; 14: 978–83.
LiliemarkJ, AlbertioniF, EdlundCBioavailability and bacterial degradation of rectally administered 2-chloro-2′-deoxyadenosine. J Pharm Biomed Anal1995; 13: 661–5.
22.
LiliemarkJ, JuliussonG.On the pharmacokinetics of 2-chloro-2′-deoxyadenosine (CdA) in the cerebrospinal fluid (CSF) (abstract). Blood1992; 80(suppl 1):471.
23.
KearnsCM, BlakleyRL, SantanaVMPharmacokinetics of cladribine (2-chlorodeoxyadenosine) in children with acute leukemia. Cancer Res1994; 54: 1235–9.
LiliemarkJ, JuliussonG.On the pharmacokinetics of 2-chloro-2′deoxyadenosine in humans. Cancer Res1991; 51: 5570–2.
28.
AlbertioniF, HassanM, LiliemarkJ.Kinetics of 2-chloro-2′-deoxyadenosine and 2-chloro-2′-arabino-fluoro-2′-deoxyadenosine in isolated perfused rat liver. Eur J Drug Metab Pharmacokinet1995; 30: 225–32.
29.
MarksRS, RichardsonRL, ReidJMA Phase I and pharmacologic study of 2-chlorodeoxyadenosine in patients with advanced solid tumors (abstract). Proc Am Soc Clin Oncol1994; 13: 416.
30.
AlbertioniF, PetterssonB, ReichelovàVAnalysis of 2-chloro-2′-deoxyadenosine in human blood samples and urine by high-performance liquid chromatography using solid-phase extraction. Ther Drug Monit1995; 16: 413–8.
31.
SipeJC, RomineJS, KoziolJA, McMillanR, ZyroffJ, BeutlerE.Development of cladribine treatment in multiple sclerosis. Mult Scler1996; 1: 343–7.
32.
SipeJC, RomineJS, KoziolJA, McMillanR, ZyroffJ, BeutlerE.Cladribine in treatment of chronic progressive multiple sclerosis. Lancet1994; 344: 9–13.
33.
SipeJC, KnoblerRL, BrahenySL, RiceGP, PanitchHS, OldstoneMB. A neurologic rating scale (NRS) for use in multiple sclerosis. Neurology1984; 34: 1368–72.
34.
KurtzkeJF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology1983; 33: 1444–52.
LearySM, ThompsonAJ. Primary progressive multiple sclerosis: current and future treatment options. CNS Drugs2005; 19: 369–76.
38.
RomineJS, SipeJC, KoziolJA, ZyroffJ, BeutlerE.A double-blind, placebo-controlled, randomized trial of cladribine in relapsing–remitting multiple sclerosis. Proc Assoc Am Physicians1999; 111: 35–44.
39.
FilippiM, RovarisM, RiceGPThe effect of cladribine on T(1) 'black hole' changes in progressive MS. J Neurol Sci2000; 176: 42–4.
40.
FilippiM, RovarisM, IannucciG, MenneaS, SormaniMP, ComiG.Whole brain volume changes in patients with progressive MS treated with cladribine. Neurology2000; 55: 1714–8.
41.
StelmasiakZ, SolskiJ, NowickiJ, JakubowskaB, RybaM, GriebP.Short-term effects of 2-chlorodeoxyadenosine (2-CDA) in remitting–relapsing multiple sclerosis (abstract). J Neurol1994; 241(suppl 1):S90.
GriebP, StelmasiakZ, SolskiJ, NowickiJ, JakubowskaB, RybaM.Effects of repeated treatments with cladribine (2-chlorodeoxyadenosine) on blood counts in multiple sclerosis patients. Arch Immunol Ther Exp1995; 43: 323–7.
44.
BeutlerE, SipeJC, RomineJS, McMillanR, ZyroffJ, KoziolJA. Treatment of multiple sclerosis and other autoimmune diseases with cladribine. Semin Hematol1996; 33(suppl 1):45–52.
45.
2005 Drug topics red book. Montvale, NJ: Thomson Medical Economics, 2005.
46.
Safety and efficacy of oral cladribine in subjects with relapsing-remitting MS. Phase III Clinical Trial: Identifier # NCT00213135. Food and Drug Administration, 2005. www.clinicaltrials.gov/ct/show/NCT00213135?order=5 (accessed 2006 Mar 27).
47.
CleggA, BryantJ.Immunomodulatory drugs for multiple sclerosis: a systematic review of clinical and cost effectiveness. Expert Opin Pharmacother2001; 2: 623–39.
