472750 MSJ19910.1177/1352458512472750Multiple Sclerosis JournalTanaka et al.
`
`2013
`
`Letter to the Editor
`
`MULTIPLE
`SCLEROSIS MSJ
`JOURNAL
`
`Multiple Sclerosis Journal
`19(9) 1244 –1245
`© The Author(s) 2013
`Reprints and permissions:
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`DOI: 10.1177/1352458512472750
`msj.sagepub.com
`
`Reduced fingolimod dosage treatment
`for patients with multiple sclerosis and
`lymphopenia or neutropenia
`
`Fingolimod has been approved as the first oral treatment
`for relapsing–remitting multiple sclerosis (RRMS). In a
`Japanese clinical trial,1 8.9% of patients treated with
`0.5mg of fingolimod showed lymphocyte counts of < 200
`× 106/l and a reduction of the mean absolute neutrophil
`count of 14% and 25% from baseline at day 15 and month
`6, respectively.
`The maximum fingolimod concentration increased and
`nadir lymphocyte count decreased with dose after a single
`oral dose of fingolimod.2 Steady-state plasma concentra-
`tions were attained 1–2 months after treatment initiation.3
`The steady-state plasma maximum drug concentrations were
`calculated from the maximum plasma concentration (Cmax)
`and elimination half-life (T1/2) of fingolimod. Steady-state
`Cmax levels correlated with total doses for six contiguous
`days (dosing ranged from daily to every three days) (data
`not shown).
`Patient 1: a 71-year-old woman with disease duration of
`12 years. Two weeks after starting daily fingolimod treat-
`ment (0.5 mg/day: 3.0 mg/6 days) her lymphocyte counts
`decreased from 800 to 176 × 106/l. Lymphocytes increased
`to 300 × 106/l after changing administration from daily to
`every other day (0.5 mg e.o.d.: 1.5 mg/6 days: three weeks
`after initiation).
`Patient 2: a 28-year-old woman with disease duration
`of one year and seven months. Five weeks after initiation,
`her lymphocyte count decreased (from 1292 × 106/l to
`244 × 106/l) and gradually increased to 474 × 106/l after
`changing from daily (0.5 mg/day: 3 mg/6 days) to 5
`times/6 days (0.5 mg/day: 2.5 mg/6 days) 15 weeks after
`initiation.
`Patient 3: a 35-year-old woman with disease duration of
`14 years. Her neutrophil count decreased from 2457 to
`1336 × 106/l (38% reduction) seven weeks after initiation.
`Neutrophils increased to 1985 × 106/l after changing to
`4 times/6 days (0.5 mg/day: 2.0 mg/6 days).
`None of the three patients showed any clinical relapses
`in the 34–38 weeks from initiation.
`Previous clinical trials of fingolimod have not shown
`that any patients with lymphopenia or neutropenia had to
`
`discontinue the study drug; however, we administered
`fingolimod to patients with small body habitus who may
`have shown higher drug blood concentration after phos-
`phorylation. The body surface area (BSA) of our patients
`was 1.46, 1.55 and 1.45 m2. Plasma concentration should
`be considered when treating women with small BSA. In
`an earlier, ethnic based study, no differences in blood
`concentration after single-dose administration were found
`between Caucasian and Japanese individuals, but the
`authors did not discuss BSA.4 We should consider alterna-
`tive treatment schedules that may include drug holidays
`within a weekly dosing schedule if patients show a rapidly
`decreasing lymphocyte count 2–4 weeks after initiation.
`The mechanisms of neutrophil reduction are not known,
`but there was no relationship between lymphocyte and
`neutrophil counts for these three patients.
`We suggest that the lymphocyte count may correlate
`with the dosage of fingolimod (cumulative dose over
`several weeks) and that the lymphocyte can be controlled
`satisfactorily by administering the same 0.5 mg tablet at
`varying intervals.
`
`Conflict of interest
`The authors declare that there are no conflicts of interest.
`
`Funding
`This study was supported by the Ministry of Health, Labor, and
`Welfare of Japan (Health and Labor Sciences Research Grants
`for research on intractable diseases).
`
`References
`1. Saida T, Kikuchi S, Itoyama Y, et al. A randomized, controlled
`trial of fingolimod (FTY720) in Japanese patients with multiple
`sclerosis. Mult Scler J. [Epub ahead of print 21 February 2012,
`DOI: 10.1177/1352458511435984].
`2. Budde K, Schmouder RL, Brunkhorst R, et al. First human
`trial of FTY720, a novel immunomodulator, in stable renal
`transplant patients. J Am Soc Nephrol 2002; 13: 1073-1083.
`3. Scott LJ. Fingolimod. A review of its use in the management
`of relapsing–remitting multiple sclerosis. CNS Drugs 2011;
`25: 673-698.
`4. Kovarik JM, Slade A, Voss B, et al. Ethnic sensitivity study of
`fingolimod in white and Asian subjects. Int J Clin Pharmacol
`Ther 2007; 45: 98-109.
`
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`

`Tanaka et al.
`
`1245
`
`Masami Tanaka1, Kwiyoung Park1 and Keiko Tanaka2
`1Multiple Sclerosis Center,
`Utano National Hospital, Kyoto, Japan.
`2Department of Neurology, Kanazawa Medical
`University, Japan.
`
`Corresponding author:
`Masami Tanaka, Multiple Sclerosis Center, Utano
`National Hospital, 8 Ondoyama, Narutaki, Ukyo-ku,
`Kyoto, 616-8255, Japan.
`Email: nra17777@nifty.com
`
`