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Pharmacokinetics

Fingolimod is absorbed efficiently with oral bioavailability of 93% and extensively bound to
protein (>99.7%). This drug is widely distributed in body tissues with high volume of distribution of
1200260L. Fingolimod half-life is around 6-9 days with steady state reached within 1 to 2 months [10]. Its
main metabolism is via CYP4F2 but very less via other main major CYP enzymes such as CYP3A4, CYP1A2,
CYP2B6, CYP2C9, CYP2C19, CYP2D6 or CYP2E1 ad eliminated primarily via kidney. This allows lesser drug
interaction with fingolimod and beneficial in patients with many concomitant medications. There are four
main papers which are landmark papers and will be discussed in this report.
Kovarik et al. conducted a study in eleven healthy subjects which were given 1 mg intravenous
fingolimod then after minimum of 30 days crossed over to 1.25 mg oral form and vice versa. Average
oral/iv ratio of dose-normalized AUCs for fingolimod showed 94% meaning oral fingolimod achieved
systemic availability compared to that of intravenous form (95% CI 0.78-1.12) [23].Fingolimod has
elimination half life about 6-9 days following single dose administration irrespective of doses[21][23].
Following single dose administration study done by Kovarik et al. in 2003, both the peak concentrations
(0.650.17 vs 0.640.18 ng ml-1) and total exposure (AUC 14965 vs 13943ng ml-1 h) did not statistically
significant difference between fasting and fed state [21]. This shows that fingolimod can be taken without
regard to meal. Important pharmacokinetic parameters of fingolimod are shown in Table 1.
Table 1: Pharmacokinetic parameters of fingolimod in landmark papers
Study

Population

Kovarik
et al.

Healthy
subjects

Kovarik
et. al

Healthy
subjects

Kovarik
et.al

Healthy
subjects

Kovarik
et. al

Severe
hepatic
impairment

Dose
(mg)
1.0
(fasting)
1.0
(fed)
1.25

Subjects

5.0

20

1.25
(oral)
1.0
(iv)
5.0
(control)
5.0
(hepatic)

11

14
14
20

11
6
6

Tmax
(h)
28
[12-36]
36
[12-36]
12
[6-16]
12
[6-16]
12
[8-36]
2
[1.5-2.0]
12
[8-36]
36
[36-96]

Cmax
(ng/ml)
0.650.17

AUC
(ng.h/ml)
14965

T1/2
(h)
7.02.8

Vd/F
(L)
1738711

Cl/F
(L/h)
7.93.2

0.640.13

13943

6.52.1

1621291

7.82.5

5.01.0

10924

7.92.2

18.24.1

39985

8.12.0

1.10.2

20131

6.11.0

4.90.8

17550

6.00.9

1199260

6.32.3

3.40.5

639105

7.32.3

2026756

8.01.5

3.71.1

1326389

10.71.8

1494437

4.01.1

Pharmacokinetics of fingolimod have been further investigated in multiple dose study by Kovarik
et. al in which two doses of 1.25 mg and 5 mg of fingolimod once daily given for 7 consecutive days.
Fingolimod concentration profile is remarkably flat in multiple doses, with low peak to trough
concentration fluctuations of 25%. After 7 days, blood levels accumulated five times since first day in
both doses showing consistency of fingolimods half life. Wash out period in this study also indicated
elimination half-life of fingolimod around 8 days [22].
[22]

It is also important to understand influence of hepatic or renal impairment on pharmacokinetic


properties of fingolimod. A clinical trial was conducted to compare levels of fingolimod in healthy and
severe hepatic impairment subjects. The results showed severe hepatic impairment patients (with Child
Pugh score 10 or class C) had a double area under the concentration time curve and a prolonged
elimination half-life of 50% while similar peak blood concentration [24]. However, mild and moderate
hepatic impairment increased slightly but not statistically significant. Therefore, only severe hepatic
impairment patients need the dose adjustment. Kovarik J. M. et al also suggested a standard first dose
could be given followed by 50% reduction of maintenance dose of fingolimod in this group of patients.
However, half life of severe renal impairment was similar in those healthy subjects, showing no need of
dosage adjustment in renal impairment patients.