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

1200±260L. 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

(0.65±0.17 vs 0.64±0.18 ng ml-1) and total exposure (AUC 149±65 vs 139±43ng 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 Dose (mg)

Subjects Tmax (h)

Cmax (ng/ml)

AUC (ng.h/ml)

T1/2 (h)

Vd/F (L)

Cl/F (L/h)

Kovarik et al.

Healthy subjects

1.0 (fasting)

1.0 (fed)

14

14

28 [12-36]

36 [12-36]

0.65±0.17

0.64±0.13

149±65

139±43

7.0±2.8

6.5±2.1

1738±711 1621±291

7.9±3.2

7.8±2.5

Kovarik et. al

Healthy subjects

1.25

5.0

20

20

12 [6-16]

12 [6-16]

5.0±1.0

18.2±4.1

109±24

399±85

7.9±2.2

8.1±2.0

Kovarik et.al

Healthy subjects

1.25 (oral) 1.0 (iv)

11

11

12 [8-36]

2 [1.5-2.0]

1.1±0.2

4.9±0.8

201±31

175±50

6.1±1.0

6.0±0.9

- 1199±260

-

6.3±2.3

Kovarik et. al

Severe hepatic

impairment

5.0 (control)

5.0 (hepatic)

6 6

12 [8-36]

36 [36-96]

3.4±0.5

3.7±1.1

639±105

1326±389

7.3±2.3

10.7±1.8

2026±756 1494±437

8.0±1.5

4.0±1.1

Pharmacokinetics of fingolimod have been further investigated in multiple dose study by Kovarik

et. al[22] 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 fingolimod’s half life. Wash out period in this study also indicated

elimination half-life of fingolimod around 8 days [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.