Table 3.
Summary of pharmacodynamic and pharmacokinetic outcomes for FTY720
| Level of evidence | Outcomes | FTY720 dosage | Study design and population | Reference |
|---|---|---|---|---|
| 2 | Drug exposure on d 7 was dose proportional for Cmax (5.0±1.0 vs 18.2±4.1 ng/mL) and for AUC (109±24 vs 399±85 ng/h per mL) for FTY720 1.25 and 5 mg/d, respectively Peripheral blood lymphocyte counts decreased from baseline to nadir (range 3–7 d after first dose) by 80 and by 88% in subjects receiving FTY720 1.25 and 5 mg, respectively. By d 35 lymphocyte counts recovered to within 75 and 50% of baseline values in the FTY 1.25 and 5 mg groups, respectively |
1.25 (n=20) or 5 mg (n=20), or placebo (n=20) once daily for 7 d | Randomized, double-blind, placebo-controlled, multiple-dose study in 60 healthy volunteers (age range 18–44 y) | Kovarik et al. 2004a |
| 2 | Both Cmax (0.65±0.17 vs 0.64±0.18 ng/mL) and AUC (149±65 vs 139±43 ng/h per mL) were unchanged by the fasting or fed states, respectively With both treatments the peripheral blood lymphocyte count decreased from baseline by 38±9% at 2 d postdose then increased towards predose values during the subsequent week |
1 mg under fasting conditions or with a high-fat meal | Randomized, two-period, crossover, single-dose study in 14 healthy male volunteers (age range 20–39 y) | Kovarik et al. 2004b |
| 2 | The absorption phase of FTY720 is prolonged, characterized by a tmax of >12 h Cmax (R2=0.966; P<0.001) and AUC (R2=0.916; P<0.001) were dose-proportional over the dose ranges (0.25–3.5 mg) All FTY720 groups showed a temporal pattern of relative lymphocyte sequestration, seen at the latest 6 h postdose. No clear dose response, but the highest doses showed a more pronounced reduction in lymphocyte numbers. Lymphocyte counts returned to ∼80% baseline values 24 h postdose Almost all lymphocyte subgroups declined following FTY720 treatment, with CD4+ and CD45RA+ cells being affected the most. Natural killer cells, granulocytes, and monocytes were not influenced by FTY720 |
0.25 (n=6), 0.5 (n=6), 0.75 (n=3), 1 (n=3), 2 (n=3), or 3.5 mg (n=3), or placebo (n=8) | Randomized, double-blind, placebo-controlled, two-center, single-dose study in 20 stable renal transplant patients (mean age 43.2 y) | Budde et al. 2002; Budde et al. 2003 |
| 2 | Steady-state concentrations of FTY720 were achieved by w 4. In the 10-fold dose range studied the pharmacokinetic profile of FTY720 was linear with dose (R2=0.679 and 0.982 for individual and mean FTY720 concentration, respectively) CS doses and whole blood concentrations were unaffected by FTY720 (or MMF). Therapeutic concentrations of CS were achieved in all groups during the study period, and required no dose adjustment During 12-w treatment with FTY720 lymphocyte sequestration was seen as early as w 1, nadir was reached at w 4 and was fully reversed 4–8 w after cessation of treatment. The pharmacodynamics were not dose-linear over the 10-fold dose range (R2=0.57 and 0.53 for lymphocyte sequestration vs drug dose and vs drug concentrations, respectively). Lymphocyte sequestration was not seen in the MMF-treated group |
0.25 (n=4), 0.5 (n=4), 1 (n=5), or 2.5 mg (n=5), vs MMF 2 g (n=5) | Randomized, multiple-dose, comparator study for 24 w (12-w treatment then 12-w follow-up). 23 renal transplant recipients (mean age 40.1 y). All patients were treated with CS and PD | Park et al. 2005 |
| 3 |
Cmax was not influenced by hepatic function (0.64±0.17, 0.65±0.12, 0.57±0.10 for controls, mild impairment, and moderate impairment, respectively). Oral clearance was reduced on average by 10 and 31% for mild and moderate hepatically impaired subjects compared with the respective controls, reduced metabolism being the likely cause The magnitude of the pharmacokinetic changes suggests that the FTY720 dose need not be adjusted in patients with mild or moderate hepatic impairment The effect on lymphocyte sequestration was similar across all groups with a mean decrease of 44% from the predose baseline |
1 mg | Open-label, single-dose, case-controlled study in 16 subjects with mild (n=8) or moderate (n=8) hepatic impairment and 16 matched controls | Kovarik et al. 2005 |
AUC, area under the concentration–time curve; Cmax, peak plasma concentration; CS, cyclosporine; d, day; h, hour; R2, correlation coefficient; tmax, time to Cmax; MMF, mycophenolate mofetil; PD, prednisone; w, week; y, year.