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`monkeys for the three doses. The PK model was chosen based
`on AIC values: they were —40.9 and —49.8 for three-compart-
`ment, and —5.8 and —8.8 for two-compartment models for
`males and females, respectively. Because simultaneous fit-
`ting of p.o. and i.v. data could not capture the i.v. data over 0
`to 2 h representing the distribution phase of the drug, data
`for the two oral doses were fitted simultaneous to get only kn,
`F, and Tlag after other parameters were obtained fiom i.v.
`data. Those parameters originating fiom i.v. data well char-
`acterized the terminal phases of the oral data for the two
`doses. There were three reasons why simultaneous fitting of
`p.o. and i.v. data did not capture the early i.v. data: First, the
`Tlag and the ka made the p.o. data during this period much
`lower than i.v. data, thereby requiring much higher weight
`(1/02) than i.v. data. Second, the T1,,g and the low ka made the
`distribution phase of the two oral doses less obvious and
`occur later than that for the i.v. dose. Third, there were two
`oral doses, but only one i.v. dose, which means that oral PK
`data have more influence than the i.v. PK.
`Overall, none of the PK parameters showed significant
`gender differences. The PK for males and females was han-
`dled separately because the PD data, especially B-cell data,
`showed significant differences between gender, and it was
`consistent to use gender-specific PK parameters.
`Pharmacodynamics. Lymphocyte homing and recircula-
`tion through conduits of blood and lymph comprise the phys-
`iological processes by which lymphocytes seek out and local-
`ize to particular tissues and to specific microenvironments
`(Smith and Ford, 1983; Butcher, 1986; Picker and Butcher,
`1992; Butcher and Picker, 1996). This underlies the proposed
`two-compartment PD model (Krzyzanski and Jusko, 2001)
`with FTY720 assumed to inhibit lymphocyte influx to blood
`(Chiba et al., 1998; Luo et al., 1999; Yagi at al., 2000).
`The Imax values in the model were calculated using eq. 14
`instead of fitting. This was necessary owing to the large
`number of parameters and initial conditions that created
`difficulties in fitting. The Imax values of 0.82 to 0.92 for all
`cells (Table 3) were consistent with the literature values of 80
`to 90% in cynomolgus monkeys (Quesniaux et al., 2000). Both
`the R0 and Imax values for females were lower than for males,
`showing that it was worthwhile to pool data for each gender.
`Another similarity to literature findings (Enosawa et al.,
`1996; Nagahara et al., 2000) was that the Imax for T cells was
`greater, showing more susceptibility than B cells. On the
`contrary, peripheral T cells were much less susceptible than
`B cells (Figs. 3—5; Table 2), especially for females, owing to
`
`Dose
`
`Lymphocyte
`B Cell
`T Cell
`Lymphocyte
`B Cell
`T Cell
`Blood ABEC (X 100 cells >< h/pl)
`0.1 mg/kg p.o.
`3917
`1.0 mg/kg p.o.
`9261
`0.1 mg/kg i.v.
`5216
`Blood ABEC/AUC (><10a cells/pg)
`0.1 mg/kg p.o.
`64.25
`1.0 mg/kg p.o.
`15.19
`0.1 mg/kg i.v.
`27.02
`Mean reduction percentage of peripheral counts (%)
`0.1 mg/kg p.o.
`1.26
`1.0 mg/kg p.o.
`2.79
`0.1 mg/kg i.v.
`1.66
`
`Females
`
`427
`1209
`543
`
`5.07
`1.44
`2.89
`
`7.83
`21.68
`9.90
`
`3494
`7897
`4138
`
`41.51
`9.38
`22.02
`
`0.039
`0.082
`0.046
`
`the larger apparent distribution volume (VP) of T cells than B
`cells (Table 3).
`This model justifies why the lymphocyte responses in blood
`attained a trough before blood FTY720 reached Cm“. Accord-
`ing to the PD fittings, the cell counts in blood attained a
`trough at 12.3 h, where 98.6% reduction occurs during the
`first 6 h for an oral dose of 1 mg/kg and 94.5% for 0.1 mg/kg,
`whereas according to the PK fittings, Tmax is 10.9 h for males
`and 12.1 h for females. This indicates that the maximum
`effect of FTY720 is actually attained at 6 h, much earlier
`than Tm“. Also, the higher the dose, the earlier the maxi-
`mum effect. This phenomenon is due to the low I050 values in
`Table 3 (0.45 ug/l). This phenomenon was also seen in human
`FTY720 data (V. Brinkman, L. Chodoff, M. Figlimeni, P.
`Heining, J. Jaffe, T. Sabinski, R. Schmouder, unpublished
`observations), indicating FTY720 has a remarkably strong
`effect on trafficking of blood lymphocytes.
`This model can explain why the maximum effects of
`FTY720 on cell trafficking are achieved at doses smaller than
`that producing protection against graft rejection in FTY720
`therapy (Yanagawa et al., 1998b). For the oral dose of 1
`mg/kg, when T cell counts in blood are already reduced by
`90%, counts in the peripheral compartment were reduced no
`more than 0.01% (Figs. 3—5), thus almost nothing would
`happen to prevent these cells fiom infiltrating to the graft (if
`accessible). Only after a long period of larger doses of FTY720
`administration could the peripheral T-cell counts be reduced
`to a level that is low enough to prevent infiltration to the
`graft. Of further complexity, the model assumes that num-
`bers of cells in the general pool are not perceptibly altered by
`FTY720. The significance of timing of FTY720 administra-
`tion on graft survival is also justified by this model: FTY720
`should be given before or soon after graft implantation to
`prevent T cells from infiltrating to the graft. This necessity
`for FTY720 was reported recently (Yanagawa et al., 2000).
`Although there was an absorption delay of about 0.4 h for
`oral doses, both PD nadir time and nadir level for 0.1 mg/kg
`p.o. were almost equal to those for 1 mg/kg p.o. and 0.1 mg/kg
`i.v. The nonlinear ABEC/AUC ratio values in Table 2 may
`account for the approximate nadir level values: the lower the
`AUC (exposure) value, the stronger the PD effect for per unit
`exposure. The consistency in nadir time indicated that the
`PD effect might occur before FTY720 was absorbed into sys-
`tematic blood for oral doses. It was indeed found that Peyer’s
`patches gathered lymphocytes before lymph nodes for oral
`FTY720 doses in rats (Yanagawa et al., 1998a).
`
`

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