10.1177/0091270004264165ARTICLE
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`KOVARIK ET ALMULTIPLE-DOSE FTY720PHARMACOKINETICS AND PHARMACODYNAMICS
`
`Multiple-Dose FTY720: Tolerability,
`Pharmacokinetics, and Lymphocyte
`Responses in Healthy Subjects
`
`John M. Kovarik, PhD, FCP, Robert Schmouder, MD, Denise Barilla,
`Gilles-Jacques Riviere, PhD, Yibin Wang, PhD, and Thomas Hunt, MD
`
`FTY720 is a sphingosine-1-phosphate receptor agonist being
`developed as an immunomodulator for acute rejection pro-
`phylaxis after organ transplantation. This study was per-
`formed to characterize the pharmacokinetics of and lympho-
`cyte response to multiple-dose FTY720. In this randomized,
`double-blind study, three groups of 20 healthy subjects each
`received either placebo, 1.25 mg/day FTY720, or 5 mg/day
`FTY720 for 7 consecutive days. FTY720 blood concentra-
`tions and lymphocyte counts were assessed over the
`weeklong treatment phase and over a month-long washout
`phase. The relationship between FTY720 blood concentra-
`tions and lymphocyte counts was explored by an inhibitory
`Emax model. First-dose exposure was consistent with dose
`proportionality between the low- and high-dose groups.
`Blood levels accumulated fivefold over the treatment period.
`Exposure on day 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/
`mL). Washout pharmacokinetics after the last dose indicated
`an elimination half-life averaging 8 days. Lymphocyte counts
`decreased by 80% in subjects receiving the lower dose to a na-
`
`dir of 0.4 ± 0.1 × 109/L and by 88% in subjects receiving the
`upper dose to a nadir of 0.2 ± 0.1 × 109/L. Descriptive exposure-
`response modeling estimated that the lymphocyte response
`at 5 mg/day is near the maximal response achievable. By the
`end-of-study evaluation on day 35, lymphocyte counts had
`recovered to within 75% and 50% of baseline in the low- and
`high-dose groups, respectively. In summary, systemic expo-
`sure to FTY720 was consistent with dose-proportionality af-
`ter both single- and multiple-dose administration. Total lym-
`phocyte counts decreased from baseline by 80% and 88% at
`regimens of 1.25 and 5 mg/day, respectively. Exposure-re-
`sponse modeling provided evidence that 5 mg/day FTY720
`resulted in a near-maximal dynamic effect of this drug on
`lymphocytes.
`
`Keywords: FTY720; sphingosine-1-phosphate receptor
`agonists; pharmacokinetics; lymphocyte re-
`sponse; immunosuppressants; tolerability
`Journal of Clinical Pharmacology, 2004;44:532-537
`©2004 the American College of Clinical Pharmacology
`
`Classical immunosuppressants used in organ trans-
`
`plant medicine inhibit either the activation or pro-
`liferation of T lymphocytes. A new paradigm in trans-
`plantation drug development focuses on agents that
`alter lymphocyte trafficking to impede T lymphocytes
`from reaching the grafted organ, thereby preventing
`acute rejection episodes.1,2 FTY720 is the first in a new
`class of immunomodulators called sphingosine-1-
`phosphate receptor agonists. This immunomodulator
`
`From Novartis Pharmaceuticals, Basel, Switzerland and East Hanover,
`New Jersey (Dr. Kovarik, Dr. Schmouder, Ms. Barilla, Dr. Riviere, Dr. Wang)
`and PPD Development Clinics, Austin, Texas (Dr. Hunt). Submitted for pub-
`lication September 11, 2003; revised version accepted February 8, 2004.
`Address for reprints: John M. Kovarik, Novartis Pharma AG, Building WSJ
`27.4093, 4002 Basel, Switzerland.
`DOI: 10.1177/0091270004264165
`
`has a unique mode of action that protects transplanted
`grafts by reducing the recirculation of lymphocytes to
`blood and peripheral tissues without impairing activa-
`tion, expansion, or memory at clinically relevant drug
`concentrations. This mode of action is in marked con-
`trast to classical immunosuppressants.3,4 Early devel-
`opment trials in renal transplantation used FTY720 in
`multidrug regimens with corticosteroids and either
`cyclosporine or everolimus. These trials provided ini-
`tial evidence of the effectiveness of FTY720 in prevent-
`ing acute rejection episodes when dosed in the range
`2.5 to 5 mg once daily.5,6
`Characterizing the pharmacokinetics and pharma-
`codynamics of a new drug in the target patient population
`is an essential component of rational drug develop-
`ment. Nonetheless, it can be particularly challenging in
`
`532 • J Clin Pharmacol 2004;44:532-537
`
`Apotex v. Novartis
`IPR2017-00854
`NOVARTIS 2045
`
`

`

`MULTIPLE-DOSE FTY720
`
`organ transplant patients to discern drug-specific
`tolerability concerns and pharmacological effects
`against a background of multiple comorbidities and
`comedications.2 Moreover, in the case of FTY720,
`coadministration of corticosteroids and other im-
`munosuppressants that affect lymphocytes could ob-
`scure the FTY720-specific effect on these target cells.
`Accordingly, we conducted a multiple-dose, placebo-
`controlled study of FTY720 in healthy subjects to assess
`short-term tolerability and safety and to characterize
`the lymphocyte response under conditions unencum-
`bered by comedications. We chose a subtherapeutic
`and a therapeutic dose of FTY720 to span a broad range
`of exposures and responses.
`
`METHODS
`
`Study Design
`
`This was a randomized, double-blind, placebo-
`controlled study in healthy subjects. The protocol
`was approved by a local medical ethics committee, and
`the study was performed at PPD Clinical Development
`(Austin, TX). Subjects were judged eligible for the
`study based on their past medical history, a physical
`examination, vital signs, standard clinical laboratory
`parameters, and an electrocardiogram performed at a
`screening visit. Subjects gave written informed consent
`to participate in the trial.
`The study was divided into three phases: (1) a base-
`line phase, during which clinical evaluations were per-
`formed; (2) a treatment phase in which subjects re-
`ceived once-daily dosing of 1.25 mg FTY720 (n = 20), 5
`mg FTY720 (n = 20), or placebo (n = 20) capsules for 7
`days, with an end-of-study evaluation on day 8; and (3)
`a month-long washout phase in which subjects re-
`turned to the clinic for follow-up pharmacokinetic
`blood sampling and lymphocyte counts. Subjects
`fasted for 10 hours before drug administration until 4
`hours after the dose on day 1. On other study days,
`breakfast was served 1 hour after the drug was adminis-
`tered. Subjects were domiciled at the study center
`throughout the baseline and treatment phases and
`were discharged on day 8.
`
`Clinical Assessments
`
`Safety assessments included physical examinations,
`vital signs, clinical laboratory parameters (biochemis-
`try, hematology, urinalysis), and electrocardiograms at
`baseline, at multiple time points during the treatment
`phase, and at the end-of-study evaluation. Total lym-
`phocyte counts were obtained each morning during the
`
`treatment phase and at each visit during the washout
`period. Lymphocyte counts were part of the routine
`complete blood count determined at the clinical labo-
`ratory of the study center. Extensive cardiac function
`testing was performed during the baseline and
`treatment phases; these will be reported separately.
`
`Pharmacokinetic Assessments and Bioanalytics
`
`Venous blood samples were obtained before FTY720
`administration and then at 1, 2, 4, 6, 8, 12, 16, 20, and
`24 hours after the first dose on day 1 and at these same
`time points after the last dose on day 7. On days 2 to 6,
`blood samples were obtained before (trough) and 6 to 8
`hours after the daily dose (peak). During the washout
`phase, subjects returned to the clinic on days 10, 14, 21,
`28, and 35 for pharmacokinetic blood sampling. Each
`blood sample was 2.7 mL in volume collected in an
`EDTA-containing vacuum tube. Sample tubes were in-
`verted several times to mix the tube contents and
`frozen at –20°C. FTY720 whole-blood concentrations
`were determined by a validated liquid chromatogra-
`phy method with mass spectrometry, as described pre-
`viously.7 Assay performance was judged on the basis of
`three quality control concentrations: 0.02, 1.5, and 40
`ng/mL. Assay accuracy ranged from 97.5% to 108.7%
`and precision coefficients of variation from –2.5%
`to 8.7%. The lower limit of quantification was 0.08
`ng/mL.
`
`Data Evaluation and Statistics
`
`Standard noncompartmental pharmacokinetic param-
`eters were derived from the concentration-time data.
`These included the predose concentration, C(0); the
`peak concentration, Cmax; the time of its occurrence,
`tmax; the area under the concentration-time curve over
`the 24-hour dose interval, AUCτ; the average concentra-
`tion over the dose interval, Cavg (Cavg = AUCτ/24); the
`percent peak-trough fluctuation, PTF (PTF = [Cmax –
`C(0)] /Cavg); and the elimination half-life, t1/2. Dose-
`normalized Cmax and AUCτ were log-transformed and
`tested in an ANOVA for dose proportionality.
`Total lymphocyte counts were graphed with respect
`to time and inspected for temporal trends. Response
`parameters derived from the lymphocyte-time curves
`included the lymphocyte nadir count and the time of
`its occurrence. Exposure-response data were explored
`using an inhibitory Emax model, including a baseline
`parameterized as E = E0 – [(Emax • C)/(EC50 + C)], where
`E0 is the baseline response, Emax is the maximal re-
`sponse, EC50 is the exposure at which half-maximal
`response occurs, and C is the FTY720 exposure met-
`
`PHARMACOKINETICS AND PHARMACODYNAMICS
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`533
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`

`

`KOVARIK ET AL
`
`ric as described below. Both pharmacokinetic and
`exposure-response evaluations were performed in
`WinNonlin, version 4.0 (Pharsight Corporation,
`Mountain View, CA).
`
`RESULTS
`
`Study Population, Tolerability, and Safety
`
`A total of 66 subjects were enrolled in the study. Six of
`these subjects withdrew from participation during the
`baseline phase before receiving FTY720 because of ab-
`normal cardiac rhythms (n = 4), viral infection (n = 1),
`and family emergency (n = 1). The remaining 60 sub-
`jects completed the study. The full study population
`consisted of 32 men and 34 women. They were 28.7 ±
`7.0 years old (range: 18-44) and weighed 74.2 ± 12.5 kg
`(range: 50-111). The study population was 52% white,
`4% black, 2% Asian, and 42% other ethnicities.
`Multiple-dose FTY720 was generally well tolerated.
`There were a total of 114 adverse events reported by 36
`subjects. The temporal distribution was 14% during
`the baseline phase, 65% during the treatment phase,
`and 21% during the washout phase. Roughly half the
`events consisted of headache (31%), dizziness (9%),
`and nausea (7%). Adverse events did not show a partic-
`ular treatment distribution with 36% in the placebo
`group, 16% in the 1.25-mg FTY720 group, and 48% in
`the 5-mg FTY720. There were no clinically relevant
`changes in biochemistry or urinalysis parameters over
`the course of the study. Among hematology parame-
`ters, there was a mean decrease in platelets and a mean
`increase in monocytes, neutrophils, and basophils on
`day 7; however, most values remained in the normal
`range. The effects of FTY720 on total lymphocyte
`counts are described below. Effects of FTY720 on
`cardiac function will be described in a separate report.
`
`First-Dose Pharmacokinetics
`
`Table I and Figure 1 summarize the pharmacokinetic
`data. FTY720 concentration profiles exhibited a
`biphasic rise in blood concentrations, with the first oc-
`curring between administration and 4 hours and the
`second between 4 and 12 hours. During the second,
`broad rise in concentrations, the peak concentration
`occurred at a median of 12 hours at both dose levels,
`with an individual range from 8 to 16 hours. Cmax was
`consistent with dose proportionality based on the geo-
`metric mean ratio (95% confidence interval [CI]) of the
`dose-normalized values of 1.04 (0.92-1.17). After
`reaching the maximum, concentrations declined very
`slightly over the remainder of the 24-hour dosing inter-
`
`534 • J Clin Pharmacol 2004;44:532-537
`
`Table I
`
`Pharmacokinetic Parameters
`
`Parameter
`
`1.25 mg/day
`
`5 mg/day
`
`12 (8-16)
`4.2 ± 0.8
`3.3 ± 0.5
`79 ± 13
`
`12 (12-16)
`1.1 ± 0.2
`0.9 ± 0.2
`20 ± 4
`
`Day 1
`tmax (h)
`Cmax (ng/mL)
`C(24) (ng/mL)
`AUCτ (ng•h/mL)
`Day 7
`14.0 ± 2.7
`3.7 ± 0.8
`C(0) (ng/mL)
`12 (6-16)
`12 (6-16)
`tmax (h)
`18.2 ± 4.1
`5.0 ± 1.0
`Cmax (ng/mL)
`399 ± 85
`109 ± 24
`AUCτ (ng•h/mL)
`16.6 ± 3.5
`4.5 ± 1.0
`Cavg (ng/mL)
`15.7 ± 3.5
`4.3 ± 1.1
`C(24) (ng/mL)
`25 ± 6
`27 ± 8
`PTF (%)
`8.1 ± 2.0
`7.9 ± 2.2
`t1/2 (days)
`Data are mean ± standard deviation, except for tmax, which is median
`(range). C(x), blood concentration × hours postdose; tmax, time to reach peak;
`Cmax, peak blood concentration; AUCτ, area under the concentration-time
`curve over the dosing interval; Cavg, average concentration; PTF, peak-
`trough fluctuation; t1/2, half-life.
`
`val before the next dose administration. AUCτ was also
`consistent with dose proportionality after the first
`dose, with a ratio of 1.00 (0.90-1.12). Both Cmax and
`AUCτ exhibited moderate interindividual variability,
`with coefficients of variation between 16% and 20%.
`
`Multiple-Dose Pharmacokinetics
`
`Figure 1 shows that predose trough concentrations C(0)
`and approximate peak concentrations at 6 to 8 hours
`postdose C(8) increased daily over the multiple-dose
`treatment phase. From day to day, the ratio of C(0)s be-
`tween dose levels remained relatively constant and av-
`eraged 3.8, reflecting the fourfold difference in doses. A
`similar pattern occurred for C(8). Drug accumulation in
`blood over the full study course from days 1 to 7 was
`quantified by the day 7 to day 1 ratio of AUCτ, which
`averaged 5.5 ± 0.8 at 1.25 mg/day and 5.0 ± 0.7 at 5 mg/
`day. If C(24) was used to assess accumulation, a similar
`result was obtained: 4.9 ± 0.7 and 4.7 ± 0.6 at the two
`dose levels, respectively. Hence, the overall accumula-
`tion in blood over 7 days of daily dosing was fivefold
`regardless of dose level.
`Comparison of the mean concentration profiles on
`day 7 with those from day 1 emphasizes the flatness of
`drug exposure over the dose interval during multiple
`dosing. Nonetheless, the biphasic nature of drug input
`was still evident, with tmax reached at a median 12 hours
`postdose, similar to the pattern seen after the first dose.
`On day 7, the difference in exposure between dose lev-
`
`

`

`MULTIPLE-DOSE FTY720
`
`baseline lymphocyte count was similar in all groups. In
`subjects receiving placebo, mean lymphocyte counts
`exhibited small fluctuations around the baseline dur-
`ing the 7-day treatment period. The daily mean counts
`on treatment days ranged from 1.7 to 1.9 × 109/L. In the
`washout period, mean counts rose slightly to 2.2 × 109/L
`by the end of the study on day 35.
`In subjects receiving FTY720, mean lymphocyte
`counts were decreased at the first postdose lymphocyte
`sampling time point on day 2 to 0.8 and 0.4 × 109/L in
`the low- and high-dose groups, respectively. These rep-
`resented 58% and 76% reductions from baseline. The
`absolute lymphocyte nadir subsequently occurred be-
`tween days 3 to 7 across all FTY720-treated subjects. In
`subjects receiving 1.25 mg/day, the nadir averaged
`0.4 ± 0.1 × 109/L, corresponding to an 80% decrease
`from baseline. In subjects receiving 5 mg/day, the mean
`nadir count was half that measured in the low-dose
`group, 0.2 ± 0.1 × 109/L, or an 88% decrease from
`baseline.
`Since the lymphocyte nadir occurred across sub-
`jects on different days over the course of the weeklong
`treatment, we chose the cumulative area under the
`curve of FTY720 trough concentrations from days 1 to
`8, or AUC(1-8), as an overall uniform exposure metric.
`This was used to explore for an exposure-response re-
`lationship to lymphocyte nadir. Figure 3 shows that an
`inhibitory Emax model including a baseline parameter
`could reasonably describe the data. The model esti-
`mated a baseline E0 of 1.53 × 109/L (coefficient of varia-
`tion [CV] = 4.7%), with a cumulative exposure yielding
`half-maximal inhibition of 3.0 ng•days/mL (CV =
`74.6%). The maximal lymphocyte response (Emax) was
`a decrease by 1.37 × 109/L (CV = 70.0%) to an estimated
`minimal nadir count of 0.16 × 109/L.
`A gradual lymphocyte recovery was evident during
`the washout phase between days 9 to 35, as seen in Fig-
`ure 2. The recovery was more rapid at the lower com-
`pared with the higher dose group. At the end-of-study
`visit, mean absolute lymphocyte counts were 1.4 ± 0.4 ×
`
`21
`
`18
`
`15
`
`12
`
`0369
`
`FTY720 (ng/ml)
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`Day
`
`Figure 1. Mean FTY720 concentration profiles over the dosing in-
`terval from days 1 to 7 at 1.25 mg/day (䊊) and 5 mg/day (䊉). A full
`AUC profile was obtained after the first and last doses and trough
`and peak concentrations on the intermediate days. Bars represent
`95% confidence intervals.
`
`els was consistent, with the fourfold difference of doses
`based on the dose-normalized parameter ratio (95% CI)
`for C(0) of 1.06 (0.94-1.21), Cmax of 1.09 (0.96-1.25), and
`AUCτ of 1.09 (0.95-1.25). The flatness of the profiles
`was underscored by the remarkably narrow peak-
`trough fluctuation of about 25%. The fact that C(24) was
`higher than the predose C(0) indicated that steady state
`was not reached in 7 days, as anticipated.
`The decline in concentrations after the last dose was
`gradual and parallel at the two dose levels. Accordingly,
`the half-lives were similar between doses and averaged
`about 8 days. Inasmuch as these values were derived
`from six concentrations obtained over the month-long
`washout phase, they are likely robust estimates.
`
`Lymphocyte Responses
`
`Table II summarizes the lymphocyte response data,
`and Figure 2 shows the lymphocyte trajectories. The
`
`Table II Lymphocyte Response Parameters
`
`Parameter
`
`Placebo
`1.9 ± 0.5
`Baseline lymphocytes (109/L)
`1.8 ± 0.4
`Day 2 lymphocytes (109/L)
`1.5 ± 0.5
`Nadir lymphocytes (109/L)
`81 ± 20
`Nadir lymphocytes (% of baseline)
`4 (2-8)
`Time of nadir (day)
`1.8 ± 0.6
`Day 8 lymphocytes (109/L)
`2.2 ± 0.7
`Day 35 lymphocytes (109/L)
`Values are mean ± standard deviation, except for time of nadir, which is median (range).
`
`1.25 mg FTY720
`1.9 ± 0.5
`0.8 ± 0.2
`0.4 ± 0.1
`20 ± 6
`7 (4-7)
`0.5 ± 0.2
`1.4 ± 0.4
`
`PHARMACOKINETICS AND PHARMACODYNAMICS
`
`5 mg FTY720
`1.7 ± 0.4
`0.4 ± 0.2
`0.2 ± 0.1
`12 ± 4
`4 (3-7)
`0.3 ± 0.2
`0.8 ± 0.4
`
`535
`
`

`

`KOVARIK ET AL
`
`events for which none of the subjects required treat-
`ment. These results are encouraging inasmuch as daily
`doses up to 5 mg are currently used in clinical trials in
`renal transplantation. In addition, the disposition of
`FTY720 observed in these healthy subjects is similar to
`that in transplant recipients.8 For example, after a 2-mg
`single dose (a dose intermediate between those we
`used in this study), the Cmax in patients was 1.2 ± 0.3 ng/
`mL, AUC(0-24) was 23 ± 5 ng•h/mL, and half-life was 6.5
`± 0.8 days.8 Hence, healthy subject studies are an ap-
`propriate vehicle for learning about the clinical phar-
`macology of FTY720 under controlled conditions and
`applying these lessons to the clinical setting with
`appropriate confirmatory data in the target patient
`population.
`FTY720 peak and total exposure on day 1 at the two
`dose levels were consistent with dose-proportional
`disposition. Cmax and AUCτ exhibited moderate
`interindividual variability of 20% or less. The delayed
`tmax that ranged from 8 to 16 hours postdose appears
`consistent with the slow absorption of dietary
`sphingolipids inasmuch as FTY720 is a structural ana-
`log of this lipid class. Over the treatment phase, blood
`concentrations accumulated fivefold. The concentra-
`tion profile during multiple dosing was remarkable for
`its flatness, as manifested by the narrow peak-trough
`fluctuation of around 25%. This is consistent with
`FTY720’s prolonged half-life relative to the 24-hour
`dosing interval. The moderate interindividual varia-
`tion in exposure observed after the first dose was also
`the case on day 7, with Cmax and AUCτ variation around
`22%.
`It was anticipated that steady state would not be at-
`tained in a weeklong treatment phase, and this was
`confirmed by the pharmacokinetic data. Rather, this
`dosing period was chosen to gain short-term experi-
`ence with multiple dosing in healthy subjects and to
`provide normative data on the lymphocyte response to
`FTY720, which reaches its maximal effect in individ-
`ual patients within a few days after starting treatment
`and is maintained with continued dosing. Hence, a
`weeklong treatment phase was deemed adequate to ex-
`plore this exposure-response relationship. Moreover,
`the broad range of doses from 1.25 to 5 mg/day and
`AUCs from 15 to 111 ng•h/mL constituted a robust da-
`tabase for exploring the associated lymphocyte
`response to FTY720.
`Daily morning lymphocyte counts remained rela-
`tively stable over the treatment phase in placebo-
`treated subjects and rose slightly thereafter. In FTY720-
`treated subjects, lymphocyte counts decreased from
`baseline by about 60% in the low-dose group and by
`about 75% in the high-dose group by the morning after
`
`2.5
`
`2.0
`
`1.5
`
`1.0
`
`0.5
`
`0.0
`
`Lymphocytes (10^9/L)
`
`0
`
`7
`
`14
`
`21
`
`28
`
`35
`
`Day
`
`Figure 2. Mean lymphocyte trajectories over the treatment phase
`(days 1-8) and during the washout phase (days 9-35) in subjects re-
`ceiving placebo (䊊), 1.25 mg/day FTY720 (䊏), and 5 mg/day FTY720
`(䉱). Bars represent 95% confidence intervals.
`
`2.5
`
`2.0
`
`1.5
`
`1.0
`
`0.5
`
`0.0
`
`Lymphocyte nadir (10^9/L)
`
`0
`
`20
`
`60
`40
`AUC(1-8) (ng.days/ml)
`
`80
`
`100
`
`Figure 3. Relationship between FTY720 cumulative AUC over the
`weeklong treatment phase (days 1-8) versus the nadir lymphocyte
`count. Shown is the line from the fit of an inhibitory Emax model to the
`data.
`
`109/L, or 74% of baseline in the low-dose group, and
`0.8 ± 0.4 × 109/L, or 47% of baseline in the high-dose
`group.
`
`DISCUSSION
`
`Daily administration of FTY720 over 1 week was well
`tolerated up to the maximal dose used in this study of 5
`mg/day. There were generally mild, transient adverse
`
`536 • J Clin Pharmacol 2004;44:532-537
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`

`

`MULTIPLE-DOSE FTY720
`
`drug administration. The absolute nadir lymphocyte
`counts occurred between days 3 and 7, averaging 0.4
`and 0.2 × 109/L in the low- and high-dose groups. An
`inhibitory Emax model reasonably described the rela-
`tionship between the cumulative exposure to FTY720
`over the weeklong treatment phase versus the nadir
`lymphocyte count. The model-estimated parameters
`indicated that the maximum effect of FTY720 is being
`approached or reached at the 5-mg/day dose level inas-
`much as the nadir count was 0.2 × 109/L and the model-
`estimated minimum was 0.16 × 109/L. Within a few
`days of the last FTY720 dose, lymphocyte counts began
`to recover. The rate of recovery appeared to be dose re-
`lated, as evidenced by counts returning to within 75%
`of baseline in the low-dose group and within 50% of
`baseline in the high-dose group by the end-of-study
`evaluation.
`This study is instructive insofar as it provides nor-
`mative data on FTY720 disposition and lymphocyte re-
`sponses in healthy subjects not receiving concomitant
`immunosuppressives in contrast to studies in organ
`transplant patients. It demonstrates the generally good
`acute tolerability of FTY720 at clinically relevant daily
`dose regimens and the fact that short-term multiple-
`dose studies can be safely performed in healthy sub-
`jects. Descriptive exposure-response modeling pre-
`dicts that near-maximal lymphocyte responses are
`likely achieved at the doses currently used in clinical
`trials; however, this theory needs to be tested in studies
`employing regimens greater than 5 mg/day. This study
`also supports the use of daily dose regimens in clinical
`
`trials inasmuch as the return of lymphocytes to the
`blood occurs within days of stopping treatment.
`
`REFERENCES
`
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`ceptors for sphingosine 1-phosphate in transplantation and
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