0041-1337/03/7607-1079/0
`TRANSPLANTATION
`Copyright © 2003 by Lippincott Williams & Wilkins, Inc.
`
`Vol. 76, 1079–1084, No. 7, October 15, 2003
`Printed in U.S.A.
`
`PHARMACODYNAMICS, PHARMACOKINETICS, AND SAFETY
`OF MULTIPLE DOSES OF FTY720 IN STABLE RENAL
`TRANSPLANT PATIENTS: A MULTICENTER, RANDOMIZED,
`PLACEBO-CONTROLLED, PHASE I STUDY
`
`BARRY D. KAHAN,1,8 JANET L. KARLIX,2 RONALD M. FERGUSON,3 ALAN B. LEICHTMAN,4
`SHAMKANT MULGAONKAR,5 THOMAS A. GONWA,6 ANDREJ SKERJANEC,7 ROBERT L. SCHMOUDER,7 AND
`LAWRENCE CHODOFF7
`
`blood lymphocytes without an enhanced incidence of
`collateral toxicities, except possibly bradycardia.
`
`Background. FTY720, a novel immunomodulator,
`displays potent immunosuppressive activity in a vari-
`ety of preclinical transplant models. This study exam-
`ined the safety, pharmacodynamics, and pharmacoki-
`netics of multiple doses of FTY720 in stable renal
`transplant patients.
`Methods. This randomized, multicenter, double-
`blind, placebo-controlled, phase I study included
`adults who had been maintained on a regimen of cy-
`closporine A (CsA) microemulsion and prednisone (or
`its equivalent) for at least 1 year after renal transplan-
`tation. Patients received once-daily doses of 0.125,
`0.25, 0.5, 1.0, 2.5, or 5.0 mg FTY720, or placebo for 28
`days. After completion of study drug administration,
`the patients were monitored until day 56 by serial
`laboratory tests, clinical examinations, and recording
`of adverse events. The study includes 76 treatment
`courses (61 FTY720 and 15 placebo), with 65 patients
`enrolled once and 11 reenrolled.
`Results. FTY720 doses greater than or equal to 1.0
`mg/day produced a significant reduction in peripheral
`blood lymphocyte count by up to 85%, which reversed
`within 3 days after discontinuation of study medica-
`tion. Compared with placebo-treated patients, FTY720
`subjects did not show a major increase in adverse
`events or a change in renal function. Pharmacokinetic
`measurements revealed that FTY720 displayed linear
`relations of doses and concentrations over a wide
`range, but had no effect on CsA exposure.
`Conclusions. At doses up to 5.0 mg/day for 28 days,
`stable renal transplant patients treated with FTY720
`in combination with CsA and prednisone displayed a
`dose-dependent, reversible decline in peripheral
`
`1 Department of Surgery, University of Texas Health Science
`Center at Houston, Houston, TX.
`2 Department of Pharmacy Practice, University of Florida,
`Gainesville, FL.
`3 Division of Transplantation, The Ohio State University Medical
`Center, Columbus, OH.
`4 Nephrology Division, University of Michigan Medical Center,
`Ann Arbor, MI.
`5 Division of Transplantation, St. Barnabas Medical Center,
`Livingston, NJ.
`6 Department of Transplantation, Mayo Clinic, Jacksonville, FL.
`7 Novartis Pharmaceuticals Corporation, Clinical Pharmacology
`and Biostatistics, East Hanover, NJ.
`8 Address correspondence to: Barry D. Kahan, Ph.D., M.D., Division
`of Immunology and Organ Transplantation, Department of Surgery,
`University of Texas Medical School, 6431 Fannin, Suite 6.240, Houston,
`TX 77030. E-mail: barry.d.kahan@uth.tmc.edu.
`Received 13 September 2002. Revision requested 9 October 2002.
`Accepted 23 May 2003.
`DOI: 10.1097/01.TP.0000084822.01372.AC
`
`FTY720 is a synthetic analogue of the natural compound
`myriocin, which is derived from the ascomycete Isaria sin-
`clairii (1, 2). This agent is unique from other immunosup-
`pressants, because it does not impair T- or B-lymphocyte
`activation, cytokine synthesis, growth factor-driven prolifer-
`ation, effector function, or memory cell generation by human
`cells in vitro (3) or in rodent models of alloimmunity (4) or
`viral
`infection (5). At clinically relevant concentrations,
`FTY720 appears to reduce the circulating peripheral blood
`lymphocyte pool not because of apoptosis (6–9), but rather by
`preferentially increasing cellular chemotaxis responses to
`homing more than inflammatory chemokines. This action
`accelerates lymphocyte migration to secondary lymphoid
`structures (3, 4, 10–12), which constitutively express high
`levels of homing chemokines (13). The sequestration pre-
`vents circulating lymphocytes from migrating to, becoming
`activated in, and subsequently destroying allografts (14).
`The molecular mechanism of drug action has not yet been
`entirely clarified. After phosphorylation by sphingosine ki-
`nase, FTY720-phosphate binds to a subgroup of sphingosine-
`1-phosphate (S1P) G-protein receptors (formerly called EDG
`receptors)—S1P1 (EDG1), S1P4 (EDG6), and S1P5 (EDG8)—
`triggering a cascade that enhances actin polymerization and
`augments cell motility (15, 16). Because FTY720 displays
`synergistic immunosuppressive effects with cyclosporine A
`(CsA) (17–21), everolimus (18), tacrolimus (22), and sirolimus
`(21) in several animal transplant models, its unique mecha-
`nisms of action seem to complement those of other agents.
`Administration of single oral doses of FTY720, ranging
`from 0.25 to 3.5 mg, to stable renal transplant patients main-
`tained on a regimen of CsA and prednisone caused a dose-
`dependent, although transient, reduction in peripheral blood
`CD4⫹ and CD8⫹ T and B cells (23). At doses greater than 1.0
`mg, the mean nadir counts were 30% to 60% below the
`baseline values. FTY720 was well tolerated except for the
`occurrence of bradycardic episodes, which were not associ-
`ated with clinical symptoms or hypotension, and which re-
`solved spontaneously without medical intervention. Pharma-
`cokinetic analysis of whole blood concentrations after
`administration of a single dose revealed that FTY720 dis-
`plays an extensive volume of distribution (1,116–1,737 L)
`and a moderate clearance rate (130–200 mL/min), resulting
`in a long terminal half-life (t1/2), ranging from 89 to 157 hr. In
`addition, co-administration of single FTY720 doses did not
`affect blood concentrations of CsA.
`1079
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`1080
`
`TRANSPLANTATION
`
`Vol. 76, No. 7
`
`The present trial extended the single-exposure study by
`using multiple doses of FTY720 administered to stable renal
`transplant patients under treatment with CsA microemul-
`sion and prednisone, seeking to evaluate the safety of the
`agent and its pharmacokinetics and pharmacodynamics, be-
`fore the inception of trials to assess its therapeutic efficacy.
`
`PATIENTS AND METHODS
`
`Study Design
`This multiple-dose study used a randomized, multicenter, double-
`blind, placebo-controlled design of time-lagged, ascending-dose, se-
`quential-group entry. Each local committee for the protection of
`human subjects approved the trial, and patients signed informed
`consent documents before their participation.
`
`Patient Population
`Male and female renal transplant patients aged 18 to 65 years
`were enrolled if they were in stable clinical condition for at least 12
`months after a first or second cadaveric or living-donor renal trans-
`plant. The study enrolled 65 patients for a first course: 11 were
`reenrolled for a second course to obtain 76 treatment courses (61
`with FTY720 and 15 with placebo). All subjects had been receiving a
`constant dose of CsA microemulsion (Neoral; Novartis, Basel, Swit-
`zerland) and prednisone for at least 3 months before enrollment.
`Administration of azathioprine, mycophenolate mofetil, or cyclophos-
`phamide was mandated to be discontinued at least 14 days before the
`first dose of study medication. Indeed, the majority of patients were
`treated at centers that do not routinely use purine synthesis antag-
`onists for maintenance therapy. Furthermore, eligible patients were
`required to display acceptable laboratory values, vital signs, weight,
`and physical condition at screening and baseline, including a serum
`creatinine less than or equal to 3.0 mg/dL, an absolute (total) lym-
`phocyte count greater than or equal to 1,200 cells/mm3, and a pulse
`rate of 60 to 90 beats/min. Patients of childbearing potential were
`required to practice an approved method of birth control during the
`study and for 3 months after the last dose of study medication.
`Exclusion criteria included graft rejection within 6 months of
`randomization; administration of other investigational medications,
`of trimethoprim-sulfamethoxazole, of ganciclovir, or of lymphocyto-
`lytic therapy to treat an acute rejection episode within 1 year of
`randomization; multiple organ transplants; clinically significant
`anemia; a history of significant coexistent liver disease, systemic
`infection, malignancy, immunocompromise, or active hepatitis; se-
`vere autonomic dysfunction; acute or chronic bronchospastic disease;
`heart disease or electrocardiographic abnormalities; any condition
`that significantly alters absorption, distribution, metabolism, or ex-
`cretion of any pharmaceutic; illicit drug or alcohol abuse or tobacco
`product use within 12 months; or positivity for hepatitis B surface
`antigen. Because of the potential for FTY720-induced bradycardia,
`the protocol excluded the use of ␤-adrenergic blockers and diltiazem
`or verapamil, but not the dihydropyridine class of calcium channel
`blockers. Clonidine was prescribed for 12 of 61 (20%) patients in the
`FTY720 group and for 4 of 15 (27%) in the placebo arm.
`Discontinuation of study medication was mandated in the event of
`an adverse reaction, protocol violation, withdrawal of consent, loss to
`follow-up, abnormalities in laboratory values or test procedure re-
`sults, or administrative reason. Discontinuation was mandated
`when the therapeutic effect seemed to be excessive: if three consec-
`utive measurements showed nadir (predose) total peripheral blood
`counts of less than 200 lymphocytes/mm3 or less than 75 CD4⫹
`cells/mm3.
`
`Medication Administration
`Patients were randomized in time-lagged groups on the basis of
`the oral dose of FTY720 (0.125, 0.25, 0.5, 1.0, 2.5, or 5.0 mg) or
`placebo. Study drug was ingested on days 1 through 28 in the
`
`morning simultaneously with CsA and at least 30 to 60 min before
`meals. Patients were only enrolled into the next higher dose of
`FTY720 after at least eight patients had received at least 21 days of
`therapy with a benign course in the opinion of the investigators, the
`Data Safety Monitoring Board, the U.S. Food and Drug Administra-
`tion, and the sponsor. Eligible patients were allowed to reenroll into
`a higher dose cohort after a washout period of at least 3 months.
`Throughout the study, CsA doses were selected to maintain whole
`blood morning 12-hr trough levels (Cminss) between 100 and 200
`ng/mL; the dose of prednisone was stipulated to be less than or equal
`to 15 mg/day. No reduction in CsA or prednisone doses was allowed;
`in the event of a clinically relevant biologic abnormality, the study
`medication was discontinued.
`
`Assays
`Blood concentrations of FTY720 were determined in a central
`laboratory (Novartis Drug Metabolism and Pharmacokinetics; Basel,
`Switzerland) using high-performance liquid chromatography cou-
`pled to mass spectrometry (Finnigan; Thermo Electron, Waltham,
`MA) with a quantification limit of 0.044 ng/mL. The method was
`validated by analysis of quality control spiked samples concurrently
`with the study samples. The mean accuracy and precision for nom-
`inal concentrations ranging from 0.057 to 10 ng/mL was 101.2% and
`8.6%, respectively. Whole blood concentrations of CsA were mea-
`sured at each center’s local laboratory by a fluorescence polarization
`immunoassay using a parent compound-specific monoclonal anti-
`body with a detection limit of 25 ng/mL (TDX; Abbott Laboratories,
`North Chicago, IL).
`
`Procedures
`The study schedule included four phases: screening (days ⫺60 to
`⫺1), baseline (day 0; before administration of study drug), treatment
`(days 1–28), and follow-up (days 29–56). In addition to screening and
`baseline visits, patients were examined on days 2, 3, and 4 and every
`3 to 4 days thereafter through day 28 (the last day of study drug
`administration). Daily follow-up examinations were performed from
`day 29 to day 35 and every 3 to 4 days from day 38 to day 56. When
`the absolute lymphocyte count had not recovered to within 90% of
`the baseline value by day 56, the counts were monitored every 2
`weeks thereafter for up to 3 months.
`Laboratory evaluations included biochemistry, urinalysis, hema-
`tology, and flow cytometry enumeration of lymphocyte subsets bear-
`ing the surface markers CD3, CD4, CD8, CD14, CD16, CD20,
`CD45RO, and CD45RA. The baseline value was defined as the av-
`erage of at least four and up to six measurements of the total
`lymphocyte count on day 0, namely, at 1, 2, 4, 6, and 12 hr on the day
`before administration of study medication. In addition, electrocar-
`diogram, home pulse-blood pressure monitoring, pulmonary function
`tests, exercise oximetry, and ophthalmologic examinations were per-
`formed before and serially after drug administration.
`FTY720 and CsA trough concentrations were monitored at all
`visits throughout the treatment and the follow-up courses. CsA phar-
`macokinetics were profiled by multiple samples drawn over a 12-hr
`interval on day 0 and on day 28. In addition to FTY720 pharmaco-
`kinetic profiles, including multiple blood samples on day 1 and day
`28, trough FTY720 concentrations were measured on days 2, 3, 4, 7,
`10, 14, 17, 21, and 24 and at each visit during the next 4 weeks after
`the day-28 dose.
`
`Analyses
`All randomized patients who received at least one dose of study
`medication and had at least one evaluation were included in the
`safety analyses. Patients who reentered the trial were treated as new
`subjects. Results were summarized by treatment group and by visit.
`An adverse event was defined as any undesirable medical event
`reported spontaneously by the patient or discovered by the investi-
`gator, regardless of whether it was attributed to the treatment.
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`October 15, 2003
`
`KAHAN ET AL.
`
`1081
`
`Adverse events were monitored throughout the study; coded using
`the Sandoz Medical Terminology Thesaurus; and rated as mild,
`moderate, or severe. A serious adverse event was any event that was
`fatal; life-threatening; required or prolonged inpatient hospitaliza-
`tion; caused permanent disability; or was associated with cancer,
`congenital anomaly, overdose, graft loss, or an acute rejection epi-
`sode. Severe adverse events were defined as symptoms that caused
`discomfort of such a severity that the patient ceased study medica-
`tion treatment or required additional agents or hospitalization to
`control it.
`Noncompartmental methods implemented in the WinNonlin
`ProVersion 3.1 computer program (Pharsight Corporation. Mountain
`View, CA) were used to estimate pharmacokinetic parameters,
`namely, the maximal concentration (Cmax), the corresponding time to
`maximal concentration (tmax), the area under the concentration-time
`curve (AUC0 –24h calculated by the linear trapezoidal method), the
`oral clearance (CL) (calculated as the quotient of the AUC0 –24h and
`the dose on day 28), the elimination phase t1/2, and the accumulation
`index (AUCday28/AUCday1). Dose proportionality was evaluated by
`the power model approach (24). The effect of FTY720 co-administra-
`tion on CsA pharmacokinetics was evaluated using linear mixed-
`effect models (AUC0 –12h and Cmax) and the Wilcoxon signed rank test
`(tmax).
`
`RESULTS
`Demographics
`The demographic features, including doses of concomitant
`immunosuppressive medications, were similar between
`study groups (Table 1) and consistent with those of a renal
`transplant population. The most common concomitant med-
`ical conditions in the FTY720 versus placebo patients were
`hypertension (92% vs. 87%) and urinary system disorders
`(82% vs. 87%).
`
`Pharmacodynamics
`During day 1, all patients showed a decrease in the abso-
`lute lymphocyte count from the baseline value. During the
`first 24 hr, subjects treated with 0.125 or 0.25 mg FTY720
`showed changes similar to patients treated with placebo.
`Although recipients administered 0.5 mg or 1.0 mg FTY720
`showed more profound changes, they displayed recovery to
`the baseline value at 20 hr. However, members of the 2.5-
`and 5.0-mg FTY720 groups showed reductions in peripheral
`
`TABLE 1. Demographics and immunosuppressive therapy of
`enrolled patientsa
`
`Feature
`
`FTY720
`(n⫽61) (%)
`
`Placebo
`(n⫽15) (%)
`
`blood lymphocyte counts by 60% of baseline that persisted to
`the end of the day (data not shown).
`Figure 1 reveals that throughout the 28-day treatment
`period, the morning absolute lymphocyte counts showed a
`dose-dependent decrease from baseline in all treatment
`groups compared with the increase in the placebo group.
`Lymphocyte counts were reduced by up to 85% in the 5.0-mg/
`day group, with sustained mean lymphocyte counts of 300 to
`400 cells/mm3. All dose groups showed a trend toward recov-
`ery within 3 days after study medication discontinuation. By
`day 56,
`lymphocyte counts were above baseline in the
`0.125-mg group, within 10% of baseline in the 0.25- and
`0.5-mg groups, and trending toward the baseline value in the
`remaining treatment groups. The patterns of both the dose-
`dependent decreases from baseline and the recoveries were
`similar for lymphocyte subsets bearing CD3, CD4, CD8,
`CD16, CD20, CD45RA, and CD45RO surface markers. No
`effects were observed on the number of peripheral blood
`granulocytes, monocytes,
`eosinophils,
`erythrocytes,
`or
`platelets.
`
`Other Laboratory and Clinical Evaluations
`The mean serum creatinine and blood urea nitrogen values
`remained stable and similar over time in all treatment
`groups. A greater proportion of placebo- than FTY720-
`treated patients displayed increases in total cholesterol to
`values greater than 275 mg/dL, namely, 23% versus 5%,
`respectively (P⫽not significant [NS]). In contrast, although
`the mean values were not different, the incidence of hypo-
`magnesemia was reported to be numerically, although not
`significantly, higher among the FTY720 versus the placebo
`group. The lack of consistent effects of FTY720 on either the
`serum magnesium or serum creatinine suggested that the
`agent did not potentiate CsA-induced renal dysfunction (Ta-
`ble 2). Three patients (one each in the 0.5-mg FTY720,
`5.0-mg FTY720, and placebo groups) experienced mild sinus
`bradycardia without other notable changes in electrocardio-
`graphic or vital signs. In all treatment groups, the mean
`heart rate and the oxygen saturation during cardiopulmo-
`
`47.4⫾11.2 42.5⫾11.8
`20–63
`27–63
`35 (57.4)
`9 (60.0)
`
`FIGURE 1. Impact of dose on the kinetics of percent change
`from baseline of the absolute lymphocyte count by study
`day during FTY720 treatment (28 days) and posttreatment
`(open squares) Placebo;
`(filled
`(days 29 –56) periods.
`squares) 0.125 mg; (filled circles) 0.25 mg; (open triangles)
`0.5 mg; (open diamonds) 1.0 mg; (asterisks) 2.5 mg; (filled
`triangles) 5.0 mg.
`
`Age (yr)
`Mean⫾SD
`Range
`Male gender
`Ethnicity
`White
`African American
`Asian
`Other (primarily Hispanic)
`Diabetes mellitus
`Weight (kg)
`80.7⫾13.5 74.4⫾15.8
`Mean⫾SD
`55.5–126.4 47.9–106.7
`Range
`Cyclosporine A dose, mean⫾SD (mg/day) 243.8⫾91.3 213.3⫾105.1
`Corticosteroid dose, mean⫾SD (mg/day)
`9.6⫾13.4
`7.7⫾2.9
`a None of the differences was significant.
`
`34 (55.7)
`6 (9.8)
`0
`21 (34.4)
`24 (39)
`
`5 (33.3)
`4 (26.7)
`1 (6.7)
`5 (33.3)
`5 (33.3)
`
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`1082
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`TRANSPLANTATION
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`Vol. 76, No. 7
`
`Dose
`(mg)
`
`TABLE 2. Mean values of FTY720 pharmacokinetic parameters on day 28a
`Mean values (%CV)
`
`Mean values (SD)
`
`Mg2⫹
`
`SCr
`
`1.93 (0.2)
`1.94 (0.3)
`1.81 (0.3)
`1.93 (0.2)
`1.95 (0.2)
`1.94 (0.3)
`1.96 (0.3)
`
`1.13 (0.5)
`1.45 (0.5)
`1.51 (0.4)
`1.33 (0.5)
`1.33 (0.4)
`1.39 (0.3)
`1.53 (0.5)
`
`No.
`
`9
`9
`10
`9
`9
`5
`
`c
`b
`t1/2
`CL
`AUC0–24h
`tmax
`Cmax
`(hr)
`(L/hr)
`(ng/hr/mL)
`(hr)
`(ng/mL)
`168 (136–281)
`7.7 (20)
`16.9 (21)
`11.9 (0.6–22.2)
`0.74 (79)
`0.125
`184 (141–252)
`23.7 (190)
`28.2 (52)
`18.8 (11.4–24.5)
`1.4 (42)
`0.25
`205 (145–528)
`7.4 (28)
`72.7 (29)
`21.3 (0.3–24.2)
`3.1 (39)
`0.5
`199 (133–399)
`9.5 (47)
`129.5 (48)
`11.9 (1.3–22.7)
`5.7 (50)
`1.0
`220 (134–526)
`13.4 (65)
`236.8 (45)
`11.8 (10.0–24.0)
`11.2 (49)
`2.5
`212 (157–338)
`9.4 (33)
`575.9 (31)
`11.5 (11.3–12.1)
`24.9 (54)
`5.0
`NA
`NA
`NA
`NA
`NA
`Placebo
`%CV, Percent coefficient of variation; CL, clearance; NA, not applicable; SCr, serum creatinine.
`a t1/2 was assessed during the terminal elimination phase (days 28–56).
`b Median value (range).
`c Harmonic mean (range).
`
`nary exercise tests increased over time. No clinically signif-
`icant treatment-related changes were noted in any group for
`one-second forced expiratory volume, forced vital capacity, or
`diffusion capacity for carbon monoxide.
`
`Pharmacokinetics
`FTY720 pharmacokinetic profiles were obtained from 51
`patients (Table 2). The AUC0 –24h and Cmax showed approxi-
`mately linear relations to FTY720 dose over a wide range
`(Fig. 2), with 21% to 52% interindividual coefficients of vari-
`ation of the AUC0 –24h (Table 2). The values of tmax, CL, and
`t1/2 appeared to be dose independent. Across all dose groups,
`the mean t1/2 was estimated to be approximately 200 hr.
`During 28 days of daily dosing, the long t1/2 led to an approx-
`imately 10-fold drug accumulation on the basis of comparison
`of day-28 versus day-1 AUC values. There was no evidence of
`a drug-drug interaction between FTY720 and CsA (Fig. 3).
`Neither the rate (measured by Cmax or tmax) nor the extent of
`CsA absorption (measured by AUC0 –12h) was affected by
`co-administration of various doses of FTY720 as documented
`by comparing pharmacokinetic profiles obtained on day 0 and
`day 28.
`
`Adverse Events
`Although more adverse events were reported among mem-
`bers of the FTY720 group than the placebo arm (88.5% vs.
`73.3%, respectively), the difference was not significant. Table
`3 shows the events reported in more than 10% of patients in
`each group. Both serious (9.8% vs. 20.0%, respectively;
`
`TABLE 3. Adverse events occurring among more than 10%
`of patients
`
`Adverse event
`
`Any adverse event
`Any serious adverse event
`Any severe adverse event
`Lymphocytopenia
`Coughing
`Rhinitis
`Urinary tract infection
`Headache
`Gastroenteritis
`Increased blood urea nitrogen
`
`FTY720
`(n⫽61)
`(%)
`54 (88.5)
`6 (9.8)
`4 (6.6)
`18 (29.5)
`9 (14.8)
`9 (14.8)
`7 (11.5)
`6 (9.8)
`1 (1.6)
`1 (1.6)
`
`Placebo
`(n⫽15)
`(%)
`11 (73.3)
`3 (20.0)
`3 (20.0)
`1 (6.7)
`1 (6.7)
`1 (6.7)
`1 (6.7)
`4 (26.7)
`2 (13.3)
`2 (13.3)
`
`P⫽NS) and severe (6.6% vs. 20.0%, respectively; P⫽NS)
`events were experienced by a greater frequency of placebo-
`than FTY720-treated patients. Events attributed to the
`study drug were mostly mild or moderate in severity and
`tended to be more common among FTY720-treated patients.
`Only two patients treated with FTY720 experienced events
`that the investigators considered to be drug-related (i.e.,
`fatigue-dyspnea and transiently elevated liver function tests).
`
`FIGURE 2. The relationship between FTY720 dose vs. AUC0 –
`24h (a) and Cmax (b) on the last day (day 28) of drug adminis-
`tration. (vertical lines) Standard deviations (SD).
`
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`

`October 15, 2003
`
`KAHAN ET AL.
`
`1083
`
`megalovirus antibody at screening converted to positive at
`day 29.
`Approximately one third of all patients experienced infec-
`tions; the incidences and patterns (bacterial vs. viral vs.
`fungal) were similar across all groups. Most infections (i.e.,
`mild urinary or respiratory tract infections) were not serious
`(Table 4). Among these patients, two experienced severe in-
`fections: transplant pyelonephritis caused by multiple bacte-
`rial species on day 32 in a patient receiving 0.125 mg
`FTY720, and gastroenteritis on day 4 in a placebo-treated
`patient.
`
`DISCUSSION
`Multiple oral doses of FTY720 ranging from 0.125 to 5.0 mg
`produced a dose-dependent decrease in peripheral blood lym-
`phocyte count during and delay in recovery over 3 days after
`discontinuation of FTY720 therapy despite its long t1/2. At
`daily doses of 1.0 mg or higher, FTY720 produced approxi-
`mately an 85% reduction in peripheral blood lymphocytes.
`All subsets of lymphocytes, but neither monocytes nor gran-
`ulocytes, were affected by the drug.
`FTY720 appeared to be well tolerated for up to 28 days in
`stable renal transplant patients maintained on CsA and
`prednisone. Comprehensive evaluations revealed no evidence
`of incremental safety risks compared with placebo-treated
`patients. All patients underwent the stipulated follow-up;
`however, 11 subjects discontinued study medication before
`completing the 28-day course primarily because of lymphope-
`nia on the basis of an arbitrary definition of excessive phar-
`macodynamic effect. Severe and serious adverse events were
`reported two to three times more frequently in placebo- than
`in FTY720-treated patients.
`The immunosuppressive effects of FTY720 were not asso-
`ciated with enhanced paralysis of nonspecific host responses.
`The incidence of infections was similar among patients in the
`treatment and placebo groups, consistent with a lack of al-
`teration in primary or memory responses to bacterial and
`viral infectious challenges, an observation that confirms pre-
`
`FIGURE 3. Mean (SD) of CsA blood concentrations vs. time
`before (a) and after (b) a 28-day course of FTY720 dosing.
`(open squares) Placebo; (filled squares) 0.125 mg; (filled cir-
`cles) 0.25 mg; (open triangles) 0.5 mg; (open diamonds) 1.0 mg;
`(asterisks) 2.5 mg; (filled triangles) 5.0 mg.
`
`Although bradycardia, which was defined as a decrease in
`pulse rate by 4 to 11 beats/min, had been reported as a
`frequent event among patients treated with FTY720 in a
`previous single-dose study (23), only 2 of 61 (3.27%) FTY720
`patients and 1 of 15 (6.6%) placebo patients displayed this
`complication. One FTY720-treated patient experienced bra-
`dycardia on day 1 with recurrences on days 2 and 8. The
`second FTY720 patient displayed bradycardia on day 8. The
`placebo patient developed bradycardia on day 29.
`Among the 11 patients (18% of the FTY720 group) who
`discontinued study medication prematurely, 9 met the pro-
`tocol-defined criterion of a severe reduction in lymphocyte
`count. One of the other two subjects was discontinued be-
`cause of an adverse event (dyspnea) and another because of
`elevated liver function tests on day 4, although the latter
`patient resumed therapy on day 13 and completed the 28-day
`course without recurrence or sequelae.
`No deaths, episodes of rejection, or emergence of malig-
`nancy occurred in either group during the treatment and the
`follow-up phases. No patients who tested negative for cyto-
`
`TABLE 4. Enumeration of serious adverse events in all groups
`Day
`reported
`
`Serious adverse event
`
`Dose
`
`Suspected relation to
`study medication
`
`Pneumonia
`Urinary tract infection
`Fatigue
`Dyspnea
`Anxiety
`Palpitation
`Fever
`Nausea
`Vomiting
`Diarrhea
`Herpes zoster
`␥-Glutamyl transferase increased
`NPN increased
`Hepatic enzymes increased
`
`Cerebrovascular disorder
`Tachycardia supraventricular
`Gastroenteritis
`
`21
`32
`2
`2
`2
`2
`32
`32
`32
`32
`7
`–1
`3
`3
`
`24
`37
`4
`
`No
`No
`Yes
`Yes
`Yes
`Yes
`No
`No
`No
`No
`No
`Yes
`Yes
`Yes
`
`No
`No
`No
`
`Age/gender
`
`FTY720
`58/Male
`50/Female
`54/Female
`
`0.125 mg
`0.125 mg
`0.125 mg
`
`21/Female
`
`0.25 mg
`
`50/Female
`51/Female
`
`5.0 mg
`5.0 mg
`
`Placebo
`NA
`47/Female
`NA
`63/Male
`NA
`30/Male
`NPN, non-protein nitrogen.
`
`SUN - IPR2017-01929, Ex. 1031, p. 5 of 6
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`

`

`1084
`
`TRANSPLANTATION
`
`Vol. 76, No. 7
`
`clinical studies (3, 5). Furthermore, in striking contrast to
`certain other agents that display nonspecific myelosuppres-
`sive effects (azathioprine, mycophenolate mofetil, sirolimus),
`FTY720 produced a sustained, reversible reduction limited to
`the lymphocyte count, with no evidence of an effect on other
`peripheral blood elements.
`In contrast to the single-dose phase I study (23), bradycar-
`dia occurred infrequently in the present study. The low inci-
`dence may have been because of the exclusion of patients
`with baseline resting pulse rates of less than 60 beats/min or
`those who were under treatment with ␤-adrenergic antago-
`nists or the calcium channel blockers diltiazem or verapamil.
`There was no association between bradycardia and clonidine
`administration in the 12 FTY720 and 4 placebo patients who
`were receiving this antihypertensive agent before study
`inception.
`The apparent toxicities of hypertrophy, hyperplasia, and
`constriction of bronchial smooth muscle and increased lung
`weight previously observed in some animal species treated
`with high doses of FTY720 were not observed in the previous
`single-dose (23) or the present multiple-dose study. In con-
`trast to the calcineurin inhibitors, no case of neurotoxicity or
`hyperglycemia was reported with FTY720. In contrast to
`calcineurin inhibitors, FTY720 does not appear to be neph-
`rotoxic by itself or to augment the renal dysfunction produced
`by CsA.
`favorable characteristics for
`FTY720 exhibited several
`transplant pharmacotherapy, namely, linear dose-propor-
`tional exposure over a wide range of doses with only moder-
`ate interpatient variability and a long t1/2 of approximately
`200 hr. Furthermore, metabolism of FTY720 by cytochrome
`P-450 4F is distinct from the cytochrome P-450 3A4 mixed
`oxidase system used by CsA, tacrolimus, and sirolimus. The
`use of a loading dose is currently under evaluation, because
`administration of a constant maintenance dose imposes a
`4-day delay to reach the nadir lymphocyte count which, when
`established, is sustained with little fluctuation using once-
`daily dosing. Because rapid establishment of the immuno-
`suppressive effect is critical during the induction phase, a
`loading dose may provide a more effective regimen de novo,
`particularly because postoperative gastrointestinal ileus may
`impair drug absorption.
`The present study demonstrates that doses of up to 5.0 mg
`daily of FTY720 administered for 28 days in combination
`with CsA and prednisone provide a sustained reduction in
`peripheral blood lymphocyte counts in stable renal trans-
`plant patients without the collateral toxicities associated
`with other immunosuppressive agents. The duration, inten-
`sity, and delay in recovery of the significant decrease in
`peripheral blood lymphocyte counts display FTY720 dose
`dependence. These findings support the inception of studies
`in humans to document the efficacy of FTY720 to augment
`the immunosuppressive actions of other agents for prophy-
`laxis of acute rejection episodes.
`
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