Abstracts
`
`KIDNEY: PHARMACOGENETICS, KINETICS AND NEW DRUG
`
`to calculate the effect when FTY720 dose or concentrations were equal to zero. The PD
`effect was calculated as a % reduction compared to the lymphocyte count before the
`administration of the first dose of FTY720 or MMF. FTY720 blood concentrations were
`measured by HPLC/MS/MS method. PK/PD modeling was utilized to find the best-fit
`model of the correlation between % reduction in peripheral lymphocyte count and
`increasing doses or blood concentrations of the FTY720. RESULTS: Mean age was 40
`years, 61% white, 61% males and mean BMI was 22.8±2.6 kg/m². FTY720 dose
`associated with best efficacy in preventing acute rejection was 2.5 mg/day. Mean FTY720
`concentrations were 0.36±0.05 (0.25 mg), 0.73±0.12 (0.5 mg), 3.26±0.51 (1 mg), and
`7.15±1.41 ng/mL (2.5 mg). Between weeks 4 to 12, best-fit PK/PD modeling for dose-
`effect or concentration-effect relationship was the simple Emax model [E = (Emax * C) / (C
`+ EC50), where E is the effect at a given concentration C, Emax is the maximum effect
`attributed to the drug, and EC50 is the drug concentration which produces 50% of
`maximum effect]. For dose-effect relationship, Emáx=87,8±5,3% and ED50=0,48±0,08 mg
`(r²=0,94). For concentration-effect relationship Emáx=78,3±2,9% and EC50=0,592±0,091
`ng/mL (r²=0,89). CONCLUSION: According to the PK/PD model, EC50 was achieved
`at FTY720 doses of 0.5 mg and blood concentrations of 0.6 ng/mL. Since FTY720 PK
`are dose-linear and effective doses of FTY720 are 2.5 and 5 mg/day, the
`immunosuppressive effect of FTY720 may depend upon induction of high degree of
`lymphopenia (~80%) and/or be associated with other FTY720 effects out of the blood
`compartment, perhaps in secondary lymphoid tissues where lymphocyte home.
`
`Abstract# 708
`PHARMACOKINETICS OF MYCOPHENOLATE MOFETIL IN
`RENAL TRANSPLANT IMMUNOSUPPRESSION: RISKS OF
`USING A FIXED DOSE REGIMEN. Kazuharu Uchida,1 Yoshihiro
`Tominaga,1 Toshito Haba,1 Akio Katayama,1 Susumu Matsuoka,1
`Norihiko Goto,1 Tsuneo Ueki,1 Tetsuhiko Sato,1 Asami Takeda,1 Kunio
`Morozumi,1 Takaaki Kobayashi,2 Hirosi Takagi,3 Akimasa Nakao.2 1Dept.
`of Transplant Surgery, Nagoya Daini Red Cross Hospital, Nagoya,
`Aichi, Japan; 2Dept. of Surgery II, Nagoya University, Nagoya, Aichi,
`Japan; 3Surgery, JR Tokai General Hospital, Nagoya, Aichi, Japan.
`Pivotal pharmacokinetic studies that evaluated Mycophenolate Mofetil (MMF) in renal
`transplantation have demonstrated low intrapatient and interpatient variability
`resulting in the adoption of fixed dose recommendations for MMF therapy. We
`investigated comparative pharmacokinetics, including intrapatient and interpatient
`variability over time up to the 6th postoperative week; to evaluate the MMF fixed dose
`regimen in renal transplantation . Study population and Methods: The study included
`45 de novo renal transplant recipients treated with prednisolone, MMF and CNI’s,
`(CsA = 24, FK= 21). Drug exposure in the first four hours post-dose (AUC) of CNI’s
`and mycophenolic acid (MPA) were measured once or twice a week from the 4th
`postoperative day to the 6th postoperative week. MMF dosing was initiated with a
`fixed dose at 3g/day (BID) from the 2nd postoperative day, with a dose change to 2 g/
`day from the 15th or 29th postoperative day. Results&Conclusion: The study data
`demonstrate that interpatient variability in MPA pharmacokinetics is high (CV; 50-
`80%), although intrapatient variation is lower (CV; 25-45%). The MPA C0 level
`increased gradually, reaching a steady state at the 2nd-3rd postoperative week (2-3
`fold from baseline), and lowered after changing the dose to 2 g. The MPA AUC in the
`same patients remained steady without declining even after decreasing the dose from 3
`g/day to 2 g/day. Our evaluation of MPA pharmacokinetics demonstrates that MPA
`interpatient variability is high, and that the trough level elevates gradually over time
`without MMF dose changes. The MPA AUC changes are not dose-dependant. These
`results indicate a potential risk for variable MPA exposure with a MMF fixed dose
`regimen, and suggest TDM of MPA for individualization of MMF doses.
`1. MPA mean values plus inter-patient variation for C0 (mcg/mL) and AUC0-4h (mcg·h/mL)
`Day(MMF dose)
`#4d (3g)
`#14d (3g)
`#35 (2g)
`#42d (2g)
`Mean C0 (%CV)
`1.3±0.7(75.8)
`0.8±2.1(76.7)
`3.7±3.0(82.5)
`3.7±2.3(61.0)
`Mwan AUC(%CV)
`39.1±21.7(55.5)
`37.7±18.6(49.3)
`44.5±22.5(50.6)
`45.5±21.1(46.4)
`2. Intrapatient variability during the administration period for 3 g/day and
`2 g/day fixed doses per patient
`3g-period
`2.6±1.6(45.8)
`41.9±12.0(26.9)
`
`2g-period
`3.1±1.5(39.8)
`40.2±10.1(25.1)
`
`Mean C0 (%CV)
`Mean AUC(%CV)
`
`and 11 (range, 114 - 1432 umol/L) did not influence exposure. Indicators of hepatic
`function including bilirubin (1 - 39 umol/L), AST (7 - 283 U/L), ALT (3 - 373 U/L), and
`albumin (25 - 46 g/L) did not impact on exposure. CL/F was not different in diabetics
`(n = 31) compared with nondiabetics. CL/F was also not influenced by comedication
`with the beta-blockers atenolol (n = 29), labetolol (n = 16), metoprolol (n = 41),
`propranolol (n = 14). Conclusions: (1) Dose adjustment of FTY on the basis of weight
`(mg/kg) does not appear necessary; (2) FTY blood concentrations remained stable
`despite changes in renal function posttransplant; (3) Concomitant use of beta-blockers
`did not alter the pharmacokinetics of FTY; (4) No special patient populations were
`identified in this analysis for which FTY dose regimens need to be modified.
`
`Abstract# 706
`ORAL BIOAVAILABILITY OF FK 506 RAISES PARALLEL WITH
`DECREASING CORTICOSTEROID DOSES IN RENAL
`TRANSPLANT PATIENTS. Wim Lemahieu,1 Kathleen Claes,1 Pieter
`Evenepoel,1 Dirk Kuypers,1 Bart Maes,1 Yves Vanrenterghem.1 1Internal
`Medicine, Division of Nephrology, UZ Gasthuisberg KULeuven,
`Belgium.
`Background: Catabolism by intestinal and hepatic cytochrome P450 3A4 (cyp 3A4)
`and excretion by P-glycoprotein (Pgp) is considered to have a major influence on oral
`bio availability of FK 506. Since it is known that high doses of corticosteroids (CS)
`induce both enzymes, the effect of changing CS exposure on the oral bio availability of
`FK506 was studied. Methods: A cohort of 203 renal transpant patients was analysed.
`At transplantation (tx), all received induction with steroids (500 mg methylprednisone)
`in addition to FK506 and MMF. Afterwards, CS doses, starting from 20 mg/d, were
`progressively tapered. CS exposure was calculated as mean daily dose in mg/kg body
`weight during the time intervals: day 0-30, 31-60, 61-90, 91-180 and 181-365 post tx.
`Bio availability of FK506 was calculated as an index (BAI): {through level (mg/l) /
`dose (mg/kg)}multiplied by 100 at 30, 60, 90, 180 and 365 days post tx. CS exposure
`and BAI were compared at the given time intervals with one way ANOVA. Results: CS
`exposure dropped significantly (p<0.0001) from 0.58 at 1 month to 0.17, 0.15, 0.09 and
`0.06 at 2, 3, 6 and 12 months post tx respectively. Parallel, BAI raised by 11% from 9.9
`at 1 month to 11 at 2 months (p=0.0003), by 16% to 11.54 at 3 months, by 43% to 14.2
`at 6 months and by 48% to 14.69 at 12 months post tx (p<0.0001). As shown in the
`figure, BAI increases in correlation with decreasing corticoid exposure in function of
`time after tx. Conclusions: In renal transplant patients higher doses of CS were associated
`with lower oral bio availability of FK506, suggestive for the inducing effects of CS on
`cyp 3A4 and Pgp.
`
`Abstract# 707
`PERIPHERAL BLOOD FTY720 PHARMACOKINETIC/
`PHARMACODYNAMIC (PK/PD) MODELING IN RENAL
`TRANSPLANTED RECIPIENTS. Sung I. Park,1 Cláudia R. Felipe,1
`Paula G. Machado,1 Riberto Garcia,1 Andrej Skerjanec,2 Robert
`Schmouder,2 Hélio Tedesco-Silva,1 José O. Medina-Pestana.1 1Hospital
`do Rim e Hipertensão - Nephrology Division, Universidade Federal de
`São Paulo, São Paulo, SP, Brazil; 2Novartis Pharmaceuticals, East
`Hanover, NJ.
`INTRODUCTION: FTY720 is a lymphocyte homing drug that induces peripheral
`blood lymphopenia. The relationship between FTY720 dose or blood concentration
`and peripheral lymphopenia is not clear. This study investigates models of FTY720
`PK/PD relationships in the blood compartment. METHODS: 23 kidney transplant
`recipients were randomized to receive FTY720 (0.25, 0.5, 1.0 or 2.5 mg QD) or MMF
`(2gm/day) in combination with Neoral and steroids. FTY720 was administered for 12
`weeks post-transplant. FTY720 dose, blood concentrations and peripheral blood
`lymphocyte counts were obtained weekly in all 5 groups, before and at weeks 4 to 12
`after transplantation. Peripheral blood lymphocyte counts from MMF group were used
`
`333
`
`ATC3D1 Abstracts 401-800.p65
`
`333
`
`3/28/03, 8:12 AM
`
`Black
`
`Apotex v. Novartis
`IPR2017-00854
`NOVARTIS 2048
`
`

`

`KIDNEY: WAIT LIST ISSUES / ECONOMICS
`
`KIDNEY: WAIT LIST ISSUES/ECONOMICS
`
`Abstract# 709
`DIFFERENCES IN HEALTH INSURANCE ARE ASSOCIATED
`WITH ACCESS TO THE KIDNEY TRANSPLANT WAITLIST.
`Robert A. Wolfe,1,2 Valarie B. Ashby,1,2 Alan B. Leichtman,1,2 Friedrich
`K. Port,1 Akinlolu O. Ojo,1,2 Francis L. Delmonico,3 Winfred W.
`Williams, Jr.,3 Robert D. Higgins,4 Denise Y. Alveranga,5 Philip J. Held.1
`1SRTR/URREA, Ann Arbor, MI; 2University of Michigan, Ann Arbor,
`MI; 3Massachusetts General Hospital, Boston, MA; 4Virginia
`Commonwealth University, Richmond, VA; 5Lifelink Transplant Institute,
`Tampa, FL.
`Background: Previous studies have assessed cadaveric renal transplantation rates
`among different patient groups, and multivariate analyses have shown that minorities,
`females, the elderly, and diabetics were relatively less likely to receive a renal transplant.
`This analysis examines the relationship between the type of insurance (primary and
`secondary) at initiation of dialysis (ESRD) and access to the transplant waitlist.
`Methods: We used national (CMS) data for insurance status and characteristics of all
`dialysis patients at time of first dialysis and SRTR data for time of first waitlisting. The
`study population consists of 258,391 dialysis patients (age < 65) beginning dialysis
`between 1995 and 2001. Relative rates of waitlisting (RR-WL) from ESRD onset were
`calculated for kidney dialysis patients by type of insurance using a Cox regression
`model of time to waitlisting (censored at death, living donor transplant, or end of study
`on 6/30/2002). Pre-emptive waitlists were excluded. The model was adjusted for age,
`gender, diagnosis, race, incidence year, ethnicity, 20 comorbidities, type of dialysis
`facility, and geography (state). Results: The table below shows the relative waitlisting
`rate by type of insurance coverage. Patients with Medicare only, Medicaid only, or
`Medicare and Medicaid only have significantly lower waitlisting rates than do other
`patients.
`p-value
`RR-WL
`%
`N
`Insurance Coverage
`Medicare Only
`ref
`1.00
`7.7
`19,784
`Medicaid Only
`<.01
`0.93
`20.1
`51,989
`Medicare and Medicaid Only
`<.01
`0.88
`7.7
`19,871
`Employer Group Health Insurance Only
`<.01
`1.97
`7.0
`18,041
`Medicare and Any Other Insurance
`<.01
`1.27
`27.2
`75,026
`Other Medical Insurance
`<.01
`1.55
`16.1
`41,603
`No Medical Insurance Listed
`0.20
`1.03
`14.3
`36,909
`Patients with only Medicaid insurance had an overall waitlisting rate 34% lower (RR-
`WL=0.66, p<0.01) than patients with all other types of insurance. Although this RR-
`WL varied by state (22% to 68% lower), it remained statistically significant in 43
`states. Conclusions: These newly reported results by state reveal dramatic geographic
`differences in access to the kidney transplant waitlist by patient insurance status at
`initiation of dialysis.
`
`Abstract# 710
`KIDNEY TRANSPLANTATION RATES FROM THE WAITLIST
`REVEAL DISPARITIES IN ACCESS BY INSURANCE STATUS.
`Alan B. Leichtman,1,2 Valarie B. Ashby,1,2 Robert A. Wolfe,1,2 Friedrich
`K. Port,2 Akinlolu O. Ojo,1,2 Francis L. Delmonico,3 Winfred W.
`Williams, Jr.,3 Robert D. Higgins,4 Denise Y. Alveranga,5 Philip J. Held.2
`1University of Michigan, Ann Arbor, MI; 2URREA, Ann Arbor, MI;
`3Massachusetts General Hospital, Boston, MA; 4Virginia Commonwealth
`University, Richmond, VA; 5Lifelink Transplant Institute, Tampa, FL.
`Background: Minorities, females, and the elderly have been shown to be less likely
`to receive cadaveric donor kidney transplants. This analysis looks at the relationship
`between patient insurance at the time of entry onto the transplant waitlist and cadaveric
`transplant access. Methods: Transplant rates (RR-Tx) for waitlisted patients were
`calculated using a Cox regression model (censored at removal from waitlist or end of
`study [6/30/02]) among 112,319 registrants entering the kidney waiting list for the
`first time from 1995-2001. Waitlist dates before first dialysis were moved to onset of
`ESRD. Pre-emptive transplants were excluded. The model was adjusted for age, gender,
`diagnosis group, blood type, race, ethnicity, waitlist year, previous transfusions, state
`of residence, initial PRA, time from first dialysis to waitlisting, dialysis modality at
`waitlist, and HLA antigens. Results: The table below shows adjusted transplantation
`rates by type of insurance coverage. Patients with Medicare only, Medicaid only, and
`HMO/PPO only have significantly lower waitlisting rates than do patients with private
`or multiple types of insurance.
`p-value
`RR-Tx
`%
`N
`Insurance Coverage
`Medicare Only
`ref
`1.00
`11.0
`13,009
`Medicaid Only
`0.68
`0.99
`6.1
`7,171
`Medicare + Other
`<.01
`1.09
`34.4
`40,627
`Private Only
`0.01
`1.05
`20.4
`24,147
`HMO/PPO Only
`<.01
`0.86
`5.6
`6,602
`Private/HMO/PPO + Other
`<.01
`1.11
`16.7
`19,717
`Other source of payment
`0.09
`1.05
`5.0
`5,860
`Missing source of payment
`0.20
`0.85
`0.9
`1,046
`Waitlisted patients with only Medicaid insurance had an overall transplantation rate
`in the U.S. 10% lower (RR=0.90, p<0.01) than patients with all other types of insurance.
`The disparity was greater than 10% for 20 states (3 of them with p<0.05), while in 6
`states Medicaid patients had significantly higher rates (p<0.05). Conclusions: These
`
`results indicate substantial disparities in access to cadaveric transplantation for
`waitlisted patients by insurance type and by geography. These disparities are less
`extreme than those observed in access to the waitlist itself. Patients with insurance
`types (HMO/PPO only, Medicare only, and Medicaid only) at waitlist are most
`disadvantaged.
`
`Abstract# 711
`COST EFFECTIVENESS OF EXTENDED MEDICARE COVERAGE
`OF IMMUNOSUPPRESSIVE MEDICATIONS TO LIFE IN RENAL
`TRANSPLANTATION. Eugene F. Yen,1 Karen Hardinger,2 Daniel C.
`Brennan,1 Mark A. Schnitzler.3 1Department of Internal Medicine,
`Washington University School of Medicine, St. Louis, MO; 2St. Louis
`College of Pharmacy, St. Louis, MO; 3Health Administration Program,
`Washington University School of Medicine, St. Louis, MO.
`A substantial number of renal transplant recipients lose Medicare coverage of
`immunosuppressive medications after 36 months post-transplant. One’s ability to afford
`these medications is correlated with non-adherence to treatment and graft loss, especially
`among patients of lower socioeconomic status. Woodward et al.(AJT 1:69-73, 2001)
`determined that extending Medicare immunosuppression coverage from one to three
`years correlated with a 27% greater improvement in graft survival in the majority of
`patients stratified by income. We sought to compare the economic costs and quality of
`life benefits of extension of immunosuppressive coverage to life. Methods: The United
`States Renal Data System (USRDS) was analyzed for recipients of renal transplants
`from 1995-1999. A Markov model was designed to assess the outcomes of patients who
`receive a renal transplant. This model compared current immunosuppressive coverage
`of 3 years to a model representing lifetime immunosuppressive medication coverage,
`both measured over a 20-year period. Probabilities of all outcomes were calculated
`including graft function, graft loss with death, graft loss with return to dialysis, and
`death. Costs, calculated from the perspective of Medicare, along with quality adjusted
`life year (QALY) benefits, were estimated according to each associated outcome.
`Results: The previously reported graft loss reduction from extending
`immunosuppression coverage translates into an increase in overall survival from 55.4%
`with current coverage to 61.7% after 20 years with lifetime coverage. In addition, lifetime
`immunosuppressive medication coverage produced an average of 0.30 additional
`QALYs per individual transplant over existing coverage. Since Medicare spends
`approximately $79,400 per QALY to care for wait-listed patients on dialysis, we felt
`it reasonable to follow that precedent for renal transplantation. We found that the QALY
`benefit of lifetime immunosuppression coverage would be cost-effective relative to
`dialysis if the average annual cost of immunosuppression to Medicare were $5,570.
`Conclusions: The average annual cost of immunosuppression can be considerably
`higher than the cost-effective threshold calculated here. However, providing lifetime
`coverage through Medicare as secondary insurance, available to patients without
`alternatives, those truly at risk, may yield the previously observed benefits of extended
`coverage while bringing the average cost of lifetime coverage down to cost-effective
`levels.
`
`Abstract# 712
`DID INSURANCE REDUCE RACIAL DISPARITIES IN KIDNEY
`GRAFT SURVIVAL? Robert S. Woodward,1 Andrea Kutinova,1 Mark
`A. Schnitzler,2 Daniel C. Brennan.3 1HMP and Economics, University
`of New Hampshire, Durham, NH; 2Health Administration Program,
`Washington University, St. Louis, MO; 3Internal Medicine, Washington
`University, St. Louis, MO.
`Purpose: It had been previously reported that the additional two years of
`immunosuppression insurance benefits Medicare added between 1993 and 1995
`effectively eliminated graft survival differences associated with income disparities. (
`Am J Transplant, 2001) The current study determined whether that same additional
`immunosuppression coverage had an equally beneficial effect on the graft survival
`differences associated with ethnicity. Methods: We first merged patient-level clinical
`data from the USRDS-distributed UNOS registry with median family income for each
`patient’s ZIP code from the 1990 Census. We then compared only the first cadaveric
`single-organ renal transplants performed in 1992-3 in the highest and lowest income
`quartiles with the similar transplants performed in 1995-7. We used Cox Proportional
`Hazards models to compare graft survival in the second and third years post-transplant
`among i) the 4,441 patients transplanted in 1992 and 1993 that survived at least one
`year and ii) the 6,496 set of similar patients transplanted between 1995 and 1997.
`(Medicare maintenance immunosuppression insurance benefits were available only to
`the second of these 2 cohorts.) Results: In a model controlling for other significant
`donor, recipient, and transplant characteristics, the extra two years of Medicare
`immunosuppression insurance more than eliminated the 23% (Hazard Ratio Confidence
`Interval, HRCI, 1.05 to 1.44; P=0.009) greater graft loss associated with the lowest
`incomes. But the extra Medicare insurance produced no such beneficial impact on the
`greater graft loss associated with black ethnicity. Black ethnicity was associated with
`a 42% additional graft failure (HRCI 1.09 to 1.85, P=0.009). On top of that, the lowest
`income black recipients were associated with an additional 32% graft loss (HRCI 1.02
`to 1.72; P=0.037). All variables testing for the value of the extra Medicare insurance
`benefits to blacks generally and to low-income blacks in particular were highly
`insignificant. Conclusions: Gaston (Am J Transplant, 2002) and others have expressed
`
`ATC3D1 Abstracts 401-800.p65
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`
`3/28/03, 8:12 AM
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`Black
`
`334
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