Combined immunosuppression with cyclosporine (Neoral) and SDZ RAD in non-human primate lung transplantation: Systematic pharmacokinetic-based trials to improve efficacy and tolerability

被引:48
作者
Hausen, B
Ikonen, T
Briffa, N
Berry, GJ
Christians, U
Robbins, RC
Hook, L
Serkova, N
Benet, LZ
Schuler, W
Morris, RE
机构
[1] Stanford Univ, Med Ctr, Dept Cardiothorac Surg, Stanford, CA 94305 USA
[2] Stanford Univ, Med Ctr, Dept Pathol, Stanford, CA 94305 USA
[3] Univ Calif San Francisco, Sch Pharm, Dept Biopharmaceut Sci, San Francisco, CA 94143 USA
[4] Novartis Pharma AG, Dept Transplantat Res, Basel, Switzerland
关键词
D O I
10.1097/00007890-200001150-00015
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Background. We studied the efficacy and tolerability of combined immunosuppressive therapy with cyclosporine A microemulsion (Neoral) plus the macrolide SDZ RAD 40-0 (2-hydroxyethyl) rapamycin (RAD) in a stringent cynomolgus monkey lung graft model in comparison with cyclosporine or SDZ RAD monotherapy. Methods. Thirty-nine cynomolgus monkeys received mixed lymphocyte reaction (MLR) mismatched unilateral lung transplants. Immunosuppressants were administered orally as single daily doses. The observation period was 28 days and follow-up included serial trough blood drug concentrations measured by high performance liquid chromatography/mass spectrometry, blood analyses, chest radiographs, open lung biopsies, as well as tissue drug concentrations and graft histology at necropsy. Results. Graft biopsies in monkeys treated with vehicle (n = 4), Neoral (day 1-7: 150 mg/kg/day; day 8-28: 100 mg/kg/day; n = 6; mean +/- SE trough level (MTL): 292 +/- 17 ng/ml) or SDZ RAD monotherapy (1.5 mg/kg/day; n = 6; MTL: 15 +/- 1 ng/ml) showed severe rejection. Coadministration in two transplant monkeys of Neoral (150/100 mg/kg/day) and SDZ RAD (1.5 mg/kg/day) caused their early death; In both animals, SDZ RAD blood levels were more than 5-fold higher than under monotherapy (MTL: 82 +/- 18 ng/ml). Simultaneous administration (n = 6) of Neoral (150/100 mg/kg/day; MTL: 217 +/- 16 ng/ml) and SDZ RAD (0.3 mg/kg/day; MTL: 24 +/- 2 ng/ml) improved graft outcome (mild rejection), Side effects included renal failure (n = 2) and seizures (n = 1). Three monkeys survived to day 28, In this group the MTL for cyclosporin was 143 +/- 13 and for RAD 38 +/- 3. Staggered treatment completely prevented rejection in four of six grafts. However, five of six monkeys had moderate to severe diarrhea, in a concentration-controlled trial of simultaneously administered Neoral and SDZ RAD in transplant monkeys (target SDZ RAD MTL: 20-40 ng/ml; cyclosporine MTL: 100-200 ng/ml) all six monkeys survived with improved drug tolerability and an average biopsy score of mild rejection. Conclusion. Combination of orally administered SDZ RAD and Neoral showed excellent immunosuppressive efficacy in a stringent lung transplant model, The drug interaction and the narrow therapeutic index of this drug combination required careful dose adjustments to optimize tolerability and efficacy.
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页码:76 / 86
页数:11
相关论文
共 36 条
  • [1] Immunopharmacology of rapamycin
    Abraham, RT
    Wiederrecht, GJ
    [J]. ANNUAL REVIEW OF IMMUNOLOGY, 1996, 14 : 483 - 510
  • [2] OBLITERATIVE BRONCHIOLITIS AFTER LUNG AND HEART-LUNG TRANSPLANTATION - AN ANALYSIS OF RISK-FACTORS AND MANAGEMENT
    BANDO, K
    PARADIS, IL
    SIMILO, S
    KONISHI, H
    KOMATSU, K
    ZULLO, TG
    YOUSEM, SA
    CLOSE, JM
    ZEEVI, A
    DUQUESNOY, RJ
    MANZETTI, J
    KEENAN, RJ
    ARMITAGE, JM
    HARDESTY, RL
    GRIFFITH, BP
    [J]. JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY, 1995, 110 (01) : 4 - 14
  • [3] Intestinal drug metabolism and antitransport processes: A potential paradigm shift in oral drug delivery
    Benet, LZ
    Wu, CY
    Hebert, MF
    Wacher, VJ
    [J]. JOURNAL OF CONTROLLED RELEASE, 1996, 39 (2-3) : 139 - 143
  • [4] BILLINGHAM ME, 1995, TRANSPLANT P, V27, P2013
  • [5] Molecular mechanisms of action of new xenobiotic immunosuppressive drugs: Tacrolimus (FK506), sirolimus (rapamycin), mycophenolate mofetil and leflunomide
    Brazelton, TR
    Morris, RE
    [J]. CURRENT OPINION IN IMMUNOLOGY, 1996, 8 (05) : 710 - 720
  • [6] EFFECTS OF RAPAMYCIN ON GROWTH FACTOR-STIMULATED VASCULAR SMOOTH-MUSCLE CELL-DNA SYNTHESIS - INHIBITION OF BASIC FIBROBLAST GROWTH-FACTOR AND PLATELET-DERIVED GROWTH-FACTOR ACTION AND ANTAGONISM OF RAPAMYCIN BY FK506
    CAO, W
    MOHACSI, P
    SHORTHOUSE, R
    PRATT, R
    MORRIS, RE
    [J]. TRANSPLANTATION, 1995, 59 (03) : 390 - 395
  • [7] COLLIER DS, 1991, TRANSPLANT P, V23, P2246
  • [8] LUNG TRANSPLANTATION
    COOPER, JD
    [J]. ANNALS OF THORACIC SURGERY, 1989, 47 (01) : 28 - 44
  • [9] DINGEMANSE SA, 1998, TRANSPLANTATION, V65, P138
  • [10] ACUTE REJECTION OF LUNG ALLOGRAFTS WITH VARIOUS IMMUNOSUPPRESSIVE PROTOCOLS
    GRIFFITH, BP
    HARDESTY, RL
    ARMITAGE, JM
    KORMOS, RL
    MARRONE, GC
    DUNCAN, S
    PARADIS, I
    DAUBER, JH
    YOUSEM, SA
    WILLIAMS, P
    BOLMAN, RM
    LADOWSKI, J
    STARNES, VA
    [J]. ANNALS OF THORACIC SURGERY, 1992, 54 (05) : 846 - 851