Summary
Most experience of the therapeutic drug monitoring of immunosuppressive agents has been acquired in the field of solid organ transplantation; however, agents such as cyclosporin (cyclosporin A) are being increasingly utilised for the management of autoimmune diseases.
Cyclosporin is the most widely studied immunosuppressant, but in spite of this many controversies still exist as to the optimum strategy for monitoring this drug. Owing to its widely variable pharmacokinetics and metabolism, and the absence of a simple method to measure therapeutic effectiveness, many factors should be considered. In most circumstances, measuring whole blood trough concentrations of cyclosporin with a specific assay methodology is warranted. In addition, knowledge of other factors that may alter the pharmacokinetics (such as liver function, concomitant food or medications, gastrointestinal status, and time since transplantation) should be taken into account so that therapy can be appropriately adjusted. Other methods of monitoring have been investigated, such as AUC (area under the concentration-time curve) monitoring and immunological monitoring. However, further refinement of these techniques and greater experience with their efficacy must be accumulated before their role in the monitoring of cyclosporin can be defined.
Tacrolimus, like cyclosporin, shares many of the difficulties in monitoring for efficacy and toxicity due largely to the variable pharmacokinetics; similarly to cyclosporin, whole blood trough concentration monitoring should be utilised in combination with knowledge of the factors that may affect the pharmacokinetics.
Muromonab CD3 (OKT3) is a monoclonal antibody used for the treatment and prophylaxis of acute allograft rejection. Several immunological monitoring techniques have been investigated for this agent. Monitoring CD3+ levels can assist clinicians in determining therapeutic efficacy, while measuring antimuromonab CD3 antibody titres can help determine if xenosensitisation has occurred, causing therapeutic ineffectiveness.
The clinical monitoring of azathioprine, one of the first immunosuppressive agents used in transplantation, has historically been limited to monitoring complete blood counts for bone marrow suppression. However, newer techniques measuring intracellular DNA nucleotides appear to be promising.
The new immunosuppressants on the horizon include mycophenolate mofetil and rapamycin. The clinical experience with therapeutic drug monitoring of these 2 compounds is scant in the literature; however, both agents have demonstrated efficacy in preventing or treating allograft rejection while maintaining a relatively well tolerated toxicity profile in recent clinical trials.
Routine monitoring does not appear to be warranted for immunosuppressive therapy in autoimmune diseases.
Similar content being viewed by others
References
Starzl TE, Marchioro TL, Waddell WR. The reversal of rejection in human renal homografts with subsequent development of homog raft tolerance. Surg Gynecol Obstet 1963; 117: 385–95
Standards Committee of American Society of Transplant Surgeons. Current results and expectations of renal transplantation. JAMA 1981; 246: 1330–1
Tilney NL, Milford EL, Araujo JL, et al. Experience with cyclosporine and steroids in clinical renal transplantation. Ann Surg 1984; 200: 605–13
Cecka JM, Terasaki PI. The UNOS Scientific Renal Transplant Registry. In: Terasaki PI, Cecka JM, editors. Clinical transplants 1992. Los Angeles: UCLA Tissue Typing Laboratory, 1993: 1–16
Schreiber SL, Crabtree IR. The mechanism of action of cyclosporine and FK506. Immunol Today 1992; 13: 136–42
Tu Y, Stepkowski SM, Chou TC, et al. The synergistic effects of cyclosporine, sirolimus, and brequinar on heart allograft survival in mice. Transplantation 1995; 59: 177–83
Kahan BD, Chou T, Teipal N, et al. Synergistic effects of cyclosporin analogs — A, D, G, IMM-125 — with rapamycin and/or brequinar. Transplant Proc 1994; 26: 3021–4
Kahan BD, Gibbons S, Tejpal N, et al. Synergistic interactions of cyclosporine and rapamycin to inhibit immune performances of normal human peripheral blood lymphocytes in vitro. Transplantation 1991; 51: 232–9
Yatscoff RW, Shaw LM. Therapeutic monitoring of cyclosporine, FK-506, and rapamycin. Ther Drug Monit 1992; 14: 267–8
Faulds D, Goa KL, Benfield P. Cyclosporin: a review of pharmacodynamic and pharmacokinetic properties, and therapeutic use in immunoregulatory disorders. Drugs 1993; 45: 953–1040
Borel JF, Feurer C, Gubler HU, et al. Biological effects of cyclosporine A: a new antilymphocyte agent. Agents Actions 1976; 6: 468–75
Handschumacher RE, Harding MW, Rice J, et al. Cyclophilin: a specific cytosolic binding protein for cyclosporin A. Science 1984; 226: 544–7
Elliot JF, Lin Y, Mizel SB, et al. Induction of interleukin-2 messenger RNA inhibited by cyclosporine A. Science 1984; 226: 1439–41
Palacios R. Cyclosporine inhibits antigen and lectin-induced but not constitutive production of interleukin 3. Eur J Immunol 1985; 15: 204–6
Cirillo R, Triggiani M, Siri L. Cyclosporin A rapidly inhibits mediator release from human basophils presumably by interacting with cyclophilin. J Immunol 1990; 144: 3891–7
Sung SS, Jung LK, Walters JA, et al. Production of tumor necrosis factor/cachectin by human B cell lines and tonsillar B cells. J Exp Med 1988; 168: 1539–51
Reem GH, Cook LA, Vilcek J. Gamma interferon synthesis by human thymocytes and T lymphocytes inhibited by cyclosporine A. Science 1983; 221: 63–4
Christians U, Sewing KF. Cyclosporin metabolism in transplant patients. Pharmacol Ther 1993; 57: 291–345
Yatscoff RW, Rosano TG, Bowers LD. The clinical significance of cyclosporine metabolites. Clin Biochem 1991; 24: 23–35
Kahn D, Cervio G, Mazzaferro V, et al. Relationship between the dose and whole blood level of cyclosporine after liver and kidney transplantation. J Clin Lab Immunol 1992; 37: 163–71
Stiller C, Keown P. Failure of 125I-tracer selective monoclonal antibody levels on whole blood matrix to predict rejection or nephrotoxic episodes in renal transplant patients under antilymphocyte globulin and prednisone therapy. Transplant Proc 1990; 22: 1253–4
Uchida K, Yamada N, Orihara A, et al. Minimal low dosage of cyclosporine therapy in renal transplantation by careful mon-itoring of high-performance liquid chromatography whole blood trough levels. Transplant Proc 1988; 20 (2 Suppl. 2): 394–401
Sommer BG, Sing DE, Henry ML, et al. Serum cyclosporinekinetic profile. Failure to correlate with nephrotoxicity or rejection episodes following sequential immunotherapy for renal transplantation. Transplantation 1988; 45: 86–90
Klintmalm G, Sawe J, Fingden O, et al. Cyclosporine plasma levels in renal transplant patients. Transplantation 1985; 39: 132–7
Henry ML, Bowers VD, Fanning WJ, et al. Cyclosporine levels are not helpful. Transplant Proc 1988; 20 (2 Suppl. 2): 419–21
Martinez L, Foradori A, Vaccarezza A, et al. Monitoring of cyclosporine blood levels with polyclonal and monoclonal assays during episodes of renal graft dysfunction. Transplant Proc 1989; 21: 1490–1
Kahan BD, Wideman CA, Reid M, et al. The value of serial serum trough cyclosporine levels in human renal transplantation. Transplant Proc 1984; 16: 1195–9
Irschik E, Tilg H, Niederwieser D, et al. Cyclosporine blood levels do correlate with clinical complications. Lancet 1984; 2: 692–3
Holt DW, Marsden JT, Johnston A, et al. Cyclosporine monitoring with polyclonal and specific monoclonal antibodies during episodes of renal allograft dysfunction. Transplant Proc 1989; 21: 1482–4
Bowers LD, Canafax DM, Singh J, et al. Studies of cyclosporine blood levels: analysis, clinical utility, pharmacokinetics, metabolites, and chronopharmacology. Transplant Proc 1986; 28 (6 Suppl. 5): 137–43
Moyer TP, Post GR, Sterioff S, et al. Cyclosporine nepllrotoxicity is minimized by adjusting dosage on the basis of drug concentration in blood. Mayo Clin Proc 1988; 63: 241–7
Braunlin EA, Canter CE, Olivari MT, et al. Rejection and infection after pediatric cardiac transplantation. Ann Thorac Surg 1990; 49: 385–90
Gunson BK, Jones SR, Buckels JAC, et al. Liver transplantation in Birmingham — use of cyclosporine — clinical correlations with drug measurements. Transplant Proc 1990; 22: 1312–8
Lindholm A. A prospective study of cyclosporine monitoring in renal transplantation. Transplantion 1990; 22: 1260–3
Lindholm A, Dahlqvist I, Groth GG, et al. A prospective study of cyclosporine concentration in relation to its therapeutic effect and toxicity after renal transplantation. Br J Clin Pharmacol 1990; 30: 443–52
Shaw LM, Audet PR, Grossman RA, et al. Adjustment of cyclosporine dosage in renal transplant patients based on concentration measured specifically in whole blood: clinical outcome results and diagnostic utility. Transplant Proc 1990; 22: 1267–73
Sridhar N, Schroeder TJ, Pesce AJ, et al. Clinical correlations of cyclosporine HPLC and FPIA levels in renal transplant recipients. Transplant Proc 1990; 22: 1257–9
Taube D, Marsden J, Palmer A, et al. Value of cyclosporine measurements in renal transplant recipients irmmuno-suppressed with triple therapy. Transplant Proc 1990; 22: 1251–2
Ghalie R, Fitzsimmons WE, Weinstein A, et al. Cyclosporine monitoring improves graft-versus-host disease prophylaxis after bone marrow transplantation. Ann Pharmacother 1994; 28: 379–82
Nankivell BJ, Hibbins M, Chapman JR. Diagnostic, utility of whole blood cyclosporine measurements in renal transplantation using triple therapy. Transplantation 1994; 58: 989–96
Holt DW, Marsden JT, Johnston A, et al. Blood cyclosporine concentrations and renal allograft dysfunction. BMJ 1986; 293: 1057–9
Rogerson ME, Marsden JT, Reid KE, et al. Cyclosporine blood concentrations in the management of renal transplant recipients. Transplantation 1986; 41: 276–8
Lindholm A, Lundgren G, Fehrman I, et al. Influence of early cyclosporine dosage and plasma and whole blood levels on acute rejections in cadaveric renal allograft recipients. Transplant Proc 1988; 20: 444–6
Yee GC, Self SG, McGuire TR, et al. Serum cyclosporine concentration and risk of acute graft-versus-host disease after allogeneic marrow transplantation. N Engl J Med 1988; 319: 65–70
Best NG, Trull AK, Kan KKC, et al. Blood cyclosporin concentrations and the short-term risk of lung rejection following heart-lung transplantation. Br J Clin Pharmacol 1992; 34: 513–20
White D, Rose M, Wright L, et al. Failure of whole blood cyclosporine levels to provide a reliable measure of immuno-suppression in clinical heart and heart/lung transplantation. Transplant Proc 1988; 20 (2 Suppl. 2): 422–5
Wonigeit K, Kohlhaw K, Winkler M, et al. Cyclosporine monitoring in liver allograft recipients: two distinct patterns of blood level derangement associated with nephrotoxicity. Transplant Proc 1990; 22: 1305–11
Calne RY, White DJG, Thiru S, et al. Cyclosporin A in patients receiving renal allografts from cadaver donors. Lancet 1978; 2: 1323–7
Rosano TG, Freed BM, Pell MA, et al. Involvement of cyclosporine metabolites in therapeutic monitoring and immunosuppression. Transplant Proc 1987; 19: 1699–703
Kahan BD, Napoli K, Welsh M, et al. Comparison of the utility of 3H-based specific monoclonal antibody assay on whole blood samples with the fluorescence polarization nonspecific immunoassay on serum samples for diagnosis of adverse events in renal transplant patients. Transplant Proc 1990; 22: 1274–9
Woo J. Therapeutic monitoring of cyclosporine. Ann Clin Lab Sci 1994; 24: 60–8
Kahan BD, Shaw LM, Holt D, et al. Consensus document: Hawk’s Cay meeting on therapeutic drug monitoring of cyclosporine. Clin Chem 1990; 36: 1510–6
Napoli KL, Kahan BD. I Considerations for monitoring cyclosporine in transplant recipients. Clin Lab Med 1991; 11: 671–91
Salm P, Norris RLG, Taylor PJ, et al. A reliable high-performance liquid chromatography assay for high-throughput routine cyclosporin A monitoring in whole blood. Ther Drug Monit 1993; 15: 65–9
Poirier J-M, Lebot M, Cheymol G. Cyclosporine in whole blood: drug monitoring difficulties and presentation of a reliable normal-phase liquid Chromatographie assay. Ther Drug Monit 1994; 16: 388–9
Lindholm A, Napoli K, Rutzky L, et al. Specific monoclonal radioimmunoassay and fluorescence polarization immunoassay for trough concentration and area-under-the-curve monitoring of cyclosporine in renal transplantation. Ther Drug Monit 1992; 14: 292–300
Holt DW, Fashola TOA, Johnston A. Monitoring cyclosporine: is it still important? Immunol Lett 1991; 29: 99–104
Tjandra-Maga B, Verbsselt R, Schärpe S, et al. Comparison of cyclosporin A measurement in whole blood by six different methods. J Clin Chem Clin Biochem 1990; 28: 53–7
Hirvisalo E-L, Kivisto KT, Neuvonen PJ. Therapeutic cyclosporine monitoring: comparison of radioimmunoassay and high-performance liquid chromatography methods in organ transplant recipients. Ther Drug Monit 1990; 12: 353–8
Armijo JA, Navarro FA, de Cos MA. Is the monoclonal fluorescence polarization immunoassay for cyclosporine specific? Comparison with specific radioimmunoassay. Ther Drug Monit 1992; 14: 333–8
Masri MA. Cyclosporine blood level monitoring by three specific methods; RIA H3, RIA I125, and fluorescence polarization: comparison of accuracy, cost, reproducibility and percent recovery. Transplant Proc 1992; 241: 1716–7
Lee SC, Brudzinski AM, Yasminey JL, et al. Measurement of cyclosporine A by a specific radioimmunoassay with a monoclonal antibody and 125I tracer. Clin Biochem 1991; 24: 43–8
Wong PY, Ma J. Specific and nonspecific monoclonal 1251-Incstar assays. Transplant Proc 1990; 22: 1166–70
McBride JH, Kim SS, Rodgerson DO, et al. Measurement of cyclosporine by liquid chromatography and three immunoassays in blood from liver, cardiac, and renal transplant recipients. Clin Chem 1992; 38: 2300–6
LeGatt DF, Coates JE, Simpson AI, et al. A comparison of cyclosporine assays using sequential samples from selected transplant patients. Clin Biochem 1994; 27: 43–8
Holt DW, Marsden JT, Fashola TOA, et al. Performance of the Sandoz radioimmunoassays for cyclosporine. Transplant Proc 1990; 22: 1155–9
Oellerich M, Armstrong IVW, Kahan B, et al. Lake Louise consensus conference on cyclosporin monitoring in organ transplantation: report of the consensus panel. Ther Drug Monit 1995; 17: 642–54
Kyne F, Maguire S, O’Broin S, et al. Abbott TDx ‘selective’ assay overestimates cyclosporin in whole blood. Clin Chem 1991; 37: 1657–8
Beresini MH, Davalian D, Alexander S, et al. Evaluations of EMIT cyclosporine assay for use with whole blood. Clin Chem 1993; 39: 2235–41
Dasgupta A, Saldana S, Desai M. Analytical performance of EMIT cyclosporine assay evaluates. Clin Chem 1991; 37: 2130–3
Schumann G, Petersen D, Hoyer PF, et al. Monitoring cyclosporin A (ciclosporin, INN) concentrations in whole blood: evaluation of the EMIT assay in comparison with HPLC and RIA. Eur J Clin Chem Clin Biochem 1993; 31: 381–8
Rosano TG, Pell MA, Freed BM, et al. Cyclosporine and metabolites inblood from renal allograft recipients with nephrotoxicity, rejection, or good renal function: comparative high-performance liquid chromatography and monoclonal radioimmunoassay studies. Transplant Proc 1988; 20 (2 Suppl. 2): 330–8
Vernillet L, Humbert H, Aupetit B, et al. French multicentre study: comparison of two specific and four nonspecific methods for Sandimmune (cyclosporine) blood and plasma (separated at 37°C or at 22°C) monitoring. Transplant Proc 1990; 22: 1218–23
Lindholm A, Henricsson S. Comparative analyses of cyclosporine in whole blood and plasma by radioimmunoassay, fluorescence polarization immunoassay, and high-performance liquid chromatography. Ther Drug Monit 1990; 12: 344–52
Mahoney WC, Orf JW. Derivatives of cyclosporin compatible with antibody-based assays. I: The generation of 7251-labeled cyclosporin. Clin Chem 1985; 31: 959–61
Napoli KL, Kahan BD. Nonselective measurement of cyclosporine for therapeutic drug monitoring by fluorescence polarization immunoassay with a rabbit polyclonal antibody. I: Evaluation of the serum methodology and comparison with a sheep polyclonal antibody in an 3H-tracer mediated radioimmunoassay. Transplant Proc 1990; 22: 1175–80
Nattermann U, Steimer W, Gokel JM, et al. Clinical evaluation and therapeutic range of cyclosporine A as monitored by FPIA in kidney transplantation. Transplant Proc 1990; 22: 1284–6
Shaw LM, Bowers L, Demers L, et al. Critical issues in cyclosporine monitoring: report of the task force on cyclosporine monitoring. Clin Chem 1987; 33: 1269–88
Bowers LD. Cyclosporine analysis by high-performance liquid chromatography: precision, accuracy, and minimum detectable quantity. Transplant Proc 1990; 22: 1150–4
Holt DW, Marsden JT, Johnston A. Quality assessment of cyclosporine measurements: comparison of current methods. Transplant Proc 1990; 22: 1234–9
Rosenthaler J, Keller HP. Comment on cyclosporine assay techniques: an attempt for recommendations. Transplant Proc 1990; 22: 1160–5
Quesniaux VFJ. Monoclonal antibody technology for cyclosporine monitoring. Clin Biochem 1991; 24: 37–42
Lee SC, Johanson N, Lee J. Sensitivity of CYCLO-Trac-SP (specific monoclonal immunoassay for cyclosporin A) [letter]. Clin Chem 1989; 35: 1164
Mojaverian P, Green PI. Cyclosporine monitoring in kidney and liver transplant patients: comparison between radioimmunoassay (37°C plasma) and high-performance liquid chromatography (whole blood) measurements. Transplant Proc 1988; 20: 4148
Kivisto KT. A review of assay methods for cyclosporin. Clin Pharmacokinet 1992; 23: 173–90
Loo JCK, Gallicano KD, McGilveray IJ, et al. Monitoring of blood levels of cyclosporine in renal and cardiac transplant recipients — comparison of HPLC to Incstar CYCLO-Trac SP RIA. Clin Biochem 1991; 24: 49–53
Ball PE, Munzer H, Keller HP, et al. Specific 3H radioimmunoassay with a monoclonal antibody for monitoring cyclosporine in blood. Clin Chem 1988; 34: 357–60
Schran HF, Rosano TG, Hassell AE, et al. Determination of cyclosporine concentrations with monoclonal antibodies. Clin Chem 1987; 33: 2225–9
Schroeder TJ, Pesce J, Hassan FM, et al. Comparison of Abbott TDx fluorescence polarization immunoassay, Sandoz radioimmunoassay, and high-performance liquid chromatagraphy methods for the assay of serum cyclosporine. Transplant Proc 1988;20 (2 Suppl. 2): 345–7
Rondanelli R, Regazzi MB, Gastaldi L, et al. Measurement of cyclosporine in plasma of cardiac allograft recipients by fluorescence polarization immunoassay. Ther Drug Monit 1990; 12: 182–6
Wang PP, Simpson E, Meucci V, et al. Cyclosporine monitoring by fluorescence polarization immunoassay. Clin Biochem 1991; 24: 55–8
Moyer TP, Winkels J, Krom R, et al. Evaluation of Abbott TDx monoclonal assay of cyclosporine in whole blood. Clin Chem 1991; 37: 1120–1
Dusci LJ, Hackett LP, Chiswell GM, et al. Comparison of cyclosporine measurement in whole blood by high-performance liquid chromatography, monoclonal fluorescence polarization immunoassay, and monoclonal enzyme-multiplied immunoassay. Ther Drug Monit 1992; 14: 327–32
Rogers LC, Smith FA, Jamero A. Evaluation of the Abbott TDx monoclonal cyclosporine A assay in pediatric cardiac transplant patients [abstract]. Clin Chem 1991; 37: 1014
Schroeder T, Vine W, Ruckrigi D, et al. Evaluation of the new cyclosporine monoclonal antibody fluorescent polarization immunoassay in cardiac and renal transplants [abstract]. Clin Chem 1991; 37: 990
Yatscoff RW, Copeland KR, Faraci CJ. Abbott TDx monoclonal antibody assay evaluated for measuring cyclosporin in whole blood. Clin Chem 1990; 36: 1969–73
Winkler M, Schumann G, Petersen D, et al. Monoclonal fluorescence polarization immunoassay evaluated for monitoring cyclosporine in whole blood after kidney, heart, and liver transplantation. Clin Chem 1992; 38: 123–6
Sabate 1, Gracia S, Diez O, et al. Comparison of cyclosporine blood concentrations measured by radioimmunoassay and two nonisotopic immunoassays using monoclonal antibodies. Clin Chem 1992; 38: 1187–8
Wacke R, Drewelow B, Hehl E-M, et al. Measurement of cyclosporin A in whole blood by RIA, EMIT and FPIA: a comparative study. Int J Clin Pharmacol Ther Tox 1992; 30: 502–3
Bergan S, Rugstad HE, Stokke O, et al. Cyclosporine A monitoring in patients with renal, cardiac, and liver transplants: a comparison between fluorescence polarization immunoassay and two different RIA methods. Scand J Clin Lab Invest 1993; 53: 471–7
Beutler D, Molteni S, Zeugin T, et al. Evaluation of instrumental, nonisotopic immunoassays (fluorescence polarization immunoassay and enzyme-multiplied immunoassay technique) for cyclosporine monitoring in whole blood after kidney and liver transplantation. Ther Drug Monit 1992; 14: 424–32
Morris RG, Saccoia NC, Ryall RG, et al. Specific enzyme-multiplied immunoassay and fluorescence polarization immunoassay for cyclosporin compared with Cyclotrac [125I]-radioimmunoassay. Ther Drug Monit 1992; 14: 226–33
Morris RG, Saccoia NC, Sallustio BC, et al. Experiences with the enzyme-multiplied immunoassay cyclosporine specific assay in a therapeutic drug monitoring laboratory. Ther Drug Monit 1993; 15: 11–3
Morris RG, Tett SE, Ray JE. Cyclosporin A monitoring in Australia: consensus recommendations. Ther Drug Monit 1994; 16: 570–6
Stabler TV, Siegel AL. Chemiluminescence immunoassay of cyclosporine in whole blood. Clin Chem 1990; 36: 906–8
Shaw L. Advances in cyclosporine pharmacology, measurement, and therapeutic monitoring. Clin Chem 1989; 35: 1299–308
Niederberger W, LeMarie M, Maurer G, et al. Distribution and binding of cyclosporine in blood and tissues. Transplant Proc 1983; 15: 2419–21
Ptachcinski RJ, Venkataramanan R, Burckart GJ. Clinical pharmacokinetics of cyclosporin. Clin Pharmacokinet 1986; 11: 107–32
Vine W, Bowers LD. Cyclosporine: structure, pharmacokinetics, and therapeutic drug monitoring. Crit Rev Clin Lab Sci 1987; 25: 275–311
Kahn GC, Shaw LM, Kane MD. Routine monitoring of cyclosporine in whole blood and in kidney tissue using high performance liquid chromatography. J Anal Toxicol 1986; 10: 28–34
Hanas E, Tufveson G, Lindgren P-G, et al. Concentrations of cyclosporine-A and its metabolites in transplanted human kidney tissue during rejection and stable graft function. Clin Transplant 1991; 5: 107–11
Kahan BD, Van Buren CT, Boileau M, et al. Cyclosporine A tissue levels in a cadaveric renal allograft recipient. Transplantation 1983; 35: 96–9
Lensmeyer GL, Wiebe DA, Carlson IH, et al. Con entrations of cyclosporin A and its metabolites in human tissues postmortem. J Anal Toxicol 1991; 15: 110–5
Fahr A. Cyclosporin clinical pharmacokinetics. Clin Pharmacokinet 1993; 24: 472–95
Lindholm A. Factors influencing the pharmacokinetics of cyclosporine in man. Ther Drug Monit 1991; 13: 465–77
Rodighiero V. Therapeutic drug monitoring of cyclosporin: practical applications and limitations. Clin Pharmacokinet 1989; 16: 27–37
Kahan BD, Kramer WG, Wideman C, et al Demographic factors affecting the pharmacokinetics of cyclosporine estimated by radioimmunoassay. Transplantation 1986; 41: 459–64
Awni WM, Kasiske BL, Heim-Duthoy K, et al. Long 3-term cyclosporine pharmacokinetic changes in renal transplant recipients: effects of binding and metabolism. Clin Pharmacol Ther 1989; 45: 41–8
Atkinson K, Briton K, Riggs J. Distribution and concentration of cyclosporine in human blood. J Clin Pathol 1984; 37: 1167–71
Gupta SK, Manfro RC, Tomlanovich SJ, et al. Effect of food on the pharmacokinetics of cyclosporine in healthy subjects following oral and intravenous administration. J Clin Pharmacol 1990; 30: 643–53
Naoumov NV, Tredger JM, Steward CM, et al. Cyclosporin A pharmacokinetics in liver transplant recipients in relation to biliary T-tube clamping and liver dysfunction. Gut 1989; 30: 391–6
Venkataramanan R, Gray J, Ptachcinski RJ, et al. Cyclosporine kinetics in liver disease [abstract]. Clin Pharmacol Ther 1985; 37: 234
Burckart G, Starzl T, Williams L, et al. Cyclosporine monitoring and pharmacokinetics in pediatric liver transplant patients. Transplant Proc 1985; 17: 1172–5
Ptachcinski RJ, Burekart GJ, Rosenthal JT, et al. Cyclosporine pharmaeokinetics in children following cadaveric renal transplantation. Transplant Proc 1986; 18: 766–77
Whitington PF, Emond JC, Whitington SH, et al. Small-bowel length and the dose of cyclosporine in children after liver transplantation. N Engl J Med 1990; 322: 733–8
Kronbach T, Fischer V, Meyers UA. Cyclosporine metabolism in human liver: identification of cytochrome p-450 111 gene family as the major cyclosporine-metabolizing enzyme explains interactions of cyclosporine with other drugs. Clin Pharmacol Ther 1988; 43: 630–5
Watkins PB, Wrightorh SA, Schuetz EG, et al. Identification of glucocorticoid-inducible cytochromes P-450 in the intestinal mucosa of rats and man. J Clin Invest 1987; 80: 1029–36
Hebert MF, Roberts JP, Prueksaritanont T, et al. Bioavailability of cyclosporine with concomitant rifampin administration is markedly less than predicted by hepatic enzyme induction. Clin Pharmacol Ther 1992; 52: 453–7
Gomez DY, Wacher VJ, Tomlanovich SJ, et al. The effects of ketoconazole on the intestinal metabolism and bioavailability of cyclosporine. Clin Pharmacol Ther 1995; 58: 15–9
Watkins PB. Noninvasive tests of CYP3A enzymes. Pharmacogenetics 1994; 4: 171–84
Tsunoda SM, Chang T, Hebert MF, et al. Ethnie différences in cyclosporine pharmaeokinetics [abstract]. Pharmacotherapy 1995; 15: 388
Harris RZ, Tsunoda SM, Mroczkowski P, et al. The effects of menopause and hormone replacement therapies on prednisolone and erythromycin pharmaeokinetics. Clin Pharmacol Ther. In press
Grevel J, Welsh MS, Kahan BD. Cyclosporine monitoring in renal transplantation: area under the curve monitoring is superior to trough-level monitoring. Ther Drug Monit 1989; 11: 246–8
Grevel J, Kahan BD. Area under the curve monitoring of cyclosporine therapy: the early posttransplant period. Ther Drug Monit 1991; 13: 89–95
Grevel J. Area-under-the-curve versus trough level monitoring of cyclosporine concentration: critical assessment of dosage adjustment practices and measurement of clinical outcome. Ther Drug Monit 1993; 15: 488–91
Kahan BD, Welsh M, Knight R, et al. Pharmacokinetic strategies for cyclosporin therapy in organ transplantation. 1992; 5 (Suppl. A): 333–41
Cooney GF, Heifetsv I, Bell A, et al. Utility of pretransplantation cyclosporine pharmacokinetic studies. Ther Drug Monit 1994; 16: 151–4
Grevel J, Post BK, Kahan BD. Michaelis-Menten kinetics determine cyclosporine steady-state concentrations: a population analysis in renal transplant patients. Clin Pharmacol Ther 1993; 53: 651–60
Savoldi S, Kahan BD. Relationship of cyclosporine pharmacokinetic parameters to clinical events in human renal transplantation. Transplant Proc 1986; 18 (Suppl. 5): 120–8
Lindholm A, Kahan BD. Influence of cyclosporine pharmaeokinetics, trough concentrations, and AUC monitoring on outcome after kidney transplantation. Clin Pharmacol Ther 1993; 54: 205–18
Kahan BD, Kramer WG, Wideman CA, et al. Analysis of pharmacokinetic profiles in 232 renal and 87 cardiac allograft recipients treated with cyclosporine. Transplant Proc 1986; 18 Suppl. 5: 115–9
Awni WM, Heim-Duthoy K, Kasiske BL. Monitoring of cyclosporine by serial posttransplant pharmacokinetic studies in renal transplant patients. Transplant Proc 1990; 22: 1343–4
Grevel J, Kahan BD. Abbreviated kinetic profiles in area-under-the-curve monitoring of cyclosporine therapy. Clin Chem 1991; 37: 1905–8
Johnston A, Sketris I, Marsden JT, et al. A limited sampling strategy for the measurement of cyclosporine AUC. Transplant Proc 1990; 22: 1345–6
Cantarovich F, Bizollen C, Cantarovich D, et al. Cyclosporine plasma levels six hours after oral administration. A useful tool for monitoring therapy. Transplantation 1988; 45: 389–94
Regazzi MB, Ronadanelli R, Gastaldi L, et al. Optimization of sampling time for cyclosporine monitoring in transplant patients. J Clin Pharmacol 1992; 32: 978–81
Gaspari F, Ruggenenti P, Toree L, et al. Failure to predict cyclosporine area under the curve using a limited sampling strategy. Kidney Int 1993; 44: 436–9
Watkins PB, Murray SA, Winkelman LG, et al. Erythromycin breath test as an assay of glucocorticoid-inducible liver cytochromes P-450. J Clin Invest 1989; 83: 688–97
Lown K, Kolars J, Turgeon K, et al. The erythromycin breath test selectively measures P450IIIA in patients with severe liver disease. Clin Pharmacol Ther 1992; 51: 229–38
Watkins PB, Hamilton TA, Annesley TM, et al. The erythromycin breath test as a predictor of cyclosporine blood levels. Clin Pharmacol Ther 1990; 48: 120–9
Turgeon DK, Leichtman AB, Lown KS, et al. P450 3A activity and cyclosporine dosing in kidney and heart transplant recipients. Clin Pharmacol Ther 1994; 56: 253–60
Humbert H. Metabolites of cyclosporine: blood and tissue levels. Biological activity? Int J Radiat Appl Instrum B 1990; 17: 723–7
Christians U, Kohlhaw K, Budniak J, et al. Ciclosporin metabolite pattern in blood and urine of liver graft recipients. I: Association of ciclosporin metabolites with nephrotoxicity. Eur J Clin Pharmacol 1991; 41: 285–90
Lucey MR, Kolars JC, Merion RM, et al. Cyclosporine toxicity at therapeutic blood levels and cytochrome P-450111A. Lancet 1990; 335: 11–5
Awni WM. Pharmacodynamic monitoring of cyclosporine. Clin Pharmacokinet 1992; 23: 428–48
d’Uscio CH, Aweeka FT, Prueksaritanont T, et al. Immuno-pharmacodynamic studies of cyclosporine in pre-kidney transplant patients. J Clin Pharmacol. In press
Donnelly JG, Soldin SJ. A radioreceptor assay for the measurement of cyclosporine activity: a preliminary report. Ther Drug Monit 1989; 11: 696–700
Russell RL, Donnelly JG, Palaszynski EW, et al. A preliminary study to evaluate an in vitro assay for determining patient whole blood immunosuppressive cyclosporine A and metabolite activity: a comparison with cytosolic binding assays using cyclophilin or a 50-kDa binding protein, and the Abbott TDx cyclosporine A parent, and parent and metabolites assays. Ther Drug Monit 1991; 13: 32–6
Kahan BD, Pellis NR, Leinikki P, et al. Pharmacodynamic assays of the immunosuppressive action of cyclosporine therapy in transplant recipients. Transplant Proc 1987;19: 1695–8
Cornaby A, Simpson MA, Vann Rice R, et al. Interleukin-2 production in plasma and urine, plasma interleukin-2 receptor levels, and urine cytology as a means of monitoring renal allograft recipients. Transplant Proc 1988; 20: 108–10
Simpson MA, Young-Fadok TM, Madras PN, et al. Sequential interleukin 2 and interleukin 2 receptor levels distinguish rejection from cyclosporine toxicity in liver allograft recipients. Arch Surg 1991; 126: 717–20
Kahan BD. Immunologic monitoring: utility and limitations. Transplant Proc 1985; 17: 1537–45
Reed JC, Abidi AH, Alpers JD, et al. Effect of cyclosporin A and dexamethasone on interleukin-2 receptor gene expression. J Immunol 1986; 137: 150–4
Povlsen JV, Möller BK, Christiansen BS, et al. Cyclosporin A mediated immunosuppression in vitro: effect on high affinity interleukin-2 receptor expression and turnover. Tissue Antigens 1989; 33: 4–14
McKenna RM, Schroeder TJ. Immunological monitoring in cyclosporine-treated patients. Clin Biochem 1991; 24: 75–80
McNally CM, Luckhurst E, Penny R. Cell free serum interleukin-2 receptor levels after heart transplantation. J Heart Lung Transplant 1991; 10(5 Pt 1): 769–74
Rossi SJ, Schroeder TJ, Muth KL, et al. Soluble interleukin-2 receptor monitoring during bacterial and viral infections in liver transplant recipients: a comparative evaluation. Clin Transplant 1994; 8: 479–84
Touraine F, Malcus C, Pouteil-Noble C, et al. Soluble interleukin-2 receptor (s IL-2R) in renal and pancreatic transplantation. Eur Cytokine Netw 1991; 2: 47–50
Kovarik JM, Mueller EA, van Bree JB, et al. Reduced inter- and intraindividual variability in cyclosporine pharmacokinetics from a microemulsion formulation. J Pharm Sci 1994; 83: 444–6
Kovarik JM, Mueller EA, van Bree JB, et al. Cyclosporine pharmacokinetics and variability from a microemulsion formulation — a multicenter investigation in kidney transplant patients. Transplantation 1994; 58: 658–63
Sketris IS, Lawen JG, Beauregard-Zollinger L, et al. Comparison of the pharmacokinetics of cyclosporine Sandimmune with Sandimmune Neoral in stable renal transplant patients. Transplant Proc 1994; 26: 2961–3
Vernillet L, Kovarik J, Freiburghaus R, et al. Blood cyclosporin A and metabolite kinetic profiles after administration of Sandimmune soft gelatin capsules and Neoral in transplant recipients. Transplant Proc 1994; 26: 2964–8
Kahan BD, Dunn J, Fitts C, et al. The Neoral formulation: improved correlation between cyclosporine trough levels and exposure in stable renal transplant recipients. Transplant Proc 1994; 26: 2940–3
Mueller EA, Kovarik JM, van Bree JB, et al. Pharmacokinetics and tolerability of a microemulsion formulation of cyclosporine in renal allograft recipients — a concentration-controlled comparison with the commercial formulation. Transplantation 1994; 57: 1178–82
Mueller EA, Kovarik JM, van Bree JB, et al. Influence of a fat-rich meal on the pharmacokinetics of a new oral formulation of cyclosporine in a crossover comparison with the market formulation. Pharm Res 1991; 11: 1151–5
Taesch S, Niese D, Mueller EA. Sandimmun Neoral, a new oral formulation of cyclosporin A with improved pharmacokinetic characteristics: safety and tolerability in renal transplant patients. Transplant Proc 1994; 26: 3147–9
Keown P, Lawen JG, Landsberg D, et al. Economic analysis of Sandimmune Neoral in Canada in stable renal transplant patients. Transplant Proc 1995; 27: 1845–8
Peters DH, Fitton A, Plosker GL, et al. Tacrolimus: a review of its pharmacology and therapeutic potential in hepatic and renal transplantation. Drugs 1993; 46: 746–94
Sattler M, Guengerich FP, Yun C-H, et al. Cytochrome P-450 3A enzymes are responsible for biotransformation of FK506, and rapamycin in man and rat. Drug Metab Dispos 1992; 20: 753–61
European FK506 Multicentre Liver Study Group. Randomised trial comparing tacrolimus (FK506) and cyclosporin in prevention of liver allograft rejection. Lancet 1994; 344: 423–8
US Multicenter FK506 Liver Study Group. A comparison of tacrolimus (FK 506) and cyclosporine for immunosuppression in liver transplantation. N Engl J Med 1994; 331: 1110–5
Japanese FK 506 Study Group. Japanese study of FK 506 on kidney transplantation: results of a late phase II study. Transplant Proc 1993; 25: 649–54
Japanese FK 506 Study Group. Japanese study of FK 506 on kidney transplantation: the benefit of monitoring the whole blood FK 506 concentration. Transplant Proc 1991; 23: 3085–8
Takahara S, Kokado, Kameoka H, et al. Monitoring of FK 506 blood levels in kidney transplant recipients. Transplant Proc 1994; 26: 2106–8
Backman L, Nicar M, Levy M, et al. FK506 trough levels in whole blood and plasma in liver transplant recipients. Transplantation 1994; 57: 519–25
Erden E, Warty V, Magnone M, et al. Plasma FK506 levels in patients with histopathologically documented renal allograft rejection. Transplantation 1994; 58: 397–8
Jain AB, Todo S, Fung JJ, et al. Correlation of rejection episodes with FK 506 dosage, FK 506 level, and steroids following primary orthotopic liver transplant. Transplant Proc 1991; 23: 3023–5
Winkler M, Wonigeit K, Undre N, et al. Comparison of plasma vs whole blood as matrix for FK 506 drug level monitoring. Transplant Proc 1995; 27: 822–5
Winkler M, Christians U, Stoll K, et al. Comparison of different assays for the quantitation of FK 506 levels in blood or plasma. Ther Drug Monit 1994; 16: 281–6
Jusko WJ, Thomson W, Fung J, et al. Consensus document: therapeutic monitoring of tacrolimus (FK506). Ther Drug Monit 1995; 17: 606–14
Winkler M, Jost U, Ringe B, et al. Association of elevated FK 506 plasma levels with nephrotoxicity in liver-grafted patients. Transplant Proc 1991; 23: 3153–5
Abu-Elmagd K, Fung JJ, Alessiani M, et al. The effect of graft function on FK506 plasma levels, dosages, and renal function, with particular reference to the liver. Transplantation 1991; 52: 71–7
Sandborn WJ, Lawson GM, Cody TJ, et al. Early cellular rejection after orthotopic liver transplantation correlates with low concentrations of FK506 in hepatic tissue. Hepatology 1995; 21: 70–6
Lemoine A, Azoulay D, Dennison A, et al. FK 506 renal toxicity and lack of detectable cytochrome P-450 3 A in the liver graft of a patient undergoing liver transplantation. Hepatology 1994; 20: 1472–7
Kobayashi M, Tamura K, Katayama N, et al. FK 516 assay past and present-characteristics of FK 506 ELISA. Transplant Proc 1991; 23: 2725–9
Christians U, Braun F, Kosian N, et al. High performance liquid chromatography/mass spectrometry of FK 506 and its metabolites in blood, bile, and urine of liver grafted patients. Transplant Proc 1991; 23: 2741–4
Tamura K, Kobayashi M, Hashimoto K, et al. A highly sensitive method to assay FK 506 levels in plasma. Transplant Proc 1987; 19: 23–5
Jusko WJ, D’Ambrosio R. Monitoring FK 506 concentrations in plasma and whole blood. Transplant Proc 1991; 23: 2732–5
Cadoff EM, Venkataramanan R, Krajak A, et al. Assay of FK 506 in plasma. Transplant Proc 1990; 22 Suppl. 1: 50–1
Wallemacq PE, Firdaous I, Hassoun A. Improvement and assessment of enzyme-linked immunosorbent assay to detect low FK506 concentrations in plasma or whole blood within 6 hours. Clin Chem 1993; 39: 1045–9
Grenier FC, Luczkiw JI, Bergmann M, et al. A whole blood FK 506 assay for the IMx analyzer. Transplant Proc 1991; 23: 2748–9
Donnelly JG, Russell RL, Palaszynski EW, et al. Correlation of cyclosporine and metabolite binding to cyclosporine and a 50-kDa binding protein with in vitro immunosuppression: a preliminary report. Clin Biochem 1991; 24: 71–4
Murthy JN, Chen Y, Warty VS, et al. Radioreceptor assay for quantifying FK-506 immunosuppressant in whole blood. Clin Chem 1992; 18: 1307–10
Venkataramanan R, Jain A, Warty VS, et al. Pharmacokinetics of FK 506 in transplant patients. Transplant Proc 1991; 23: 2736–40
Sewing K-F. Pharmacokinetics, dosing principles, and blood level monitoring of FK506. Transplant Proc 1994; 26: 3267–9
Machida M, Takahara S, Ishibashi M, et al. Effect of temperature and hematocrit on plasma concentration of FK 506. Transplant Proc 1991; 23: 2753–4
Beysens AJ, Wijnen FMH, Beuman GH, et al. FK 506: monitoring in plasma or in whole blood? Transplant Proc 1991; 23: 2745–7
Habucky K, Flowers J, Warty VJ, et al. Blood protein binding (BPB) of FK-506 (F) in various species [abstract]. Pharm Res 1992; 9 Suppl.: S–334
Huang M-L, Venkataramanan R, Burckart GJ, et al. Drug-binding proteins in liver transplant patients. J Clin Pharmacol 1988; 28: 505–6
Jain AB, Venkataramanan R, Cadoff E, et al. Effect of hepatic dysfunction and T tube clamping on FK 506 pharmacokinetics and trough concentrations. Transplant Proc 1990; 22 Suppl. 1: 57–9
Christians U, Kruse C, Kownatzki R, et al. Measurement of FK 506 by HPLC and isolation and characterization of its metabolites. Transplant Proc 1991; 23: 940–1
Iwasaki K, Shiraga T, Nagase K, et al. Isolation, identification, and biological activities of oxidation metabolites of FK506, a potent immunosuppressive macrolide lactone. Drug Metab Dispos 1993; 21: 971–7
Zeevi A, Eiras G, Burckart G, et al. Bioassay of plasma specimens from liver transplant patients on FK 506 immunosuppression. Transplant Proc 1990; 22 Suppl. 1: 60–3
Zeevi A, Venkataramanan R, Warty V, et al. In vitro assessment of FK 506 immunosuppressive activity in transplant patients. Transplant Proc 1991; 23: 2897–9
Todd PA, Brogden RN. Muromonab CD3: a review of its pharmacology and therapeutic potential. Drugs 1989; 37: 871–99
Ortho Multicenter Transplant Study Group. A randomized clinical trial of OKT3 monoclonal antibody for acute rejection of cadaveric renal transplants. N Engl J Med 1985; 313: 337–42
Roitt IM. OKT3: immunology, production, purification, and pharmacokinetics. Clin Transplant 1993; 7: 367–73
Singh N, Dummer JS, Kusne S, et al. Infections with cytomeg-alovirus and other herpesviruses in 121 liver transplant recipients: transmission by donated organ and the effects of OKT3 antibodies. J Infect Dis 1988; 158: 124–31
Chatenoud L. Immunologic monitoring during OKT3 therapy. Clin Transplant 1993; 7: 422–30
Goldstein G, Fuccello AJ, Norman DJ, et al. OKT3 monoclonal antibody plasma levels during therapy and the subsequent development of host antibodies to OKT3. Transplantation 1986; 42: 507–10
Cosimi AB, Burton RC, Colvin RB, et al. Treatment of acute renal allograft rejection with OKT3 monoclonal antibody. Transplantation 1981; 32: 535–9
Colvin RB, Preffer Fl. Laboratory monitoring of therapy with OKT3 and other murine monoclonal antibodies. Clin Lab Med 1991; 11: 693–715
Goldstein G, Norman DJ, Henell KR, et al. Pharmacokinetic study of orthoclone OKT3 serum levels during treatment of acute renal allograft rejection. Transplantation 1988; 46: 587–9
Alloway R, Kotb M, Hathaway D, et al. The pharmacokinetic profile of standard and low-dose OKT3 induction immunosuppression in renal transplant recipients. Transplantation 1994; 58: 249–53
Henell KR, Norman DJ. Monitoring OKT3 treatment: pharmacodynamic and pharmacokinetic measures. Transplant Proc 1993; 25 Suppl. 1: 83–5
Schroeder TJ, Michael AT, First MR, et al. Variations in serum OKT3 concentration based upon age, sex, transplanted organ, treatment regimen, and anti-OKT3 antibody status. Ther Drug Monit 1994; 16: 361–7
Shield CF, Norman DJ. Immunologic monitoring during and after OKT3 therapy. Am J Kidney Dis 1988; 11: 120–4
Thistlethwaite JR, Stuart JK, Mayes JT, et al. Complications and monitoring of OKT3 therapy. Am J Kidney Dis 1988; 11: 112–9
Colledan M, Gridelli B, Rossi G, et al. Prolonged and repeated courses of OKT3 after liver transplantation. Transplant Proc 1990; 22: 1769–71
O’Connell JB, Renlund DG, Gay WAJ, et al. Efficacy of OKT3 retreatment for refractory cardiac allograft rejection. Transplantation 1989; 47: 788–92
Shabtai M, Walter WC, Dominguez-Rafer C, et al. Prognostic significance of T cell associated surface antigen density changes during OKT3 therapy of renal allograft rejection. J Urol 1991; 145: 928–31
Chatenoud L, Baudrihaye MF, Chkoff N, et al. Immunologic follow-up of renal allograft recipients treated prophylactically by OKT3 alone. Transplant Proc 1983; 15: 643–5
Debure A, Chkoff N, Chatenoud L. One-month prophylactic use of OKT3 in cadaver kidney transplant recipients. Transplantation 1988; 45: 546–53
Kreis H, Legendre C, Chatenoud L. OKT3 in organ transplantation. Transplant Rev 1991; 5: 181–99
Wittwer CT, Knape WA, Bristow MR. The quantitative flow cytometric plasma OKT3 assay. Its potential application in cardiac transplantation. Transplantation 1989; 48: 533–5
Hammond EA, Yowell RL, Greenwood J, et al. Prevention of adverse clinical outcome by monitoring of cardiac transplant patients for murine monoclonal CD3 antibody (OKT3) sensitization. Transplantation 1993; 55: 1061–3
Schleuter KT, Pouletty C, Schroeder TJ, et al. Monitoring of OKT3 serum concentrations using a cartridge-based immunoassay system [abstract]. Ther Drug Monit 1993; 15: 151
McDiarmid SV, Millis M, Terashita G, et al. Low serum OKT3 levels correlate with failure to prevent rejection in orthotopic liver transplant patients. Transplant Proc 1990; 22: 1774–6
Schroeder TJ, First MR, Hurtubise PE, et al. Immunologie monitoring with orthoclone OKT3 therapy. J Heart Transplant 1989; 8: 371–80
Woodle ES, Thistlethwaite JR, Emond JC, et al. OKT3 therapy for hepatic allograft rejection. Differential response in adults and children. Transplantation 1991; 51: 1207–12
Hammond EH, Wittwer CT, Greenwood J, et al. Relationship of OKT3 sensitization and vascular rejection in cardiac transplant patients receiving OKT3 for rejection prophylaxis. Transplantation 1990; 50: 776–82
Zlabinger GJ, Maurer D, Ulrich W, et al. Immunologic monitoring in OKT3-treated kidney graft recipients. Transplant Proc 1990; 22: 1777–8
Carey G, Lisi PJ, Schroeder TJ. The incidence of antibody formation to OKT3 consequent to its use in organ transplantation. Transplantation 1995; 60: 151–8
Chatenoud L, Baudrih aye MF, Chkoff N, et al. Restriction of the human in vivo immune response against the mouse monoclonal antibody OKT3. J Immunol 1986; 137: 830–8
Norman DJ, Shield CF, Henell KR, et al. Effectiveness of a second course of OKT3 monoclonal anti-T cell antibody for treatment of renal allograft rejection. Transplantation 1988; 46: 523–9
First MR, Schroeder TJ, Hurtubise PE, et al. Successful retreatment of allograft rejection with OKT3. Transplantation 1989; 47: 83–91
O’Connell JB, Bristow MR, Hammond EH, et al. Anti-murine antibody to OKT3 in cardiac transplantation: implications for prophylaxis and retreatment of rejection. Transplant Proc 1991; 23: 1157–9
Mayes JT, Thistlethwaite JR, Stuart JK, et al. Reexposure to OKT3 in renal allograft recipients. Transplantation 1988; 45: 349–53
Schroeder TJ, First MR, Pouletty C, et al. Rapid detection of anti-OKT3 antibodies with the Transtat assay. Transplantation 1993; 55: 297–9
Shield CF. Summary: monitoring and complications of monoclonal therapy. Am J Kidney Dis 1988; 11: 125
Chatenoud L, Ferran C, Bach J-F. In vivo use of OKT3: main issues for the monitoring of treated patients. Transplant Proc 1990; 22: 26O5-8
Shield CF, Norman DJ, Marlett P, et al. Comparison of anti-mouse and antihorse antibody production during the treatment of allograft rejection with OKT3 or antithymocyte globlin. Nephron 1987; 46 Suppl. 1: 48–51
Hricik DE, Mayes JT, Schulak JA. Inhibition of anti-OKT3 antibody generation by cyclosporine -results of a prospective randomised trial. Transplantation 1990; 50: 237–40
Cosimi A. Clinical development of orthoclone OKT3. Transplant Proc 1987; 19 (2 Suppl. 1): 7–16
Millis JM, McDiarmid SV, Hiatt JR, et al. Randomised prospective trial of OKT3 for early prophylaxis of rejection after liver transplanation. Transplantation 1989; 47: 82–8
Norman DJ, Barry JM, Bennet WM, et al. OKT3 for induction immunosuppression in renal transplantation: a comparative study of high versus low doses. Transplant Proc 1991; 23: 1052–4
Alloway R, Kotb M, Hathaway DK, et al. Results of a prospective, randomized double-blind study comparing standard vs low-dose OKT3 induction therapy. Transplant Proc 1993; 25: 550–2
Alloway R, Kotb M, Hathaway DK, et al. Randomized double-blind study of standard versus low-dose OKT3 induction therapy in renal allograft recipients. Am J Kidney Dis 1993; 22: 36–43
Alonso-Pulpon L, Serrano-Fiz S, Rubio JA, et al. Efficacy of low-dose OKT3 as cytolytic induction therapy in heart transplantation. J Heart Lung Transplant 1995; 14: 136–42
Schutz E, Gummert J, Mohr FW, et al. Azathioprine myelotoxicity related to elevated 6-thioguanine nucleotides in heart transplantantion. Transplant Proc 1995; 27: 1298–300
Swanson MA, Schwartz RS. Immunosuppressive therapy. The relation between clinical response and immnunologic competence. N Engl J Med 1967; 277: 163–70
Winkelstein A. The effects of azathioprine and 6-mercaptopurine on immunity. J Immunopharmacol 1979; 1: 429–54
Brunschede H, Krooth RS. Studies on the xanthine oxidase activity of mammalian cells. Biochem Genet 1973; 8: 341–50
Christie NT, Drake S, Meyn RE, et al. 6-thioguanine induced DNA damage as a determinant of cytotoxicity in cultured Chinese hamster ovary cells. Cancer Res 1984; 44: 3665–71
Tidd DM, Paterson ARP. A biochemical mechanism for the delayed cytotoxic reaction of 6-mercaptopurine. Cancer Res 1974; 34: 738–46
Lennard L, Maddocks JL. Assay of 6-thioguanine nucleotide a major metabolite of azathioprine, 6-mercaptopurine and 6-thioguanine, in human red cells. J Pharm Pharmacol 1983; 35: 15–8
Bergan S, Rugstad HE, Bentdal Ø, et al. Monitoring of azathioprine treatment by determination of 6-thioguanine nucleotide concentrations in erythrocytes. Transplantation 1994; 58: 803–8
Lennard L, Van Loon JA, Weinshilboum RM. Pharmacogenetics of acute azathioprine toxicity: relationship to thiopurine methyltransferase genetic polymorphism. Clin Pharmacol Ther 1989; 46: 149–54
Snow JL, Gibson LE. The role of genetic variation in thiopurine methyltransferase activity and the efficacy and/or side effects of azathioprine therapy in dermatologic patients. Arch Dermatol 1994; 130: 1–6
Kerstens PJSM, Stolk JN, De Abrue RA, et al. Azathioprine-related bone marrow toxicity and low activities of purine enzymes in patients with rheumatoid arthritis. Arthritis Rheum 1995; 38: 142–5
Ohlman S, Lafolie P, Lindholm A, et al. Large interindividual variability in bioavailability of azathioprine in renal transplant recipients. Clin Transplant 1993; 7: 65–70
Lin S-N, Jessup K, Floyd M, et al. Quantitation of plasma azathioprine and 6-mercaptopurine levels in renal transplant patients. Transplantation 1980; 29: 290–4
Odlind B, Hartvig P, Lindstrom B, et al. Serum azathioprine and 6-mercaptopurine levels and immunosuppressive activity after azathioprine in uremic patients. Int J Immunopharmacol 1986; 8: 1–11
Lennard L, Brown CB, Fox M, et al. Azathioprine metabolism in kidney transplant recipients. Br J Clin Pharmacol 1984; 18: 693–701
Lennard L, Keen D, Lilleyman JS. Oral 6-mercaptopurine in childhood leukaemia: parent drug pharmacokinetics and active metabolite concentrations. Clin Pharmacol Ther 1986; 40: 287–92
Erdmann GR, France LA, Bostrom BC, et al. A reversed phase high performance liquid chromatography approach to determining total red blood cell concentrations of 6-thioguanine, 6-mercaptopurine, methylthioguanine and methylmercaptopurine in a patient receiving thiopurine therapy. Biomed Chromatogr 1990; 4: 47–51
Lennard L. Assay of 6-thioinosinic acid and 6-thioguanine nucleotides, active metabolites of 6-mercaptopurine in human red blood cells. J Chromatogr 1987; 423: 169–78
Lennard L. The clinical pharmacology of 6-mercaptopurine. Eur J Clin Pharmacol 1992; 43: 329–39
Weinshilboum RM, Raymond FA, Pazmino PA. Human erythrocyte thiopurine methyltransferase radiochemical microassay and biochemical properties. Clin Chem Acta 1987; 85: 323–33
Szumlanski CL, Honchel R, Scott MC, et al. Human liver thiopurine methyltransferase pharmacogenetics: biochemical properties, liver-erythrocyte correlation and presence of isozymes. Pharmacogenetics 1992; 2: 148–59
Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet 1980; 32: 651–62
Lennard L, Lilleyman JS, Van Loon JA, et al. Genetic variation in response to 6-mercaptopurine for childhood acute Iymphoblastic leukaemia. Lancet 1990; 336: 225–9
Chocair P, Duley JA, Simmonds HA, et al. The importance of thiopurine methyltransferase activity for the use of azathioprine in transplant recipients. Transplantation 1992; 3: 105–6
Allison AC, Eugui EM. Immunosuppressive and other effects of mycophenolic acid and an ester prodrug, mycophenolate mofetil. Immunol Rev 1993; 136: 5–28
Nowak I, Shaw LM. Lycophenolic acid binding to human serum albumin: characterization and relationship to pharmacodynamics. Clin Chem 1995; 41: 1011–7
Report of the Antiviral Drug Advisory Committee, Subcommittee on Immunosuppressant Drugs, March 30,1995. Rockville (MD): Food and Drug Administration
Japan RS-61443 Investigation Committee. Pilot study of mycophenolate mofetil (RS-61443) in the prevention of acute rejection following renal transplantation in Japanese patients. Transplant Proc 1995; 27: 1421–4
Sollinger HW, Deierhoi MH, Beizer FO, et al. RS-61443: a phase I clinical trial and pilot rescue study. Transplantation 1992; 51: 27–31
Sollinger, HW, for the US Renal Transplant Mycophenolate Mofetil Study Group. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. Transplantation 1995; 60: 225–32
European Mycophenolate Mofetil Cooperative Study Group. Placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection. Lancet 1995; 345: 1321–5
Freise CE, Hebert M, Osorio RW, et al. Maintenance immuno-suppression with prednisone and RS-61443 alone following liver transplantation. Transplant Proc 1993; 25: 1758–9
Ensley RD, Bristow MR, Olsen SL, et al. The use of mycophenolate mofetil (RS-61443) in human heart transplant recipients. Transplantation 1993; 56: 75–82
Kirklin JK, Bourge RC, Naftel DC, et al. Treatment of recurrent heart rejection with mycophenolate mofetil (RS-61443): initial clinical experience. J Heart Lung Transplant 1994; 13: 444–50
Sugioka N, Odani H, Ohta T, et al. Determination of a new immunosuppressant, mycophenolate mofetil, and its active metabolite, mycophenolic acid, in rat and human body fluids by high-performance liquid chromatography. J Chromatgr B 1994; 654: 249–56
Chou D. Therapeutic drug monitoring (immunosuppressive drugs). Anal Chem 1993; 65: 412R-415R
Wolfe EJ, Mathur V, Tomlanovich S, et al. Pharmacokinetic drug interaction study of mycophenolate mofetil and intravenous ganciclovir in renal transplant patients [abstract]. Clin Pharmacol Ther 1995; 57: 148
Shaw LM, Sollinger HW, Halloran P, et al. Mycophenolate mofetil: a report of the consensus panel. Ther Drug Monit 1995; 17: 690–9
Sehgal SN, Baker H, Vezina C. Rapamycin (AY-22,989) a new antifungal antibiotic. II: Fermentation, isolation and characterization. J Antibiot 1975; 28: 727–32
Flanagan WM, Crabtree GR. Rapamycin inhibits p34cdc2 expression and arrests T lymphocyte proliferation at the G1/S transition. Ann NY Acad Sci 1993; 696: 31–7
Kimball PM, Kerman RH, Kahan BD. Production of synerergistic, but non-identical mechanisms of immusuppression by rapamycin and cyclosporine. Transplantation 1991; 51: 486–90
Metcalfe SM, Richards FM. Cyclosporine, FK 506 and rapamycin: some effects on early activation events in serum-free, mitogen-stimulated mouse spleen cells. Transplantation 1990; 49: 798–802
Dumont FJ, Staruch MJ, Koprak SL, et al. Distinct mechanisms of suppression of murine T-cell activation by the related macrolides FK 506 and rapamycin. J Immunol 1990; 144: 251–8
Yatscoff RW, LeGatt F, Kneteman NM. Therapeutic monitoring of rapamycin: a new immunosuppressive drug. Ther Drug Monit 1993; 15: 478–82
Ludwin D. Cyclosporine monitoring in autoimmune and other diseases. Clin Biochem 1991; 24: 97–9
Holt DW, Johnston A. Cyclosporine monitoring: its role in autoimmune indications. J Autoimmun 1992; 5 Suppl. A: 177–82
Feutren G. The optimal use of cyclosporin A in autoimmunue diseases. J Autoimmun 1992; 5 Suppl. A: 183–95
Van Thiel DH, Wright H, Carroll P, et al. Tacrolimus: a potential new treatment for autoimmune chronic active hepatitis: results of an open-label preliminary trial. Am J Gastroenterol 1995; 90: 771–6
Thomson AW, Carroll PB, McCauley J, et al. FK 506: a novel immunosuppressant for the treatment of autoimmune disease. Rationale and preliminary clinical experience at the University of Pittsburgh. Springer Semin Immunopathol 1993; 14: 323–14
McMichael J, Lieberman R, Doyle H, et al. Computer-guided concentration-controlled trials in autoimmune disorders. Ther Drug Monit 1993; 15: 510–3
Schiff MH, Goldblum R, Rees MMC. New DMARD, mycophenolate mofetil, effectively treats refractory rheumatoid arthritis patients for one year [abstract]. Arthritis Rheum 1991; 34 Suppl.: S89
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Tsunoda, S.M., Aweeka, F.T. The Use of Therapeutic Drug Monitoring to Optimise Immunosuppressive Therapy. Clin-Pharmacokinet 30, 107–140 (1996). https://doi.org/10.2165/00003088-199630020-00003
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003088-199630020-00003