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Therapeutic Drug Monitoring of Cyclosporin

Practical Applications and Limitations

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  • Drug Concentration Monitoring
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Summary

Cyclosporin, a potent immunosuppressive agent used to prevent rejection of transplanted organs, has a narrow therapeutic range and various toxic effects, mostly concentration-dependent. The kinetics of this drug present a large intra- and interindividual variability due to many factors resulting in marked variations of blood cyclosporin concentrations, and in a poor correlation between administered dose and concentrations. The knowledge of cyclosporin peculiarities and of factors affecting blood concentrations can provide a rational basis for establishing an adequate therapy for the individual patient, in conjunction with other laboratory and clinical data. Cyclosporin monitoring is a method of evaluating whether the therapeutic choice is correct. Cyclosporin concentrations can be measured in blood, plasma and serum using radioimmunoassay or high performance liquid chromatography. Different results are obtained, depending on the technique and on biological fluids used. Cyclosporin measurement presents many problems and difficulties. There is a need for standardisation and for quality assessment programmes. The recent development of monoclonal antibodies may represent a significant advance for cyclosporin monitoring. The most important factors affecting blood concentrations are: type of transplant, bile deficit, gastrointestinal dysfunction, food, variations of lipoprotein concentrations, impairment of liver function, age, drug coadministration. Therapeutic drug monitoring should be undertaken on a regular basis after the initiation of therapy with cyclosporin. After discharge from the hospital the patient and the attending physician should be aware of the factors which may require changes in cyclosporin therapy.

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References

  • Agarwal RP, McPherson RA, Threatte GA. Evidence of a cyclosporine-binding protein in human erythrocytes. Transplantation 42: 627–632, 1986

    Article  PubMed  CAS  Google Scholar 

  • Andrews W, Fyock B, Gray S, Coln D, Hendrickse W, et al. Pediatric liver transplantation: the Dallas experience. Transplantation Proceedings 19: 3267–3276, 1987

    PubMed  CAS  Google Scholar 

  • Andrews W, Iwatsuki S, Shaw BW, Starzl TE. Letter. Transplantation 39: 338, 1985

    Article  PubMed  CAS  Google Scholar 

  • Atkinson K, Biggs JC, Britton K, Short R, Mrongovius R, et al. Oral administration of cyclosporin A for recipients of allogeneic marrow transplants: implications of clinical gut dysfunction. British Journal of Haematology 56: 223–231, 1984

    Article  PubMed  CAS  Google Scholar 

  • Atkinson K, Britton K, Pauli P, Farrell C, Concannon A, et al. Detrimental effect of intestinal disease on absorption of orally administered cyclosporine. Transplantation Proceedings 15 (Suppl. 1): 2446–2449, 1983

    Google Scholar 

  • Ballantyne CM, Jones PH, Payton-Ross C, Patsch W, Short HD, et al. Hyperlipidemia following heart transplantation: natural history and intervention with mevinolin (Lovastatin). Transplantation Proceedings 19 (Suppl. 5): 60–62, 1987

    PubMed  CAS  Google Scholar 

  • Bowers LD, Canafax DM, Singh J, Seifedlin R, Simmons RL, et al. Studies of cyclosporine blood levels: analysis, clinical utility, pharmacokinetics, metabolites and chronopharmacology. Transplantation Proceedings 18 (Suppl. 5): 137–143, 1986

    PubMed  CAS  Google Scholar 

  • Burckart G, Starzl T, Williams L, Sanghvi A, Gartner C, et al. Cyclosporine monitoring in pediatric liver transplant patients. Transplantation Proceedings 17: 1172–1175, 1985

    PubMed  Google Scholar 

  • Burckart GJ, Venkataramanan R, Ptachcinski RJ, Starzl TE, Gartner C, et al. Cyclosporine absorption following orthotopic liver transplantation. Journal of Clinical Pharmacology 26: 647–651, 1986a

    PubMed  CAS  Google Scholar 

  • Burckart GJ, Venkataramanan R, Ptachcinski RJ, Starzl TE, Griffith BP, et al. Cyclosporine pharmacokinetic profiles in liver, heart and kidney transplant patients as determined by high-performance liquid chromatography. Transplantation Proceedings 18 (Suppl. 5): 129–136, 1986b

    PubMed  CAS  Google Scholar 

  • Burckart GJ, Wang CP, Zeevi A, Venkataramanan R, Ptachcinski RJ, et al. Cyclosporine metabolites in human bile: recovery and immunologic activity. Transplantation Proceedings 20 (Suppl. 1): 190–192, 1988

    Google Scholar 

  • Busuttil RW, Goldstein LI, Danovitch M, Ament ME, Memsic LDF. Liver transplantation today. Annals of Internal Medicine 104: 377–389, 1986

    PubMed  CAS  Google Scholar 

  • Cabrol C, Gandjbakhch I, Pavie A, Cabrol A, Corcos T, et al. Indications and contraindications for cardiac transplantation: new trends in immunosuppressive therapy and results. Transplantation Proceedings 4 (Suppl. 3): 35–38, 1986

    Google Scholar 

  • Calabresi P, Parks RE. Chemotherapy of neoplastic diseases. In Goodman & Gilman (Eds) The pharmacological basis of therapeutics, pp. 1240–1306, MacMillan Company, New York, 1985

    Google Scholar 

  • Elston RA, Taylor J. Possible interaction of ciprofloxacin with cyclosporin A. Journal of Antimicrobial Chemotherapy 21: 679–680, 1988

    Article  PubMed  CAS  Google Scholar 

  • Follath F, Wenk M, Vozeh S, Thiel G, Brunner F, et al. Intravenous cyclosporine kinetics in renal failure. Clinical Pharmacology and Therapeutics 34: 638–643, 1983

    Article  PubMed  CAS  Google Scholar 

  • Freed BM, Rosano TG, Lempert N. In vitro immunosuppressive properties of cyclosporine metabolites. Transplantation 43: 123–127, 1987a

    Article  PubMed  CAS  Google Scholar 

  • Freed BM, Rosano TG, Quick C, Lempert N. Effect of cyclosporine metabolites M17 and M18 on proliferation and IL-2 production in the mixed lymphocyte culture. Transplantation Proceedings 19: 1223–1226, 1987b

    PubMed  CAS  Google Scholar 

  • Frey BM, Appenzeller M, Gautschi K, Keller B, Vadas L, et al. Measurement of cyclosporine A by RIA in different centers are not comparable. Transplantation Proceedings 19: 1713–1714, 1987

    PubMed  CAS  Google Scholar 

  • Hillebrand G, Castro LA, Van Scheidt W, Beukelmann D, Land W, et al. Valproate for epilepsy in renal transplant recipients receiving cyclosporine. Transplantation 43: 915–916, 1987

    PubMed  CAS  Google Scholar 

  • Holt DW, Marsden JT, Johnston A. Measurement of cyclosporine: methodological problems. Transplantation Proceedings 18 (Suppl. 5): 101–110, 1986

    PubMed  CAS  Google Scholar 

  • Irschik E, Tilg H, Niederwieser D, Gastl G, Huber Ch, et al. Cyclosporin blood levels do correlate with clinical complications. Lancet 2: 692–693, 1984

    Article  PubMed  CAS  Google Scholar 

  • Johnston A, Marsden JT, Hla KK, Henry A, Holt DW. The effect of vehicle on the oral absorption of cyclosporin. British Journal of Clinical Pharmacology 21: 331–333, 1986a

    Article  PubMed  CAS  Google Scholar 

  • Johnston A, Marsden JT, Holt DW. The United Kingdom cyclosporin quality assessment scheme. Therapeutic Drug Monitoring 8: 200–204, 1986b

    Article  PubMed  CAS  Google Scholar 

  • Johnston A, Marsden JT, Holt DW. The influence of haematocrit on blood cyclosporin measurements in vivo. British Journal of Clinical Pharmacology 25: 509–513, 1988

    Article  PubMed  CAS  Google Scholar 

  • Jones RJ, Lee SK, Beschorner WE, Vogel VG, Grochow LB, et al. Venocclusive disease of the liver following bone marrow transplantation. Transplantation 44: 778–783, 1987

    Article  PubMed  CAS  Google Scholar 

  • Kahan BD. Individualization of cyclosporine therapy using pharmacokinetic and pharmacodynamic parameters. Transplantation 40: 457–476, 1985

    Article  PubMed  CAS  Google Scholar 

  • Kahan BD, Kramer WG, Wideman C, Flechner SM, Lorber MI, et al. Demographic factors affecting the pharmacokinetics of cyclosporine estimated by radioimmunoassay. Transplantation 41: 459–464. 1986a

    Article  PubMed  CAS  Google Scholar 

  • Kahan BD, Kramer WG, Wideman CA, Frazier OH, Lorber MI, et al. Analysis of pharmacokinetic profiles in 232 renal and 87 cardiac allograft recipients treated with cyclosporine. Transplantation Proceedings 18 (Suppl. 5): 115–119, 1986b

    PubMed  CAS  Google Scholar 

  • Kahan BD, Ried M, Newburger J. Pharmacokinetics of cyclosporine in human renal transplantation. Transplantation Proceedings 15: 446–453, 1983

    Google Scholar 

  • Kalayoglu M, Stratta RJ, Hoffmann RM, Sollinger HW, Beizer FO. Quadruple immunosuppressive therapy for liver transplantation. Transplantation Proceedings 20 (Suppl. 1): 524–529, 1988

    PubMed  CAS  Google Scholar 

  • Kennedy MS, Yee GC, McGuire TR, Leonard TM, Crowley JJ, et al. Correlation of serum cyclosporine concentration with renal dysfunction in marrow transplant recipients. Transplantation 40: 249–253, 1985

    Article  PubMed  CAS  Google Scholar 

  • Keogh A, Day R, Critchley L, Duggin G, Baron D. The effect of food and cholestyramine on the absorption of cyclosporine in cardiac transplant recipients. Transplantation Proceedings 20: 27–30, 1988

    PubMed  CAS  Google Scholar 

  • Keown PA, Stiller CR, Laupacis AL, Howson W, Coles R, et al. The effects and side effects of cyclosporine: relationship to drug pharmacokinetics. Transplantation Proceedings 14: 659–661, 1982

    PubMed  CAS  Google Scholar 

  • Keown PA, Stiller CR, Sinclair NR, Carruthers G, Howson W, et al. The clinical relevance of cyclosporine blood levels as measured by radioimmunoassay. Transplantation Proceedings 15 (Suppl. 1): 2438–2441, 1983

    Google Scholar 

  • Keown PA, Stiller CR, Stawecki M, Freeman D. Pharmacokinetics of cyclosporine in solid organ transplantation. Transplantation Proceedings 18 (Suppl. 5): 160–164, 1986

    PubMed  CAS  Google Scholar 

  • Klare B, Walter JV, Hahn H, Emmrich P, Und W. Cyclosporin in renal transplantation in children. Lancet 2: 692, 1984

    Article  PubMed  CAS  Google Scholar 

  • Kreft-Jais C, Billaud EM, Gaudry C, Bedrossian J. Effect of josamycin on plasma cyclosporine levels. European Journal of Clinical Pharmacology 32: 327–328, 1987

    Article  PubMed  CAS  Google Scholar 

  • Lemaire M, Maurer G, Wood AJ. Pharmacokinetics and metabolism. Progress in Allergy 38: 93–107, 1986

    PubMed  CAS  Google Scholar 

  • Lindholm A, Henricsson S, Lind M, Dahlqvist R. Intraindividual variability in the relative systemic availability of cyclosporin after oral dosing. European Journal of Clinical Pharmacology 34: 461–464, 1988

    Article  PubMed  CAS  Google Scholar 

  • Lithell H, Odlind B, Selinus I, Lindberg A, Lindström B, et al. Is the plasma lipoprotein pattern of importance for treatment with cyclosporine? Transplantation Proceedings 18: 50–51, 1986

    Google Scholar 

  • Mehta MU, Venkataramanan R, Burckart GJ, Ptachcinski RJ, Delamos B, et al. Effect of bile on cyclosporin absorption in liver transplant patients. British Journal of Clinical Pharmacology 25: 579–584, 1988

    Article  PubMed  CAS  Google Scholar 

  • Mover TP. Measurement of cyclosporine: a challenge to the professional laboratory organizations. Therapeutic Drug Monitoring 7: 123–124, 1985

    Google Scholar 

  • Mover TP, Johnson P, Faynor SM, Sterioff S. Cyclosporine: a review of drug monitoring problems and presentation of a simple, accurate liquid Chromatographic procedure that solves these problems. Clinical Biochemistry 19: 83–89, 1986

    Article  Google Scholar 

  • Mraz W, Sido B, Knedel M, Hammer C. Concomitant immunosuppressive and antibiotic therapy: reduction of cyclosporine A blood levels due to treatment with imipenem/cilastatin. Transplantation Proceedings 19: 4017–4020, 1987

    PubMed  CAS  Google Scholar 

  • Mraz W, Zink RA, Graft A, Preis D, Illner WD, et al. Distribution and transfer of cyclosporine among the various human lipoprotein classes. Transplantation Proceedings 15 (Suppl. 1): 2426–2429, 1983

    CAS  Google Scholar 

  • Neiberger R, Weiss R, Gomez M, Greifer J, Tellis VA, et al. Elimination kinetics of cyclosporine following oral administration to children with renal transplants. Transplantation Proceedings 19: 1525, 1987

    PubMed  CAS  Google Scholar 

  • Niederberger W, Lemaire M, Maurer G, Nussbaumer K, Wagner O. Distribution and binding of cyclosporine in blood and tissues. Transplantation Proceedings 15 (Suppl. 1): 2419–2421, 1983

    CAS  Google Scholar 

  • Odlind B, Lindberg A, Tufveson G, Lindström B, Frödin L, et al. Longitudinal study of the pharmacokinetics of cyclosporine before and after renal transplantation. Transplantation Proceedings 18: 47–49, 1986

    Google Scholar 

  • Ptachcinski RJ, Burckart GJ, Rosenthal JT, Venkataramanan R, Howrie DL, et al. Cyclosporine pharmacokinetics in children following cadaveric renal transplantation. Transplantation Proceedings 18: 766–767, 1986a

    Google Scholar 

  • Ptachcinski RJ, Venkataramanan R, Burckart GJ. Clinical pharmacokinetics of cyclosporine. Clinical Pharmacokinetics 11: 107–132, 1986b.

    Article  PubMed  CAS  Google Scholar 

  • Ptachcinski RJ, Venkataramanan R, Rosenthal JT, Burckart GJ, Taylor RJ, et al. The effect of food on cyclosporine absorption. Transplantation 40: 174–176, 1985a

    Article  PubMed  CAS  Google Scholar 

  • Ptachcinski RJ, Venkataramanan R, Rosenthal JT, Burckart GJ, Taylor RJ, et al. Cyclosporine kinetics in renal transplantation. Clinical Pharmacology and Therapeutics 38: 296–300, 1985b

    Article  PubMed  CAS  Google Scholar 

  • Quesniaux V. The use of monoclonal antibodies to probe the surface of cyclosporine. Transplantation Proceedings 18 (Suppl. 5): 111–114, 1986

    PubMed  CAS  Google Scholar 

  • Quesniaux V, Tees R, Schreier MH, Maurer G, van Regenmortel MHV. Potential of monoclonal antibodies to improve therapeutic monitoring of cyclosporine. Clinical Chemistry 33: 32–37, 1987

    PubMed  CAS  Google Scholar 

  • Rosano TG. Effect of hematocrit on cyclosporine (cyclosporin A) in whole blood and plasma of renal-transplant patients. Clinical Chemistry 31: 410–412, 1985

    PubMed  CAS  Google Scholar 

  • Rosano TG, Freed BM, Pell MA, Dybas MT, Lempert N. Involvement of cyclosporine metabolites in therapeutic monitoring and immunosuppression. Transplantation Proceedings 19: 1699–1703, 1987

    PubMed  CAS  Google Scholar 

  • Rosano TG, Freed BM, Pell MA, Lempert N. Cyclosporine metabolites in human blood and renal tissue. Transplantation Proceedings 18 (Suppl. 5): 35–40, 1986

    PubMed  CAS  Google Scholar 

  • Schinella M, Perobelli L, Mazzi G, Determinazioni di ciclosporina e suoi metaboliti con anticorpi policlonali, monoclonali aspecifici e specifici (RIA) e con HPLC. Ligand Quarterly 6: 365–367, 1987

    Google Scholar 

  • Scott JP, Higenbottam TW. Adverse reactions and interactions of cyclosporin Medical Toxicology 3: 107–127, 1988

    CAS  Google Scholar 

  • Shaw LM, Bowers L, Demers L, Freeman D, Moyer T, et al. Critical issues in cyclosporine monitoring: report of the task force on cyclosporine monitoring. Clinical Chemistry 33: 1269–1288, 1987

    CAS  Google Scholar 

  • Sheil AGR. Clinical organ transplantation. Transplantation Proceedings 19: 2782–2786, 1987

    PubMed  CAS  Google Scholar 

  • Shulman HM, McDonald GB, Matthews D, Doney KC, Kopecky KJ, et al. An analysis of hepatic venocclusive disease and centrilobular hepatic degeneration following bone marrow transplantation. Gastroenterology 79: 1178–1191, 1980

    PubMed  CAS  Google Scholar 

  • Snyder DS. Interaction between cyclosporine and warfarin. Annals of Internal Medicine 108: 311, 1988

    PubMed  CAS  Google Scholar 

  • Sutherland DER, Goetz FC, Najarian JS. Improved pancreas graft survival by use of multiple drug combination immunotherapy. Transplantation Proceedings 18: 1770–1773, 1986

    Google Scholar 

  • Tufveson G, Odlind B, Sjöberg O, Lindberg A, Gabrielsson J, et al. A longitudinal study of the pharmacokinetics of cyclosporine A and in vitro lymphocyte responses in renal transplant patients. Transplantation Proceedings 18 (Suppl. 5): 16–24, 1986

    PubMed  CAS  Google Scholar 

  • Venkataramanan R, Burckart GJ, Ptachcinski RJ. Pharmacokinetics and monitoring of cyclosporine following orthotopic liver transplantation. Seminars in Liver Disease 5: 357–368, 1985a

    Article  PubMed  CAS  Google Scholar 

  • Venkataramanan R, Burckart GJ, Ptachcinski RJ, Lee A, Hardesty RL, et al. Cyclosporine pharmacokinetics in heart transplant patients. Transplantation Proceedings 18: 768–770, 1986a

    Google Scholar 

  • Venkataramanan R, Gray J, Ptachcinski RJ, Van Thiel DH, Burckart GJ, et al. Cyclosporine kinetics in liver disease. Clinical Pharmacology and Therapeutics 37: 234, 1985b

    Google Scholar 

  • Venkataramanan R, Ptachcinski RJ, Burckart GJ, Yang SL, Starzl TE, et al. The clearance of cyclosporine by hemodialysis. Journal of Clinical Pharmacology 24: 528–531, 1984

    PubMed  CAS  Google Scholar 

  • Venkataramanan R, Starzl TE, Yang S, Burckart GJ, Ptachcinski RJ, et al. Biliary excretion of cyclosporine in liver transplant patients. Transplantation Proceedings 17: 286–289, 1985c

    PubMed  Google Scholar 

  • Venkataramanan R, Yang S, Burckart GJ, Ptachcinski RJ, Van Thiel DH, et al. Diurnal variation in cyclosporine kinetics. Therapeutic Drug Monitoring 8: 380–381, 1986b

    Article  PubMed  CAS  Google Scholar 

  • Veremis SA, Maddux MS, Pollak R, Mozes MF. Subtherapeutic cyclosporine concentrations during nafcillin therapy. Transplantation 43: 913–915, 1987

    PubMed  CAS  Google Scholar 

  • Vine W, Bowers LD. Cyclosporine: structure, pharmacokinetics, and therapeutic drug monitoring. Critical Reviews in Clinical Laboratory Sciences 25: 275–311, 1987

    Article  PubMed  CAS  Google Scholar 

  • Wadhwa NK, Schroeder TJ, O’Flaherty E, Pesce AJ, Myre SA, et al. The effect of oral metoclopramide on the absorption of cyclosporine. Transplantation 43: 211–213, 1987a

    Article  PubMed  CAS  Google Scholar 

  • Wadhwa NK, Schroeder TJ, Pesce AJ, Myre SA, Clardy CW, et al. Cyclosporine drug interactions: a review. Therapeutic Drug Monitoring 9: 399–406, 1987b

    Article  PubMed  CAS  Google Scholar 

  • Wang CP, Burckart GJ, Venkataramanan R, Ptachcinski RJ, Cuellar RE, et al. Cyclosporine metabolite profiles in the blood of liver transplant patients. Transplantation Proceedings 20 (Suppl. 1): 173–175, 1988

    PubMed  Google Scholar 

  • Wassef R, Cohen Z, Langer B. In vivo interaction of cyclosporine and Intralipid. Transplantation 41: 266–278, 1986

    Article  PubMed  CAS  Google Scholar 

  • Wenk M, Follath F. Temperature dependency of apparent cyclosporin A concentrations in plasma. Clinical Chemistry 29: 1865, 1983

    PubMed  CAS  Google Scholar 

  • Whiting PH, Barnard N, Neilsch A, Simpson JG, Burke MD. Interactions between cyclosporin A, indomethacin and 16, 16-dimethyl prostaglandin E2: effects on renal, hepatic and gastrointestinal toxicity in the rat. British Journal of Experimental Pathology 68: 777–786, 1987

    PubMed  CAS  Google Scholar 

  • Yee GC, Kennedy MS, Storb R, Thomas ED. Effect of hepatic dysfunction on oral cyclosporine pharmacokinetics in marrow transplant patients. Blood 64: 1277–1279, 1984a

    PubMed  CAS  Google Scholar 

  • Yee GC, Kennedy MS, Storb R, Thomas ED. Pharmacokinetics of intravenous cyclosporine in bone marrow transplant patients. Transplantation 38: 511–513, 1984b

    Article  PubMed  CAS  Google Scholar 

  • Yee GC, Lennon TP, Gmur DJ, Kennedy MS, Deeg HJ. Age-dependent cyclosporine: pharmacokinetics in marrow transplant recipients. Clinical Pharmacology and Therapeutics 40: 438–443, 1986

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Pharmacology, University of Padova, Largo E. Meneghetti 2, 35131, Padova, Italy

    Vanni Rodighiero

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Rodighiero, V. Therapeutic Drug Monitoring of Cyclosporin. Clin-Pharmacokinet 16, 27–37 (1989). https://doi.org/10.2165/00003088-198916010-00002

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