Cyclosporin Pharmacokinetics after Intravenous and Oral Administration in Patients with Crohn’s Disease
Scand J Gastroenterol Downloaded from informahealthcare.com by University of Zuerich Zentrum fuer Zahn Mund und on 08/17/13 For personal use only.
J. BRYNSKOV, L. FREUND, M. C . CAMPANINI & J. P. KAMPMANN Dept. of Internal Medicine and Gastroenterology C, Herlev University Hospital, Herlev, Copenhagen; Dept. of Internal Medicine and Gastroenterology, Aalborg Hospital, Aalborg; Dept. of Medicine, Dronninglund Hospital, Dronninglund; Dept. of Medicine P, Bispebjerg University
Hospital, Copenhagen; Denmark; and Dept. of Internal Medicine and Gastroenterology, Ospedale Maggiore. Milan, Italy Brynskov J , Freund L, Campanini MC, Kampmann JP. Cyclosporin pharmacokinetics after intravenous and oral administration in patients with Crohn’s disease. Scand J Gastroenterol 1992;27:961-967. Cyclosporin kinetics were estimated after single-dose intravenous and oral administration in 12 patients with Crohn’s disease in accordance with a three-compartment model with zero-order inputs. Cyclosporin was measured in whole blood with a specific monoclonal radioimmunoassay.The median bioavailability (f) was 23.7% (range, &49.1%); the distribution volume at steady state, 2.3 I/kg (range, 1.0-3.5 I/kg); clearance (CL), 7.6 ml/min/kg (range, 4.8-10.8 ml/min/kg); and tl/2(z)7.9 h (range, 3.2-13.9 h). Both the extent and rate of bioavailability were significantly lower in six of the patients, who had low or undetectable cyclosporin levels during a preceding therapeutic trial. After repeated oral administration significant correlations were found between the single-dose f/CL ratios and the steady-state blood concentrations, indicating that the kinetics did not change markedly with time. We conclude that the disposition kinetics of cyclosporin in patients with Crohn’s disease are comparable to those of other groups. whereas the bioavailability may be decreased. It is suggested that cyclosporin levels should be monitored closely, and intravenous treatment should be considered in patients with a rapid gut transit time. because cyclosporin absorption seems to follow zero-order kinetics. Key words: Crohn’s disease; cyclosporin; inflammatory bowel disease; pharmacukinetics; ulcerative
colitis J . Brynskou, M . D . , Dept. of Internal Medicine and Gastroenterology C, Herleu University Hospital, DK-2730 Herleu, Copenhagen, Denmark
Cyclosporin is a potent immunosuppressant with a selective effect on T-cell functions (1). We have recently reported the final results (2) of the first controlled trial of cyclosporin treatment in patients with active chronic Crohn’s disease (3). Cyclosporin was superior to placebo at month 3 (trial endpoint) and in the 3-month tapering-off period but not at follow-up, indicating that a short course of cyclosporin treatment does not imply a long-term improvement (2,3). In that trial cyclosporin malabsorption was suspected in 10 of 37 (27%) patients, among whom 3 (8%) apparently had complete and 7 (19%) partial malabsorption (3). Although cyclosporin malabsorption was noted both in patients with and without improvement, there was a consistent tendency (significant at month 1) towards higher cyclosporin blood levels in patients who were improved (3). Furthermore, a few casuistic cases with low or variable cyclosporin levels on oral treatment have been reported to improve on intravenous administration (4,5). Cyclosporin kinetics have been reported to be highly variable among both transplant patients and healthy subjects, but only limited data are available from patients with gastrointestinal disorders (6-8),including inflammatory bowel disease (9), in which cyclosporin levels occasionally may be misleading (10). The aim of this study was t o evaluate the kinetics of
cyclosporin in patients with Crohn’s disease, particularly in patients with apparent malabsorption of the drug. PATIENTS A N D M E T H O D S The design of the original controlled trial and the patient selection criteria have been described previously (3). In brief, 71 patients with active chronic Crohn’s disease (11, 12) were randomized to 3-month cyclosporin treatment with a low starting dose (5-7.5 mg/kg/day) ( n = 37) or to placebo ( n = 34). Twelve of the above-mentioned patients, six men and six women with a median age of 36.5 years (range, 2460 years), a body weight of 63 kg (range, 3 6 9 3 kg), and a disease duration of 4.5 years (range, 1-22 years), were studied after completion of the therapeutic trial (2). Additional clinical data are presented in Table I .
Selection criteria Among the 10 patients with suspected cyclosporin malabsorption during the preceding therapeutic trial (3), six patients agreed to participate in the present investigation. Two of these patients apparently had complete cyclosporin malabsorption, as suggested from persistently undetectable 12-h trough whole blood cyclosporin concentrations ( 311. 15. Gibaldi M, Perrier D. Pharmacokinetics. 2nd edition. New York: Dekker, 1982. 16. Grevel J, Niiesch E, Abisch E , Kutz K. Pharmacokinetics of oral cyclosporin A (Sandimmun) in healthy subject. Eur J Clin Pharmacol 1986;31:211-6. 17. Reymond J-P, Steimer J-L, Niederberger W. On the dose dependency of cyclosporin A absorption and disposition in healthy volunteers. J Pharmacokin Biopharm 1988;16:331-53. 18. van de Kamer JH, Huinink HTB, Weyers HA. Rapid method for determination of fat in faeces. J Biol Chem 1949;177:42331.
Scand J Gastroenterol Downloaded from informahealthcare.com by University of Zuerich Zentrum fuer Zahn Mund und on 08/17/13 For personal use only.
Cyclosporin Pharmacokinetics 19. Gupta SK, Manfro RC, Tomlanovich SJ, Garmbertoglio JG, Garovoy MR, Benet LZ. Effect of food on the pharmacokinetics of cyclosporine in healthy subjects following oral and intravenous administration. J Clin Pharmacol 1990;30:643-53. 20. Sandborn WJ, Strong RM, Forland SC, Chase RE, Cutler RE. The pharmacokinetics and colonic tissue concentrations of cyclosporin after IV, oral, and enema administration. J Clin Pharmacol 1991;31:7680. 21. Wadhwa NK, Schroeder TJ, O'Flaherty E, Pesce AJ, Myre SA, First MR. The effect of oral metoclopramide on the absorption of cyclosporin. Transplant Proc 1987;19:1730-3. 22. Venkataramanan R, Burckart GJ, Ptachinski RJ. Pharmacokinetics and monitoring of cyclosporine following orthotopic liver transplantation. Semin Liver Dis 1985;5:357-68. 23. Drewe J, Beglinger C, Kissel T. The absorption site of cyclosporin in the human gastrointestinal tract. Br J Clin Pharmacol 1992;33:39-43. 24. Robert: R, Sketris IS, Abraham I, Givner ML, MacDonald AS. Cyclosporine absorption in two patients with short bowel syndrome. Drug Intell Clin Pharm 1988;22:570-2. 25. Kolars JC, Awni WM, Merion RM, Watkins PB. First-pass metabolism of cyclosporin by the gut. Lancet 1991;338:148890. 26. Atkinson K, Biggs JC, Britton K, et al. Oral administration of cyclosporin A for recipients of allogeneic marrow transplants: implications of clinical gut dysfunction. Br J Haematol 1984; 56:22>3 1. 27. Holt DW, Marsden JT, Johnston A. Quality assessment of cyclosporine measurements: comparison of current methods. Transplant Proc 1990;22:1234-9. 28. Speck RF, Frey FJ, Frey BM. Cyclosporine kinetics in renal transplant patients as assessed by high-performance liquid chromatography and radioimmunoassay using monoclonal and polyclonal antibodies. Transplantation 1989;47:802-6. 29. Yee GC, Kennedy MS, Storb R, Thomas ED. Pharmacokinetics of intravenous cyclosporine in bone marrow transplant patients. Transplantation 1984;38:5 11-1 3. 30. Ptachcinski RJ, Venkataramanan R, Rosenthal JT, Burckart GJ, Taylor RJ, Hakala TR. Cyclosporine kinetics in renal transplantation. Clin Pharmacol Ther 1985;38:296300. 31. Ptachcinski RJ, Burckart GJ, Rosenthal JT, et al. Cyclosporine pharmacokinetics in children following cadaveric renal transplantation. Transplant Proc 1986;18:7667. Received 12 March 1992 Accepted 7 July 1992
967
32. Ptachcinski RJ, Venkataramanan R, Burckart GJ, et al. Cyclosporine kinetics in healthy volunteers. J Clin Pharmacol 1987; 27:243-8. 33. Groen PC. Cyclosporine, low-density lipoprotein, and cholesterol. Mayo Clin Proc 1988;63:1012-21. 34. Canafax DM, Cipolle RJ, Hrushesky WJH, et al. The chronopharmacokinetics of cyclosporin and its metabolites in recipients of pancreas allografts. Transplant Proc 1988;20 Suppl2:471-7. 35. Lichtinger S, Present DH. Cyclosporin in treatment of severe active ulcerative colitis. Lancet 1990;336:1&9.
Appendix. Kinetic variables -
AUC, , AUC, : I,
Areas under the blood-concentration-time profiles after intravenous (i.v.) and per oral ( p . 0 . ) administration. Maximum drug concentration in blood. Total blood clearance. Extent of bioavailability of the p.0. dose. In case of two absorption phases, f was calculated as f = f( l ) + f(2). Zero-order absorption rate constant ( K J for drug transfer into the central compartment (VJ. In case of two absorption phases, the second phase was characterized as K,,(2)/VC. Zero-order infusion and absorption times. In case of two absorption phases, the second phase was characterized as t,,(2) (h). Lag time of appearance of drug in blood after oral administration. In case of two absorption phases, the second absorption phase was characterized as tkdg(2). Time to maximum blood concentration. Half-lives associated with the first, second (three-compartment model), and terminal phases of the blood-concentration-time profiles. Volume of distribution at steady state. Volume of distribution associated the terminal phase of the blood-concentration-time profiles.
Scand J Gastroenterol Downloaded from informahealthcare.com by University of Zuerich Zentrum fuer Zahn Mund und on 08/17/13 For personal use only.
J. BRYNSKOV, L. FREUND, M. C . CAMPANINI & J. P. KAMPMANN Dept. of Internal Medicine and Gastroenterology C, Herlev University Hospital, Herlev, Copenhagen; Dept. of Internal Medicine and Gastroenterology, Aalborg Hospital, Aalborg; Dept. of Medicine, Dronninglund Hospital, Dronninglund; Dept. of Medicine P, Bispebjerg University
Hospital, Copenhagen; Denmark; and Dept. of Internal Medicine and Gastroenterology, Ospedale Maggiore. Milan, Italy Brynskov J , Freund L, Campanini MC, Kampmann JP. Cyclosporin pharmacokinetics after intravenous and oral administration in patients with Crohn’s disease. Scand J Gastroenterol 1992;27:961-967. Cyclosporin kinetics were estimated after single-dose intravenous and oral administration in 12 patients with Crohn’s disease in accordance with a three-compartment model with zero-order inputs. Cyclosporin was measured in whole blood with a specific monoclonal radioimmunoassay.The median bioavailability (f) was 23.7% (range, &49.1%); the distribution volume at steady state, 2.3 I/kg (range, 1.0-3.5 I/kg); clearance (CL), 7.6 ml/min/kg (range, 4.8-10.8 ml/min/kg); and tl/2(z)7.9 h (range, 3.2-13.9 h). Both the extent and rate of bioavailability were significantly lower in six of the patients, who had low or undetectable cyclosporin levels during a preceding therapeutic trial. After repeated oral administration significant correlations were found between the single-dose f/CL ratios and the steady-state blood concentrations, indicating that the kinetics did not change markedly with time. We conclude that the disposition kinetics of cyclosporin in patients with Crohn’s disease are comparable to those of other groups. whereas the bioavailability may be decreased. It is suggested that cyclosporin levels should be monitored closely, and intravenous treatment should be considered in patients with a rapid gut transit time. because cyclosporin absorption seems to follow zero-order kinetics. Key words: Crohn’s disease; cyclosporin; inflammatory bowel disease; pharmacukinetics; ulcerative
colitis J . Brynskou, M . D . , Dept. of Internal Medicine and Gastroenterology C, Herleu University Hospital, DK-2730 Herleu, Copenhagen, Denmark
Cyclosporin is a potent immunosuppressant with a selective effect on T-cell functions (1). We have recently reported the final results (2) of the first controlled trial of cyclosporin treatment in patients with active chronic Crohn’s disease (3). Cyclosporin was superior to placebo at month 3 (trial endpoint) and in the 3-month tapering-off period but not at follow-up, indicating that a short course of cyclosporin treatment does not imply a long-term improvement (2,3). In that trial cyclosporin malabsorption was suspected in 10 of 37 (27%) patients, among whom 3 (8%) apparently had complete and 7 (19%) partial malabsorption (3). Although cyclosporin malabsorption was noted both in patients with and without improvement, there was a consistent tendency (significant at month 1) towards higher cyclosporin blood levels in patients who were improved (3). Furthermore, a few casuistic cases with low or variable cyclosporin levels on oral treatment have been reported to improve on intravenous administration (4,5). Cyclosporin kinetics have been reported to be highly variable among both transplant patients and healthy subjects, but only limited data are available from patients with gastrointestinal disorders (6-8),including inflammatory bowel disease (9), in which cyclosporin levels occasionally may be misleading (10). The aim of this study was t o evaluate the kinetics of
cyclosporin in patients with Crohn’s disease, particularly in patients with apparent malabsorption of the drug. PATIENTS A N D M E T H O D S The design of the original controlled trial and the patient selection criteria have been described previously (3). In brief, 71 patients with active chronic Crohn’s disease (11, 12) were randomized to 3-month cyclosporin treatment with a low starting dose (5-7.5 mg/kg/day) ( n = 37) or to placebo ( n = 34). Twelve of the above-mentioned patients, six men and six women with a median age of 36.5 years (range, 2460 years), a body weight of 63 kg (range, 3 6 9 3 kg), and a disease duration of 4.5 years (range, 1-22 years), were studied after completion of the therapeutic trial (2). Additional clinical data are presented in Table I .
Selection criteria Among the 10 patients with suspected cyclosporin malabsorption during the preceding therapeutic trial (3), six patients agreed to participate in the present investigation. Two of these patients apparently had complete cyclosporin malabsorption, as suggested from persistently undetectable 12-h trough whole blood cyclosporin concentrations ( 311. 15. Gibaldi M, Perrier D. Pharmacokinetics. 2nd edition. New York: Dekker, 1982. 16. Grevel J, Niiesch E, Abisch E , Kutz K. Pharmacokinetics of oral cyclosporin A (Sandimmun) in healthy subject. Eur J Clin Pharmacol 1986;31:211-6. 17. Reymond J-P, Steimer J-L, Niederberger W. On the dose dependency of cyclosporin A absorption and disposition in healthy volunteers. J Pharmacokin Biopharm 1988;16:331-53. 18. van de Kamer JH, Huinink HTB, Weyers HA. Rapid method for determination of fat in faeces. J Biol Chem 1949;177:42331.
Scand J Gastroenterol Downloaded from informahealthcare.com by University of Zuerich Zentrum fuer Zahn Mund und on 08/17/13 For personal use only.
Cyclosporin Pharmacokinetics 19. Gupta SK, Manfro RC, Tomlanovich SJ, Garmbertoglio JG, Garovoy MR, Benet LZ. Effect of food on the pharmacokinetics of cyclosporine in healthy subjects following oral and intravenous administration. J Clin Pharmacol 1990;30:643-53. 20. Sandborn WJ, Strong RM, Forland SC, Chase RE, Cutler RE. The pharmacokinetics and colonic tissue concentrations of cyclosporin after IV, oral, and enema administration. J Clin Pharmacol 1991;31:7680. 21. Wadhwa NK, Schroeder TJ, O'Flaherty E, Pesce AJ, Myre SA, First MR. The effect of oral metoclopramide on the absorption of cyclosporin. Transplant Proc 1987;19:1730-3. 22. Venkataramanan R, Burckart GJ, Ptachinski RJ. Pharmacokinetics and monitoring of cyclosporine following orthotopic liver transplantation. Semin Liver Dis 1985;5:357-68. 23. Drewe J, Beglinger C, Kissel T. The absorption site of cyclosporin in the human gastrointestinal tract. Br J Clin Pharmacol 1992;33:39-43. 24. Robert: R, Sketris IS, Abraham I, Givner ML, MacDonald AS. Cyclosporine absorption in two patients with short bowel syndrome. Drug Intell Clin Pharm 1988;22:570-2. 25. Kolars JC, Awni WM, Merion RM, Watkins PB. First-pass metabolism of cyclosporin by the gut. Lancet 1991;338:148890. 26. Atkinson K, Biggs JC, Britton K, et al. Oral administration of cyclosporin A for recipients of allogeneic marrow transplants: implications of clinical gut dysfunction. Br J Haematol 1984; 56:22>3 1. 27. Holt DW, Marsden JT, Johnston A. Quality assessment of cyclosporine measurements: comparison of current methods. Transplant Proc 1990;22:1234-9. 28. Speck RF, Frey FJ, Frey BM. Cyclosporine kinetics in renal transplant patients as assessed by high-performance liquid chromatography and radioimmunoassay using monoclonal and polyclonal antibodies. Transplantation 1989;47:802-6. 29. Yee GC, Kennedy MS, Storb R, Thomas ED. Pharmacokinetics of intravenous cyclosporine in bone marrow transplant patients. Transplantation 1984;38:5 11-1 3. 30. Ptachcinski RJ, Venkataramanan R, Rosenthal JT, Burckart GJ, Taylor RJ, Hakala TR. Cyclosporine kinetics in renal transplantation. Clin Pharmacol Ther 1985;38:296300. 31. Ptachcinski RJ, Burckart GJ, Rosenthal JT, et al. Cyclosporine pharmacokinetics in children following cadaveric renal transplantation. Transplant Proc 1986;18:7667. Received 12 March 1992 Accepted 7 July 1992
967
32. Ptachcinski RJ, Venkataramanan R, Burckart GJ, et al. Cyclosporine kinetics in healthy volunteers. J Clin Pharmacol 1987; 27:243-8. 33. Groen PC. Cyclosporine, low-density lipoprotein, and cholesterol. Mayo Clin Proc 1988;63:1012-21. 34. Canafax DM, Cipolle RJ, Hrushesky WJH, et al. The chronopharmacokinetics of cyclosporin and its metabolites in recipients of pancreas allografts. Transplant Proc 1988;20 Suppl2:471-7. 35. Lichtinger S, Present DH. Cyclosporin in treatment of severe active ulcerative colitis. Lancet 1990;336:1&9.
Appendix. Kinetic variables -
AUC, , AUC, : I,
Areas under the blood-concentration-time profiles after intravenous (i.v.) and per oral ( p . 0 . ) administration. Maximum drug concentration in blood. Total blood clearance. Extent of bioavailability of the p.0. dose. In case of two absorption phases, f was calculated as f = f( l ) + f(2). Zero-order absorption rate constant ( K J for drug transfer into the central compartment (VJ. In case of two absorption phases, the second phase was characterized as K,,(2)/VC. Zero-order infusion and absorption times. In case of two absorption phases, the second phase was characterized as t,,(2) (h). Lag time of appearance of drug in blood after oral administration. In case of two absorption phases, the second absorption phase was characterized as tkdg(2). Time to maximum blood concentration. Half-lives associated with the first, second (three-compartment model), and terminal phases of the blood-concentration-time profiles. Volume of distribution at steady state. Volume of distribution associated the terminal phase of the blood-concentration-time profiles.
