Pharmacokinetic optimization of immunosuppressive therapy in thoracic transplantation: part I.
Although immunosuppressive treatments and therapeutic drug monitoring (TDM) have significantly contributed to the increased success of thoracic transplantation, there is currently no consensus on the best immunosuppressive strategies. Maintenance therapy typically consists of a triple-drug regimen including corticosteroids, a calcineurin inhibitor (ciclosporin or tacrolimus) and either a purine synthesis antagonist (mycophenolate mofetil or azathioprine) or a mammalian target of rapamycin inhibitor (sirolimus or everolimus). The incidence of acute and chronic rejection and of mortality after thoracic transplantation is still high compared with other types of solid organ transplantation. The high allogenicity and immunogenicity of the lungs justify the use of higher doses of immunosuppressants, putting lung transplant recipients at a higher risk of drug-induced toxicities. All immunosuppressants are characterized by large intra- and interindividual variability of their pharmacokinetics and by a narrow therapeutic index. It is essential to know their pharmacokinetic properties and to use them for treatment individualization through TDM in order to improve the treatment outcome. Unlike the kidneys and the liver, the heart and the lungs are not directly involved in drug metabolism and elimination, which may be the cause of pharmacokinetic differences between patients from all of these transplant groups. TDM is mandatory for most immunosuppressants and has become an integral part of immunosuppressive drug therapy. It is usually based on trough concentration (C(0)) monitoring, but other TDM tools include the area under the concentration-time curve (AUC) over the (12-hour) dosage interval or the AUC over the first 4 hours post-dose, as well as other single concentration-time points such as the concentration at 2 hours. Given the peculiarities of thoracic transplantation, a review of the pharmacokinetics and TDM of the main immunosuppressants used in thoracic transplantation is presented in this article. Even more so than in other solid organ transplant populations, their pharmacokinetics are characterized by wide intra- and interindividual variability in thoracic transplant recipients. The pharmacokinetics of ciclosporin in heart and lung transplant recipients have been explored in a number of studies, but less is known about the pharmacokinetics of mycophenolate mofetil and tacrolimus in these populations, and there are hardly any studies on the pharmacokinetics of sirolimus and everolimus. Given the increased use of these molecules in thoracic transplant recipients, their pharmacokinetics deserve to be explored in depth. There are very few data, some of which are conflicting, on the practices and outcomes of TDM of immunosuppressants after thoracic transplantation. The development of sophisticated TDM tools dedicated to thoracic transplantation are awaited in order to accurately evaluate the patients' exposure to drugs in general and, in particular, to immunosuppressants. Finally, large cohort TDM studies need to be conducted in thoracic transplant patients in order to identify the most predictive exposure indices and their target values, and to validate the clinical usefulness of improved TDM in these conditions. In part I of the article, we review the pharmacokinetics and TDM of calcineurin inhibitors. In part II, we will review the pharmacokinetics and TDM of mycophenolate and mammalian target of rapamycin inhibitors, and provide an overall discussion along with perspectives.
Monchaud
Caroline
C
INSERM Unit 850, CHU Limoges, University of Limoges, Limoges, France.
Marquet
Pierre
P
D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000493:pharmacokinetics / Q000627:therapeutic use; D016903:Drug Monitoring; D016027:Heart Transplantation; D016041:Heart-Lung Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016040:Lung Transplantation; D010372:Pediatrics; D016559:Tacrolimus / Q000493:pharmacokinetics / Q000627:therapeutic use
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D016559:Tacrolimus
Ann Pharmacother. 2003 Dec;37(12):1761-7
14632536
Clin Chem. 2001 Sep;47(9):1679-87
11514403
Clin Pharmacokinet. 2007;46(1):13-58
17201457
Ther Drug Monit. 2005 Aug;27(4):417-21
16044096
Clin Pharmacokinet. 2005;44(8):769-86
16029064
Ther Drug Monit. 2008 Feb;30(1):113-6
18223473
Transplant Proc. 2005 Jun;37(5):2231-9
15964386
Ther Drug Monit. 1998 Aug;20(4):390-5
9712463
Transplant Proc. 2004 Mar;36(2 Suppl):509S-513S
15041398
J Heart Lung Transplant. 2008 Feb;27(2):141-9
18267219
Transpl Immunol. 1997 Sep;5(3):225-32
9402690
Transplant Proc. 2002 Dec;34(8):3246-8
12493435
Transplantation. 2002 Mar 27;73(6):953-9
11923699
Transplant Proc. 1997 Aug;29(5):2450-3
9270807
Pharmacol Toxicol. 2000 Oct;87(4):182-4
11097273
Clin Transplant. 2004 Apr;18(2):148-51
15016128
Transplant Proc. 2005 Mar;37(2):1355-9
15848719
Ther Drug Monit. 2003 Feb;25(1):28-35
12548141
AAPS J. 2004 Oct 15;6(4):e28
15760093
J Heart Lung Transplant. 2001 Feb;20(2):191
11250328
Transplantation. 2003 May 15;75(9):1437-43
12792493
J Heart Lung Transplant. 2005 Aug;24(8):1076-80
16102443
Transplantation. 2003 Aug 27;76(4):683-8
12973109
J Am Soc Nephrol. 2001 Apr;12(4):828-833
11274245
Clin Pharmacokinet. 2001;40(8):573-85
11523724
J Heart Lung Transplant. 2004 Oct;23(10):1170-4
15477111
Clin Pharmacol Ther. 2004 May;75(5):422-33
15116055
Clin Pharmacokinet. 1998 Jun;34(6):429-55
9646007
Transplantation. 1999 Dec 27;68(12):1839-42
10628760
Transplant Proc. 2004 Oct;36(8):2386-7
15561257
Eur Respir J. 1997 Nov;10(11):2630-7
9426106
Ther Drug Monit. 2005 Jun;27(3):315-21
15905802
Ann Pharmacother. 2002 Jun;36(6):981-5
12022896
Ther Drug Monit. 2003 Jun;25(3):407-14
12766573
Transplantation. 2003 Sep 27;76(6):903-8
14508352
Clin Pharmacokinet. 2002;41(2):115-35
11888332
Kidney Int. 2002 Sep;62(3):1060-7
12164891
J Heart Lung Transplant. 2002 Sep;21(9):1016-21
12231373
Br J Clin Pharmacol. 1992 Dec;34(6):513-20
1493084
Clin Pharmacol Ther. 1998 Dec;64(6):672-83
9871432
J Heart Lung Transplant. 2005 Dec;24(12):2148-52
16364864
Eur J Clin Pharmacol. 2000 Sep;56(6-7):481-7
11049011
Eur J Clin Pharmacol. 1995;48(3-4):285-9
7589056
Clin Pharmacokinet. 2004;43(4):253-66
15005639
Transplantation. 2004 Aug 27;78(4):591-8
15446320
Clin Pharmacokinet. 2006;45(11):1077-97
17048973
Clin Pharmacol Ther. 2001 Sep;70(3):247-54
11557912
Transplant Proc. 1997 Feb-Mar;29(1-2):599-601
9123148
J Pharmacokinet Biopharm. 1981 Aug;9(4):503-12
7310648
Ther Drug Monit. 2006 Dec;28(6):720-5
17164686
Am J Respir Crit Care Med. 2001 Feb;163(2):498-502
11179130
J Heart Lung Transplant. 2005 Feb;24(2):119-30
15701425
Transplant Proc. 1998 Jun;30(4):1261-3
9636512
J Heart Lung Transplant. 2008 Jan;27(1):72-7
18187090
Ther Drug Monit. 2004 Dec;26(6):600-8
15570183
Ther Drug Monit. 1999 Feb;21(1):2-7
10051048
Nephrol Dial Transplant. 1999 Mar;14(3):706-8
10193823
Clin Pharmacol Ther. 1993 Aug;54(2):205-18
8354028
Am J Transplant. 2005 Jun;5(6):1383-91
15888045
Clin Transplant. 1998 Jun;12(3):243-9
9642517
Clin Pharmacokinet. 2005;44(8):837-47
16029068
J Heart Lung Transplant. 2007 Aug;26(8):782-95
17692782
Clin Pharmacokinet. 2001;40(5):375-82
11432538
Ther Drug Monit. 2005 Jun;27(3):354-61
15905807
Ther Drug Monit. 2006 Apr;28(2):145-54
16628123
J Heart Lung Transplant. 2007 Jun;26(6):584-92
17543781
Am J Transplant. 2006 Jan;6(1):169-77
16433771
Transplant Proc. 2002 Aug;34(5):1881-3
12176612
Transplant Proc. 1998 Jun;30(4):1519-20
9636618
Transplantation. 1999 Nov 15;68(9):1356-61
10573076
Clin Chem. 2005 Mar;51(3):586-92
15650031
Pediatr Transplant. 2002 Apr;6(2):147-52
12000472
Eur Respir J. 2004 Jan;23(1):159-71
14738248
Br J Pharmacol. 2001 Mar;132(5):1027-34
11226133
Ther Drug Monit. 2006 Oct;28(5):614-22
17038875
Clin Ther. 2006 Jun;28(6):893-905
16860172
Transplant Proc. 2000 May;32(3A Suppl):53S-56S
10814750
Ther Drug Monit. 2001 Apr;23(2):119-28
11294511
J Heart Lung Transplant. 2005 Dec;24(12):2120-8
16364860
Pharmacotherapy. 1998 Jul-Aug;18(4):847-50
9692659
Br J Clin Pharmacol. 2005 Jan;59(1):18-27
15606436
Clin Chem. 1988 Oct;34(10):2012-5
3048779
Ther Drug Monit. 1992 Aug;14(4):275-80
1519300
Ther Drug Monit. 1999 Feb;21(1):17-26
10051050
Clin Chem. 1999 Mar;45(3):419-22
10053049
Ther Drug Monit. 2001 Feb;23(1):35-8
11206040
J Heart Lung Transplant. 2006 Aug;25(8):928-34
16890113
J Heart Lung Transplant. 2006 Oct;25(10):1223-9
17045935
J Heart Lung Transplant. 2001 Oct;20(10):1035-43
11595558
J Heart Lung Transplant. 2005 May;24(5):517-25
15896747
Transplantation. 1995 Feb 15;59(3):333-40
7871561
Ther Drug Monit. 2006 Aug;28(4):491-504
16885716
Clin Chem. 1991 Nov;37(11):1905-8
1934462
J Heart Lung Transplant. 2005 Apr;24(4 Suppl):S206-9; discussion S210-1
15774324
Ther Drug Monit. 2008 Apr;30(2):138-42
18367972
J Heart Lung Transplant. 2003 Oct;22(10):1117-25
14550821
J Heart Lung Transplant. 2005 Oct;24(10):1614-8
16210138
Br J Clin Pharmacol. 1982 Aug;14(2):247-56
7104175
J Heart Lung Transplant. 1999 Feb;18(2):143-9
10194038
Ther Drug Monit. 2002 Jun;24(3):390-9
12021631
Transplantation. 1996 Dec 27;62(12):1744-52
8990355
Transplantation. 2001 Sep 27;72(6):1024-32
11579295
J Heart Lung Transplant. 2006 Jun;25(6):619-25
16730566
Transplantation. 2003 Jun 27;75(12):2082-5
12829916
Drugs. 2007;67(11):1531-9
17661526
J Clin Pharmacol. 2003 Feb;43(2):141-7
12616666
Ther Drug Monit. 2008 Aug;30(4):419-27
18641552
Ther Drug Monit. 2007 Feb;29(1):96-102
17304156
J Heart Lung Transplant. 2002 Mar;21(3):297-310
11897517
Transplantation. 2005 Mar 15;79(5):577-83
15753847
Eur J Clin Pharmacol. 2003 Apr;58(12):813-20
12698308
J Clin Pharmacol. 1999 Nov;39(11):1155-61
10579146
Ther Drug Monit. 1999 Feb;21(1):35-43
10051052
Curr Gastroenterol Rep. 2007 Aug;9(4):280-5
17883974
Proteomics. 2004 Sep;4(9):2728-38
15352247
Circulation. 2004 Oct 26;110(17):2694-700
15262845
J Heart Lung Transplant. 2005 Dec;24(12):2137-43
16364862
Transplant Proc. 2001 Feb-Mar;33(1-2):1080-1
11267199
N Engl J Med. 2003 Aug 28;349(9):847-58
12944570
Am J Transplant. 2005 Jun;5(6):1477-82
15888057
Transpl Int. 2005 Jan;18(1):116-24
15612993
Clin Pharmacokinet. 2002;41(1):71-80
11825098
Ther Drug Monit. 2001 Apr;23(2):100-14
11294509
Transplantation. 1999 Jul 27;68(2):261-6
10440399
Ther Drug Monit. 2008 Jun;30(3):282-91
18520599
Clin Pharmacokinet. 2005;44(12):1317-28
16372829
Transplant Proc. 1999 Feb-Mar;31(1-2):1024-5
10083455
J Heart Lung Transplant. 1998 Sep;17(9):849-53
9773855
N Engl J Med. 2003 Sep 18;349(12):1157-67
13679531
Transplant Proc. 2001 Feb-Mar;33(1-2):1572-5
11267425
J Heart Lung Transplant. 1997 Mar;16(3):268-74
9087869
Ther Drug Monit. 2002 Apr;24(2):310-4
11897977
J Heart Lung Transplant. 2003 Jul;22(7):715-22
12873538
Transplant Proc. 2005 Nov;37(9):4014-7
16386613
J Heart Lung Transplant. 2001 Aug;20(8):897-900
11502412
Clin Pharmacokinet. 2004;43(10):623-53
15244495
BioDrugs. 2001;15(5):279-90
11437692
J Heart Lung Transplant. 2001 Apr;20(4):431-8
11295581
Transplantation. 1995 Feb 27;59(4):505-11
7878754
Transplantation. 2000 Jun 15;69(11):2326-30
10868634
Pharmacol Res. 2001 Jun;43(6):547-51
11419964
Transplant Proc. 2005 Jun;37(5):2240-3
15964387
Clin Transplant. 1997 Oct;11(5 Pt 1):399-405
9361930
Am J Transplant. 2004 Dec;4(12):2126-31
15575918
Transplant Proc. 2000 Mar;32(2):446-8
10715475
Br J Clin Pharmacol. 1997 Dec;44(6):537-42
9431828
J Chromatogr B Analyt Technol Biomed Life Sci. 2007 Jun 1;852(1-2):674-8
17350903
Transplant Proc. 1998 Aug;30(5):2200-3
9723440
N Engl J Med. 1995 Sep 7;333(10):621-7
7637722
Am J Transplant. 2002 Feb;2(2):148-56
12099517
Am J Transplant. 2007 Nov;7(11):2496-503
17908276
Drug Metab Dispos. 2005 Jan;33(1):139-46
15470161
Ther Drug Monit. 2005 Apr;27(2):116-22
15795639
Transplant Proc. 2003 Aug;35(5):1988-91
12962871
J Heart Lung Transplant. 2005 Sep;24(9):1343-6
16143255
Ther Drug Monit. 1998 Jun;20(3):284-93
9631925
J Heart Lung Transplant. 2004 Sep;23(9):1035-9
15454168
Transplantation. 1999 Jul 15;68(1):55-62
10428267
J Heart Lung Transplant. 1999 Mar;18(3):175-6
10328140
Clin Biochem. 2001 Feb;34(1):17-22
11239510
Clin Pharmacokinet. 2004;43(2):83-95
14748618
Clin Chem. 1990 Aug;36(8 Pt 1):1474-8
2387045
Transplant Proc. 2004 Oct;36(8):2388-9
15561258
Transplantation. 2008 Jun 27;85(12):1675-85
18580456
Transplant Proc. 2003 Aug;35(5):1992-3
12962872
Clin Transplant. 2008 Jan-Feb;22(1):35-40
18217903
Br J Pharmacol. 1999 Mar;126(5):1075-82
10204993
Transplant Proc. 2001 May;33(3):2163-4
11377487
Transplantation. 2001 Oct 27;72(8):1444-50
11685118
Am J Transplant. 2004 Dec;4(12):2045-51
15575908
Clin Pharmacokinet. 2006;45(11):1135-48
17048977
Am J Transplant. 2004;4 Suppl 9:38-53
15113354
Clin Ther. 2002 Mar;24(3):330-50; discussion 329
11952020
Transplantation. 2008 Apr 15;85(7):992-9
18408580
Ther Drug Monit. 1995 Dec;17(6):621-4
8588231
Ther Drug Monit. 2006 Feb;28(1):138; author reply 139
16418708
J Heart Lung Transplant. 2007 Aug;26(8):769-81
17692781
Transplant Proc. 2001 May;33(3):2386-9
11377570
Ther Drug Monit. 2005 Oct;27(5):666-76
16175142
Clin Pharmacokinet. 2000 May;38(5):427-47
10843461
Transplant Proc. 1999 Feb-Mar;31(1-2):84-7
10083018
Ther Drug Monit. 2001 Apr;23(2):163-8
11294518
Transplantation. 1999 Jul 15;68(1):67-71
10428269
J Heart Lung Transplant. 2001 Jul;20(7):734-8
11448799
Transplant Proc. 2004 Mar;36(2 Suppl):331S-336S
15041363
Ther Drug Monit. 2004 Feb;26(1):23-30
14749545
Clin Pharmacol Ther. 2008 May;83(5):711-7
17851563
J Heart Lung Transplant. 2001 May;20(5):511-7
11343977
J Heart Lung Transplant. 2001 Feb;20(2):192
11250330
Clin Pharmacol Ther. 1993 May;53(5):544-54
8491066
Ther Drug Monit. 1990 Nov;12(6):520-4
2274997
J Heart Lung Transplant. 2003 May;22(5):587-90
12742423
Pharmacotherapy. 2006 Sep;26(9):1232-40
16945044
J Heart Lung Transplant. 2000 Nov;19(11):1071-6
11077224
J Heart Lung Transplant. 2003 Feb;22(2):210-3
12581772
Kidney Int. 2006 Sep;70(6):1019-25
16837925
J Clin Gastroenterol. 2002 Jan;34(1):34-9
11743243
Clin Ther. 2008 Apr;30(4):673-83
18498916
Transplant Proc. 2002 Aug;34(5):1836-8
12176596
Am J Transplant. 2004 Sep;4(9):1495-500
15307837
Transplantation. 2004 Feb 27;77(4):568-74
15084937
Ann Pharmacother. 2006 Sep;40(9):1509-16
16882870
Clin Transplant. 2002 Jun;16(3):196-201
12010143
Clin Transplant. 2003 Apr;17(2):144-50
12709082
J Heart Lung Transplant. 2001 Mar;20(3):330-9
11257560
Transplantation. 1998 Aug 27;66(4):507-15
9734496
Clin Pharmacol Ther. 2004 May;75(5):434-47
15116056
J Heart Lung Transplant. 2006 Apr;25(4):440-6
16563975
J Heart Lung Transplant. 2007 Dec;26(12):1223-8
18096472
Transplant Proc. 2002 Feb;34(1):142-3
11959225