Integrated pharmacokinetics and pharmacodynamics in drug development.
Drug development is a complex, lengthy and expensive process. Pharmaceutical companies and regulatory authorities have recognised that the drug development process needs optimisation for efficiency in view of the return on investments. Pharmacokinetics and pharmacodynamics are the two main principles determining the relationship between dose and response. This article provides an update on integrated approaches towards drug development by linking pharmacokinetics, pharmacodynamics and disease aspects into mathematical models. Gradually, a transition is taking place from a rather empirical approach towards a modelling- and simulation-based approach to drug development. The main learning phases should be phases 0, I and II, whereas phase III studies should merely have a confirmatory purpose. In model-based drug development, mechanism-based mathematical models, which are iteratively refined along the path of development, incorporate the accumulating knowledge of the investigational drug, the disease and their mutual interference in different subsets of the target population. These models facilitate the design of the next study and improve the probability of achieving the projected efficacy and safety endpoints. In this article, several theoretical and practical aspects of an integrated approach towards drug development are discussed, together with some case studies from different therapeutic areas illustrating the application of pharmacokinetic/pharmacodynamic disease models at different stages of drug development.
Dingemanse
Jasper
J
Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland. jasper.dingemanse@actelion.com
Appel-Dingemanse
Silke
S
D002986:Clinical Trials as Topic / Q000379:methods; D016503:Drug Delivery Systems / Q000379:methods; D015195:Drug Design; D004345:Drug Industry / Q000191:economics / Q000379:methods; D006801:Humans; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism; D010599:Pharmacokinetics; D010601:Pharmacology, Clinical / Q000379:methods*
D004364:Pharmaceutical Preparations
J Pharm Sci. 1964 Mar;53:342-3
14185031
Clin Pharmacol Ther. 2001 Mar;69(3):89-95
11240971
Clin Pharmacokinet. 1998 Aug;35(2):151-66
9739481
J Pharm Pharm Sci. 2002 May-Aug;5(2):146-61
12207867
Clin Pharmacol Ther. 2001 Jul;70(1):33-41
11452242
J Vet Pharmacol Ther. 2004 Aug;27(4):211-8
15305849
Br J Clin Pharmacol. 2004 Dec;58(6):601-8
15563358
Adv Drug Deliv Rev. 2001 Mar 1;46(1-3):45-57
11259832
Antimicrob Agents Chemother. 2005 Sep;49(9):3944-7
16127078
J Pharm Sci. 1987 Apr;76(4):295-9
3298618
Clin Pharmacokinet. 1981 Nov-Dec;6(6):429-53
7032803
AAPS J. 2005 Oct 05;7(2):E363-73
16353916
J Pharmacol Exp Ther. 2004 Nov;311(2):830-5
15199095
J Pharmacokinet Pharmacodyn. 2006 Aug;33(4):441-59
16633890
AAPS J. 2005 Oct 07;7(3):E544-59
16353932
Invest New Drugs. 2003 May;21(2):195-223
12889740
Clin Pharmacokinet. 2005;44(4):331-47
15828849
J Pharmacokinet Pharmacodyn. 2003 Jun;30(3):221-35
14571692
Clin Pharmacol Ther. 1995 Dec;58(6):631-40
8529328
Pharmacoepidemiol Drug Saf. 2002 Sep;11(6):439-46
12426927
Biochem Pharmacol. 1990 Nov 1;40(9):2079-84
2242035
J Pharmacol Exp Ther. 2000 May;293(2):618-24
10773036
Eur J Drug Metab Pharmacokinet. 1993 Jan-Mar;18(1):31-9
8335037
Clin Pharmacokinet. 1997 Aug;33(2):142-52
9260036
Eur J Clin Pharmacol. 1996;51(1):59-67
8880053
Br J Pharmacol. 2001 Dec;134(8):1796-804
11739257
Br J Clin Pharmacol. 2004 Dec;58(6):618-31
15563360
Drug Discov Today. 2006 Sep;11(17-18):775-84
16935744
Pharm Res. 2005 Apr;22(4):603-12
15846468
Clin Pharmacokinet. 1996 Jun;30(6):463-81
8792058
Clin Pharmacol Ther. 1994 Oct;56(4):356-8
7955796
J Pharm Pharmacol. 2002 Jun;54(6):791-800
12078995
Clin Pharmacokinet. 2005;44(6):551-70
15932344
Clin Pharmacokinet. 1994 Sep;27(3):202-15
7988102
Methods Find Exp Clin Pharmacol. 2002;24 Suppl D:129-37
12575480
Clin Pharmacol Ther. 1999 Aug;66(2):140-51
10460068
J Pharmacokinet Pharmacodyn. 2002 Feb;29(1):1-24
12194533
Clin Pharmacokinet. 2002;41(1):1-6
11825093
Methods Find Exp Clin Pharmacol. 2004 Dec;26(10):781-8
15672121
Br J Clin Pharmacol. 1998 Mar;45(3):229-39
9517366
J Clin Pharmacol. 1997 May;37(5):355-62
9156368
Clin Pharmacol Ther. 1987 Oct;42(4):433-41
3665341
J Clin Psychopharmacol. 1995 Aug;15(4 Suppl 2):84S-94S
7593736
Clin Pharmacol Ther. 2005 Sep;78(3):260-77
16153397
Clin Pharmacol Ther. 1997 Oct;62(4):444-52
9357396
Annu Rev Pharmacol Toxicol. 2001;41:625-59
11264471
Biometrics. 1994 Jun;50(2):566-75
8068854
Res Vet Sci. 2002 Oct;73(2):105-14
12204627
Chembiochem. 2005 Sep;6(9):1592-600
16052607
Farmaco Sci. 1968 Oct;23(10):907-18
5712792
Annu Rev Pharmacol Toxicol. 2004;44:111-36
14744241
J Clin Pharmacol. 2003 Apr;43(4):329-41
12723454
Expert Opin Drug Deliv. 2005 May;2(3):519-32
16296772
J Clin Pharmacol. 2000 Dec;40(12 Pt 2):1399-418
11185661
Drug Metab Pharmacokinet. 2005 Jun;20(3):187-99
15988121
Anesthesiology. 1997 Jan;86(1):24-33
9009936
Stat Methods Med Res. 1999 Sep;8(3):217-45
10636336
J Clin Pharmacol. 2005 Oct;45(10):1123-36
16172177
Ann Pharmacother. 1996 Jan;30(1):12-9
8773159
AAPS J. 2005 Oct 07;7(3):E503-12
16353928
Curr Opin Drug Discov Devel. 2004 Jan;7(1):100-11
14982153
Pharmacogenomics. 2003 Jul;4(4):397-410
12831320
Clin Pharmacokinet. 2001;40(12):883-92
11735607
Pharm Res. 2005 Jul;22(7):1038-49
16028004
AAPS J. 2005 Oct 07;7(3):E532-43
16353931
Pharmacotherapy. 2005 Dec;25(12 Pt 2):146S-149S
16305285
Ann N Y Acad Sci. 2005 Aug;1053:505-18
16179559
Curr Drug Metab. 2002 Jun;3(3):289-309
12083322
J Clin Oncol. 2002 Dec 15;20(24):4713-21
12488418
Curr Opin Drug Discov Devel. 2002 Jan;5(1):116-26
11865665
Ther Drug Monit. 2000 Jun;22(3):354-65
10850405
J Exp Anim Sci. 1993 Sep;35(5-6):210-20
8218436
Clin Pharmacol Ther. 1996 Dec;60(6):619-35
8988064
Clin Pharmacokinet. 2001;40(5):317-25
11432535
Clin Pharmacol Ther. 2003 Jun;73(6):481-90
12811358
Clin Pharmacokinet. 2005;44(8):863-78
16029070
Eur J Pharm Sci. 2006 Oct 1;29(2):91-101
16831536
Clin Pharmacol Ther. 2000 Aug;68(2):175-88
10976549
Clin Pharmacokinet. 1997 Apr;32(4):259-67
9113436
Clin Pharmacol Ther. 1979 Mar;25(3):358-71
761446
J Pharm Sci. 1999 Nov;88(11):1101-6
10564055
Pharmacol Ther. 2000 Oct;88(1):33-58
11033383
J Clin Pharmacol. 2004 Jan;44(1):37-47
14681340
Eur J Pharm Sci. 2004 Feb;21(2-3):261-70
14757498
Ther Drug Monit. 1996 Aug;18(4):423-8
8857562
Trends Biotechnol. 2004 Aug;22(8):411-6
15283986
Clin Pharmacokinet. 2004;43(12):781-801
15355125
J Pharmacokinet Biopharm. 1993 Aug;21(4):457-78
8133465
Clin Pharmacol Ther. 1989 Nov;46(5):552-9
2684474
Nat Rev Drug Discov. 2004 Aug;3(8):711-5
15286737
Clin Pharmacokinet. 1999 Jul;37(1):41-58
10451782
Stat Med. 2004 Feb 28;23(4):531-44
14755387
Int J Antimicrob Agents. 2005 Feb;25(2):120-9
15664481
Can J Physiol Pharmacol. 2000 Mar;78(3):199-207
10721811
Clin Pharmacol Ther. 1992 Apr;51(4):465-73
1563216
Basic Clin Pharmacol Toxicol. 2005 Mar;96(3):182-92
15733213
Clin Pharmacol Ther. 1994 Sep;56(3):261-71
7924121
J Pharm Pharmacol. 2005 Jun;57(6):671-9
15969921
J Neurosci. 1995 Jan;15(1 Pt 2):821-9
7823183
J Clin Pharmacol. 2000 Dec;40(12 Pt 2):1419-27
11185662
Pharm Res. 2005 Sep;22(9):1432-7
16132354
Annu Rev Pharmacol Toxicol. 2000;40:209-34
10836134
Annu Rev Pharmacol Toxicol. 2001;41:347-66
11264461
Methods Find Exp Clin Pharmacol. 2002;24 Suppl D:139-44
12575481
Br J Clin Pharmacol. 1997 Apr;43(4):373-81
9146849
Cancer Chemother Pharmacol. 2006 Apr;57(4):412-26
16322990
Curr Pharm Des. 2003;9(11):891-902
12678873
Clin Pharmacol Ther. 1998 Jul;64(1):106-16
9695725
J Pharm Sci. 2004 Sep;93(9):2184-204
15295780
Curr Drug Metab. 2006 Jan;7(1):39-65
16454692
Anesthesiology. 1999 Aug;91(2):397-405
10443602
Pharm Res. 2002 Jan;19(1):87-91
11837705
J Pharmacokinet Pharmacodyn. 2004 Jun;31(3):243-68
15518246
Clin Pharmacol Ther. 1966 May-Jun;7(3):362-72
5937003
Clin Pharmacol Ther. 1994 Jul;56(1):1-8
8033486
Cancer Chemother Pharmacol. 2006 Apr;57(4):427-35
16322992
Ann Pharmacother. 1998 Oct;32(10):1008-12
9793590
Clin Pharmacokinet. 1999 Mar;36(3):211-31
10223169
J Pharmacokinet Biopharm. 1991 Jun;19(3):333-53
1875286
IDrugs. 2001 Sep;4(9):1017-20
15965846
AAPS J. 2005 Oct 05;7(2):E467-74
16353924
Xenobiotica. 1997 May;27(5):513-25
9179991
Drug Discov Today. 2006 Sep;11(17-18):773-4
16935743
Clin Pharmacokinet. 2000 May;38(5):449-59
10843462
Clin Pharmacokinet. 2003;42(12):997-1022
12959633
Clin Pharmacokinet. 1995 Feb;28(2):93-9
7736691
Antimicrob Agents Chemother. 2004 May;48(5):1441-53
15105091
Control Clin Trials. 1991 Dec;12(6):780-94
1665119
Invest New Drugs. 2001 May;19(2):163-9
11392450
Pharmacoeconomics. 2002;20 Suppl 3:11-29
12457422
Drug Metab Rev. 1997 Nov;29(4):923-56
9421680
Clin Cancer Res. 2005 Nov 15;11(22):7967-85
16299226
Curr Opin Pharmacol. 2005 Oct;5(5):495-9
16084767
Clin Pharmacokinet. 1998 Apr;34(4):323-33
9571304
Clin Pharmacol Ther. 2000 Nov;68(5):568-77
11103759
Rheumatology (Oxford). 2005 Jul;44(7):846-59
15855183
Drug Metab Dispos. 2003 May;31(5):510-8
12695336
J Pharmacokinet Pharmacodyn. 2006 Jun;33(3):227-79
16404503
Pharm Res. 2000 Nov;17(11):1335-44
11205725
Curr Clin Pharmacol. 2006 May;1(2):185-91
18666370
AAPS J. 2005 Oct 24;7(3):E609-24
16353940
Annu Rev Pharmacol Toxicol. 1992;32:185-209
1605567
Br J Clin Pharmacol. 1998 Oct;46(4):321-33
9803979
J Pharmacokinet Pharmacodyn. 2005 Apr;32(2):185-97
16283534
J Natl Cancer Inst. 2006 May 3;98 (9):580-98
16670384
Anesthesiology. 1996 Dec;85(6):1290-9
8968176
Curr Opin Drug Discov Devel. 2004 Mar;7(2):195-203
15603253
Antimicrob Agents Chemother. 2004 May;48(5):1713-8
15105125
Br J Clin Pharmacol. 1997 Nov;44(5):477-86
9384465
Eur J Pharm Sci. 2001 May;13(2):115-22
11297895
Drug Discov Today. 2006 Sep;11(17-18):806-11
16935748
Annu Rev Pharmacol Toxicol. 2000;40:67-95
10836128
Expert Opin Drug Metab Toxicol. 2006 Oct;2(5):651-74
17014387
J Pharmacol Exp Ther. 1999 May;289(2):1067-74
10215689
Eur J Drug Metab Pharmacokinet. 2000 Jan-Mar;25(1):49-58
11032091
Clin Pharmacol Ther. 2005 Nov;78(5):508-19
16321617
Drug Discov Today. 2003 Nov 1;8(21):990-6
14643162
Clin Pharmacokinet. 1997 May;32(5):345-56
9160169
Basic Clin Pharmacol Toxicol. 2005 Mar;96(3):206-11
15733216
Nat Rev Drug Discov. 2003 Jul;2(7):566-80
12838269
Clin Pharmacokinet. 1995 Nov;29(5):287-91
8582116
J Pharm Sci. 1996 Jun;85(6):600-7
8773956
Pharm Res. 2003 Nov;20(11):1752-9
14661918
Clin Pharmacokinet. 2006;45(2):177-97
16485916
Biopharm Drug Dispos. 2000 Mar;21(2):41-52
11100906
Clin Pharmacol Ther. 1997 Mar;61(3):275-91
9084453
J Pharm Pharmacol. 2005 Feb;57(2):183-9
15720781