Predictive ability of a semi-mechanistic model for neutropenia in the development of novel anti-cancer agents: two case studies.
In cancer chemotherapy neutropenia is a common dose-limiting toxicity. An ability to predict the neutropenic effects of cytotoxic agents based on proposed trial designs and models conditioned on previous studies would be valuable. The aim of this study was to evaluate the ability of a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for myelosuppression to predict the neutropenia observed in Phase I clinical studies, based on parameter estimates obtained from prior trials. Pharmacokinetic and neutropenia data from 5 clinical trials for diflomotecan and from 4 clinical trials for indisulam were used. Data were analyzed and simulations were performed using the population approach with NONMEM VI. Parameter sets were estimated under the following scenarios: (a) data from each trial independently, (b) pooled data from all clinical trials and (c) pooled data from trials performed before the tested trial. Model performance in each of the scenarios was evaluated by means of predictive (visual and numerical) checks. The semi-mechanistic PK/PD model for neutropenia showed adequate predictive ability for both anti-cancer agents. For diflomotecan, similar predictions were obtained for the three scenarios. For indisulam predictions were better when based on data from the specific study, however when the model parameters were conditioned on data from trials performed prior to a specific study, similar predictions of the drug related-neutropenia profiles and descriptors were obtained as when all data were used. This work provides further indication that modeling and simulation tools can be applied in the early stages of drug development to optimize future trials.
Soto
Elena
E
Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona 31080, Spain. msoto@alumni.unav.es
Keizer
Ron J
RJ
Trocóniz
Iñaki F
IF
Huitema
Alwin D R
AD
Beijnen
Jos H
JH
Schellens
Jan H M
JH
Wanders
Jantien
J
Cendrós
Josep María
JM
Obach
Rosendo
R
Peraire
Concepción
C
Friberg
Lena E
LE
Karlsson
Mats O
MO
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D055808:Drug Discovery; D005260:Female; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009503:Neutropenia / Q000097:blood / Q000139:chemically induced*; D011237:Predictive Value of Tests; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; C439829:N-(3-chloro-7-indolyl)-1,4-benzenedisulphonamide; D013449:Sulfonamides; C424962:diflomotecan; D002166:Camptothecin
Invest New Drugs. 2010 Feb;28(1):61-75
19198760
Invest New Drugs. 2005 Jun;23(3):225-34
15868378
Br J Cancer. 2007 Aug 6;97(3):290-6
17595656
Clin Cancer Res. 2001 Aug;7(8):2301-8
11489805
J Clin Oncol. 2002 Aug 15;20(16):3508-21
12177112
Clin Pharmacol Ther. 2004 Dec;76(6):567-78
15592328
Clin Cancer Res. 2003 Sep 15;9(11):4101-7
14519632
J Pharmacokinet Pharmacodyn. 2008 Jun;35(3):269-83
18446428
Cancer Chemother Pharmacol. 2010 Apr;65(5):839-48
19680655
J Theor Biol. 2005 Jun 7;234(3):311-27
15784267
Ann Oncol. 2001 Sep;12(9):1289-93
11697842
Eur J Cancer. 2003 May;39(8):1097-104
12736109
Cancer Chemother Pharmacol. 2006 Apr;57(4):412-26
16322990
Clin Pharmacol Ther. 2007 Jan;81(1):88-94
17186004
Cancer Chemother Pharmacol. 2009 May;63(6):1035-48
18791717
Br J Clin Pharmacol. 2008 Oct;66(4):485-97
18637887
J Med Chem. 1999 Sep 23;42(19):3789-99
10508428
Clin Pharmacol Ther. 1998 Nov;64(5):511-21
9834043
J Pharmacokinet Biopharm. 1998 Oct;26(5):581-93
10205772
Math Biosci. 2003 Nov;186(1):29-41
14527745
Cancer Chemother Pharmacol. 2009 Apr;63(5):945-52
18654747
Invest New Drugs. 2010 Dec;28(6):744-53
19711011
J Clin Oncol. 2002 Oct 1;20(19):4065-73
12351604
Ann Oncol. 2007 Mar;18(3):569-75
17322542
J Clin Oncol. 2002 Dec 15;20(24):4713-21
12488418
J Clin Oncol. 2003 Dec 15;21(24):4524-31
14673039
Cancer Chemother Pharmacol. 2006 Jun;57(6):727-35
16261364
Br J Clin Pharmacol. 2008 Apr;65(4):607-10
18294323
Clin Pharmacol Ther. 2008 Jun;83(6):829-39
17851564
Clin Cancer Res. 2003 Nov 1;9(14):5195-204
14613999
Clin Cancer Res. 2008 Sep 15;14(18):5856-63
18794097
Cancer Res. 1999 Jun 15;59(12):2939-43
10383158