Tumor Static Concentration Curves in Combination Therapy.
Combination therapies are widely accepted as a cornerstone for treatment of different cancer types. A tumor growth inhibition (TGI) model is developed for combinations of cetuximab and cisplatin obtained from xenograft mice. Unlike traditional TGI models, both natural cell growth and cell death are considered explicitly. The growth rate was estimated to 0.006 h-1and the natural cell death to 0.0039 h-1resulting in a tumor doubling time of 14 days. The tumor static concentrations (TSC) are predicted for each individual compound. When the compounds are given as single-agents, the required concentrations were computed to be 506 μg · mL-1and 56 ng · mL-1for cetuximab and cisplatin, respectively. A TSC curve is constructed for different combinations of the two drugs, which separates concentration combinations into regions of tumor shrinkage and tumor growth. The more concave the TSC curve is, the lower is the total exposure to test compounds necessary to achieve tumor regression. The TSC curve for cetuximab and cisplatin showed weak concavity. TSC values and TSC curves were estimated that predict tumor regression for 95% of the population by taking between-subject variability into account. The TSC concept is further discussed for different concentration-effect relationships and for combinations of three or more compounds.
Fraunhofer-Chalmers Centre, Chalmers Science Park, Gothenburg, Sweden. tim.cardilin@fcc.chalmers.se.|Department of Mathematical Sciences, Chalmers University of Technology and University of Gothenburg, Gothenburg, Sweden. tim.cardilin@fcc.chalmers.se.
Tim
T
Cardilin
Fraunhofer-Chalmers Centre, Chalmers Science Park, Gothenburg, Sweden.|Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.
Joachim
J
Almquist
Fraunhofer-Chalmers Centre, Chalmers Science Park, Gothenburg, Sweden.
Mats
M
Jirstrand
Global Early Development-Quantitative Pharmacology and Drug Disposition, Quantitative Pharmacology, Merck, Darmstadt, Germany.|Pharmaceutical Research and Early Development, Hoffmann-Le Roche, Basel, Switzerland.
Alexandre
A
Sostelly
Translation Innovation Platform Oncology, Merck, Darmstadt, Germany.
Christiane
C
Amendt
Global Early Development-Quantitative Pharmacology and Drug Disposition, Quantitative Pharmacology, Merck, Darmstadt, Germany.
Samer
S
El Bawab
Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden.
Johan
J
Gabrielsson
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D000068818:Cetuximab / Q000008:administration & dosage; D002945:Cisplatin / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000068818:Cetuximab; D002945:Cisplatin
mixture dynamics; model-based drug development; oncology; pharmacokinetic-pharmacodynamic modeling; tumor xenograft
Cell. 2015 Apr 9;161(2):205-14
25860605
Clin Cancer Res. 2005 Aug 1;11(15):5558-65
16061873
Clin Cancer Res. 2014 Sep 1;20(17):4478-87
24947928
IEEE Trans Biomed Eng. 2012 Aug;59(8):2161-70
22575633
Cancer Chemother Pharmacol. 2013 Jan;71(1):133-43
23053270
Cancer Chemother Pharmacol. 1995;37(1-2):23-31
7497593
J Pharmacokinet Pharmacodyn. 2010 Jun;37(3):221-42
20424896
IEEE Trans Biomed Eng. 2008 Dec;55(12):2683-90
19126447
Arzneimittelforschung. 1953 Jun;3(6):285-90
13081480
Elife. 2013 Jun 25;2:e00747
23805382
Nat Biotechnol. 2012 Jul 10;30(7):679-92
22781697
Int J Oncol. 1996 Aug;9(2):217-24
21541503
Clin Cancer Res. 2014 Jul 15;20(14):3763-74
24850847
Cancer Res. 1993 Oct 1;53(19):4637-42
8402640
Nat Rev Cancer. 2008 Mar;8(3):227-34
18273038
J Pharmacokinet Pharmacodyn. 2009 Apr;36(2):179-97
19387803
Cancer Treat Rev. 2013 Jun;39(4):305-12
23207060
Cancer Res. 2004 Feb 1;64(3):1094-101
14871843
J Pharmacol Exp Ther. 2004 Sep;310(3):981-6
15175417
CPT Pharmacometrics Syst Pharmacol. 2014 May 07;3:e113
24806032
Clin Lung Cancer. 2006 May;7(6):385-8
16800963
J Pharmacokinet Pharmacodyn. 2015 Jun;42(3):191-209
25801663
Eur J Cancer. 2009 Dec;45(18):3336-46
19854637
Cancer Chemother Pharmacol. 2013 May;71(5):1147-57
23430120
Pharmacol Res Perspect. 2015 Jun;3(3):e00149
26171228
Comput Methods Programs Biomed. 2014 May;114(3):e3-13
23948442
J Pharmacol Exp Ther. 2001 Sep;298(3):865-72
11504778
Cancer Res. 2010 Jan 15;70(2):440-6
20068163
Cancer. 1975 Jan;35(1):98-110
162854
Nature. 2013 Jul 18;499(7458):291-2
23868257
Clin Cancer Res. 2004 Dec 1;10(23):7994-8004
15585635
J Pharmacol Exp Ther. 2006 Oct;319(1):1-7
16670349
Eur J Pharm Sci. 2016 Jun 10;88:132-46
27050307
Cancer Chemother Pharmacol. 2013 Aug;72 (2):471-82
23812004
Cancer Chemother Pharmacol. 2010 Jul;66(2):245-54
19841922