The Virtual Anemia Trial: An Assessment of Model-Based In Silico Clinical Trials of Anemia Treatment Algorithms in Patients With Hemodialysis

Overview

Journal CPT Pharmacometrics Syst Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 2018 Jan 26

PMID 29368434

Citations 6

Authors

Doris H Fuertinger

Alice Topping

Franz Kappel

Stephan Thijssen

Peter Kotanko

Affiliations

Soon will be listed here.

Abstract

In silico approaches have been proposed as a novel strategy to increase the repertoire of clinical trial designs. Realistic simulations of clinical trials can provide valuable information regarding safety and limitations of treatment protocols and have been shown to assist in the cost-effective planning of clinical studies. In this report, we present a blueprint for the stepwise integration of internal, external, and ecological validity considerations in virtual clinical trials (VCTs). We exemplify this approach in the context of a model-based in silico clinical trial aimed at anemia treatment in patients undergoing hemodialysis (HD). Hemoglobin levels and subsequent anemia treatment were simulated on a per patient level over the course of a year and compared to real-life clinical data of 79,426 patients undergoing HD. The novel strategies presented here, aimed to improve external and ecological validity of a VCT, significantly increased the predictive power of the discussed in silico trial.

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References

Smith A, Petersen B, Ropella G, Kennedy R, Kaplowitz N, Ookhtens M . Competing Mechanistic Hypotheses of Acetaminophen-Induced Hepatotoxicity Challenged by Virtual Experiments. PLoS Comput Biol. 2016; 12(12):e1005253. PMC: 5161305. DOI: 10.1371/journal.pcbi.1005253. View

An G . In silico experiments of existing and hypothetical cytokine-directed clinical trials using agent-based modeling. Crit Care Med. 2004; 32(10):2050-60. DOI: 10.1097/01.ccm.0000139707.13729.7d. View

Ghosh S, Young D, Gadkar K, Wennerberg L, Basu K . Towards optimal virtual patients: an online adaptive control approach. Annu Int Conf IEEE Eng Med Biol Soc. 2007; 2007:3292-5. DOI: 10.1109/IEMBS.2007.4353033. View

Petersen B, Ropella G, Hunt C . Virtual Experiments Enable Exploring and Challenging Explanatory Mechanisms of Immune-Mediated P450 Down-Regulation. PLoS One. 2016; 11(5):e0155855. PMC: 4881988. DOI: 10.1371/journal.pone.0155855. View

Fuertinger D, Kappel F, Thijssen S, Levin N, Kotanko P . A model of erythropoiesis in adults with sufficient iron availability. J Math Biol. 2012; 66(6):1209-40. DOI: 10.1007/s00285-012-0530-0. View

Jamei M, Dickinson G, Rostami-Hodjegan A . A framework for assessing inter-individual variability in pharmacokinetics using virtual human populations and integrating general knowledge of physical chemistry, biology, anatomy, physiology and genetics: A tale of 'bottom-up' vs 'top-down'.... Drug Metab Pharmacokinet. 2009; 24(1):53-75. DOI: 10.2133/dmpk.24.53. View

Usvyat L, Kooman J, van der Sande F, Wang Y, Maddux F, Levin N . Dynamics of hospitalizations in hemodialysis patients: results from a large US provider. Nephrol Dial Transplant. 2013; 29(2):442-8. DOI: 10.1093/ndt/gft219. View

Palumbo P, Pizzichelli G, Panunzi S, Pepe P, De Gaetano A . Model-based control of plasma glycemia: Tests on populations of virtual patients. Math Biosci. 2014; 257:2-10. DOI: 10.1016/j.mbs.2014.09.003. View

Okazaki M, Komatsu M, Kawaguchi H, Tsuchiya K, Nitta K . Erythropoietin resistance index and the all-cause mortality of chronic hemodialysis patients. Blood Purif. 2014; 37(2):106-12. DOI: 10.1159/000358215. View

10.

Bhatt D, Mehta C . Adaptive Designs for Clinical Trials. N Engl J Med. 2016; 375(1):65-74. DOI: 10.1056/NEJMra1510061. View

11.

Le Compte A, Chase J, Lynn A, Hann C, Shaw G, Wong X . Blood glucose controller for neonatal intensive care: virtual trials development and first clinical trials. J Diabetes Sci Technol. 2010; 3(5):1066-81. PMC: 2769904. DOI: 10.1177/193229680900300510. View

12.

Leil T, Ermakov S . Editorial: The emerging discipline of quantitative systems pharmacology. Front Pharmacol. 2015; 6:129. PMC: 4485322. DOI: 10.3389/fphar.2015.00129. View

13.

Kansal A, Trimmer J . Application of predictive biosimulation within pharmaceutical clinical development: examples of significance for translational medicine and clinical trial design. Syst Biol (Stevenage). 2006; 152(4):214-20. DOI: 10.1049/ip-syb:20050043. View

14.

Cristofoletti R, Patel N, Dressman J . Assessment of Bioequivalence of Weak Base Formulations Under Various Dosing Conditions Using Physiologically Based Pharmacokinetic Simulations in Virtual Populations. Case Examples: Ketoconazole and Posaconazole. J Pharm Sci. 2016; 106(2):560-569. DOI: 10.1016/j.xphs.2016.10.008. View

15.

Moss R, Grosse T, Marchant I, Lassau N, Gueyffier F, Thomas S . Virtual patients and sensitivity analysis of the Guyton model of blood pressure regulation: towards individualized models of whole-body physiology. PLoS Comput Biol. 2012; 8(6):e1002571. PMC: 3386164. DOI: 10.1371/journal.pcbi.1002571. View

16.

Dou Y, Kruse A, Kotanko P, Rosen H, Levin N, Thijssen S . Red blood cell life span and 'erythropoietin resistance'. Kidney Int. 2012; 81(12):1275-6. DOI: 10.1038/ki.2012.54. View

17.

Chan K, Thadhani R, Maddux F . Adherence barriers to chronic dialysis in the United States. J Am Soc Nephrol. 2014; 25(11):2642-8. PMC: 4214530. DOI: 10.1681/ASN.2013111160. View

18.

Sergeyeva O, Gorodetskaya I, Ramos R, Schiller B, Larive B, Raimann J . Challenges to enrollment and randomization of the Frequent Hemodialysis Network (FHN) Daily Trial. J Nephrol. 2012; 25(3):302-9. DOI: 10.5301/jn.5000160. View

19.

Lamba M, Hutmacher M, Furst D, Dikranian A, Dowty M, Conrado D . Model-Informed Development and Registration of a Once-Daily Regimen of Extended-Release Tofacitinib. Clin Pharmacol Ther. 2016; 101(6):745-753. PMC: 5485720. DOI: 10.1002/cpt.576. View

20.

Duncan T, Reed M, Nijhout H . A population model of folate-mediated one-carbon metabolism. Nutrients. 2013; 5(7):2457-74. PMC: 3738981. DOI: 10.3390/nu5072457. View