Model-basedTherapeutic Drug Monitoring
in Oncology
Ron Keizer PharmD PhD
Chief Scientific Officer, InsightRXSan Francisco, CA
Disclosure
InsightRX isaprecisiondosingsoftwarecompany,developingsoftwareforhealthcareproviders
andpharmaindustry.
“Model-based”Why do we need it for TDM?
History: Model-based TDM
1972
1972
1969
Product Active PI / founder Since LocationInsightRX yes InsightRX 2015 USDoseMe yes Green, McLeay 2012 AustraliaUSC*Pack no Roger Jelliffe 1970s LA, USBestDose yes Michael Neely 200x LA, USNextDose ? Sam Holford 2012 AustraliaBaysient no Diane Mould 2015 USMW/Pharm yes Hans Proost 1990s The Netherlands / Czech Rep.TCIworks no Stephen Duffull 2010s New ZealandTDMS2000 no Healthware Inc 1980s San Diego, USPrecise PK yes Healthware Inc 2010s San Diego, USTDMx yes Sebastian Wicha 2015 GermanyAutoKinetics yes Paul Elbers 2015 The NetherlandsEzeCHiel no Thierry Buclin 2013 SwitzerlandTucuxi yes Thierry Buclin 2016 SwitzerlandOptimum Dosing Strategies yes Andras Farkas 2013 USMyPKFit yes Baxter 2014 US
Model-based TDM software (a selection)
TDM without modeling & simulation?
Example1: e.g.vancomycin/voriconazole
- Waitfor“steadystate”- GetCmin atrighttime- Comparetoreference/effectiverange
Drawbacks:- Oftenincorrectlydrawn
(e.g.87%ofvancomycintroughlevelsatmajorUSacademiccenter*)
- Sensitivetodataerrors
Advantages:- Intuitive/simple
Example1b:e.g.vancomycin/imatinib**
- Waitfor“steadystate”- Getsampleatanytimepoint- ExtrapolatetoCmin (orCmax /AUC)
Drawbacks:- Extrapolationusingpopulationvalue- imprecise/biased- Sensitivetodataerrors
Advantages:- Intuitive
* personal communication Deborah French et al. 2013. (“incorrect”: more than 30 minutes early, or not at steady state)** Wang Y et al. Ther Drug Monit. 2009
TDM without modeling & simulation?
Example2:e.g.busulfan
• Collectrichdata(4-8samples)eachday• CalculateAUC(usingNCA/trapezoidalrule)
Advantages• Intuitive
Drawbacks• Onlyprecisewithmanysamples• Requirestime&efforttocalculate• Sensitivetodataerrors
Model-based dosing: example
Model-based dosing: example
Model-based dosing: example
Model-based dosing: example
Model-based dosing: example
Model-based dosing: example
Model-based dosing: example
Model-based dosing: example
Model-based dosing: example
Model-based dosing: example
Model-based dosing: example
Higherprecision• Abilitytoincorporateknownpredictors(weight,eGFR,genotypes,etc)• Protectsagainstdataerrors/processnoise• Usein“apriori”and“afterTDM”setting
Lesssamples• Relaxsamplingtimewindows• Optimizesamplingwindows(throughOptimalDesign,MCsimulation)
Model-based dosing: example
Moreinformative• Comparewithpopulationà detectoutlier
Model-based dosing: example
Moreinformative• Comparewithpopulationà detectoutlier• Providesuncertaintyestimates
Model-based dosing: example
Moreinformative• Comparewithpopulationà detectoutlier• Providesuncertaintyestimates• Simulation:“what-if”scenarios• LinktoPDmeasures/outcome
TDM in OncologyExamples, Highlights, etc.
Busulfan: Improving precision
Bartelink etal.Lancet Haematol 2016
Busulfan: Improving precision
Bartelink etal.Lancet Haematol 2016
Busulfan: Improving precision
1.Savic RMetal.Biol BloodMarrowTransplant20132.Long-BoyleJetal.Therap Drug Monit 20153.Bartelink etal.LancetHaematol 20163.Keizeretal.Unpublished
<2014:Conventional(label-dose) used.TDMusingNCA(7samples/day)
2014:UCSF developspopPK modelbusulfan [1,2]
2015:UCSFstartsusingin-houseExcel app forinitialdose
2016: UCSFswitchestomodel-basedTDM
2016:popPK modelreoptimized[4]
Busulfan: Improving precision
Shukla Petal.(2017,unpublished)
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Conventional + NCA Model−based + NCA Model−based + Bayesian
Rel
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InitialdoseAUC
Busulfan: Improving precision
ShuklaPetal.(2017,unpublished)
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Conventional + NCA Model−based + NCA Model−based + Bayesian
Rel
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inm
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CumulativeAUC
TDM in Oncology
Randomizedtrials:
• MTX:Evansetal.NEJM1998
• 5-FU:Fety etal. Clin CancerRes1998• 5-FU:Gamelin etal.JCO2012
• Paclitaxel:Joerger etal.AnnOncol 2016
Why TDM not used more widely for cytotoxic drugs?
Thoughts:
• Drugcombinationsàmorecomplex
• Investigator-initiatedtrials
• Decreasedtoxicityratherthanimprovedefficacy?
• Moreinvolved(e.g.vspharmacogenetics)
• …?
BSA paradigm
“Theexposureforfluorouracilvaries30- to100-foldandfordocetaxeluptoseven-fold.[…]Itwouldbemoreappropriatetotitrateanindividualpatient’sdosetoanMTEbymeansoftherapeuticdrugmonitoring.”
Beumer JetalJCO2012
BSA paradigm
Beumer JetalJCO2012
“Letushopethat,in another50years,we arenotstillrecommendingBSA-baseddosingandthatwewillhavemovedtodosingapatientwiththerightdrugatwhateverdoserequiredtoachievetherightexposure.”
TDM in Targeted Oncology
Imatinib: TDM or not?
Demetrietal.JCO2009
Imatinib: TDM or not?
Picardetal.JCO2009
Imatinib: TDM or not?
Gotta Vetal.CancerChemother Pharmacol 2014
Imatinib: TDM or not?
Gotta V etal.Leuk Res2014
Imatinib: TDM or not?
Gotta V etal.Leuk Res2014
Imatinib: TDM or not?
Pharmacodynamicmodel-based dosing
Neutrophil-guided dosing
Wallin JE etal.BasicClin Pharmacol Tox 2010Wallin JEetal.Comput MethodsProgramsBiomed2009
Neutrophil-guided dosing
Wallin JE etal.BasicClin Pharmacol Tox 2010Wallin JEetal.Comput MethodsProgramsBiomed2009
Neutrophil-guided dosing
Neutrophil-guided dosing
Netterberg I. CancerChemotherap Pharmacol 2017
Vision: 2025
Integratedwith EMR
Linksexposure~outcomeestablished
Reimbursed bypayer
Includedindruglabel
“Companion”apps
Thank you
Slides:science.insight-rx.com
Publications:Referencesinindividualslides
Recommendedfurtherreading:WilliamClarke”TDMforcanceragents”: https://www.youtube.com/watch?v=OhDnVr3n4H8Saladax website: http://www.saladax.com/publications-2