model-based therapeutic drug monitoring in...

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

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InitialdoseAUC

Busulfan: Improving precision

ShuklaPetal.(2017,unpublished)

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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