Therapeutic drug monitoring in invasive fungal infections

- Individualized antimicrobial therapy – is it worth it?-

Center of Expertise in Mycology Radboudumc / CWZ

ECMM Diamond Center Radboud Center for Infectious Diseases (RCI) Radboudumc, Nijmegen

Dr. Roger Brüggemann, clinical pharmacologist and hospital pharmacistECCMID, April 24 2018 – Madrid

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Disclosures (Roger Brüggemann)Advisory Board Astellas, Gilead, MSD, Pfizer, F2G,

Cidara

Research Grants / unrestricted educational grants

Astellas, Gilead, MSD, Pfizer

Lectures Astellas, Gilead, MSD, Pfizer

All contracts are with Radboudumc ; All payments are made to Radboudumc

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What is TDM Why do we need TDM How do we use TDM

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• Pharmacokinetics● Concentration versus time

● What the body does to the drug : patient variability

• Pharmacodynamics

● Concentration and effect

● What the drug does to the body

PHARMACOKINETICS & PHARMACODYNAMICSDose Concentration (C) Effect (E)

EG TARGET : AUC/MIC

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What is Therapeutic Drug Monitoring

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Personalized Healthcare = the drug

• Standard dosing

• Dose adaptation

• kidney failure

• liver test abnormalities

• Therapeutic Drug Monitoring

• MIC-concentration based dosing /

Biomarker-guided dosing /

Disease progression modeling

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Uniform

Personalized ESCMID eLibrary

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“Textbook” Drug criteria for TDM

Plasma levels (drug exposure) difficult to predict from dose administered, and pharmacokinetic variability may jeopardize the effectiveness of therapy

Significant PK variability?

Specific, accurate and precise assay that provides results in a timely fashionAssay available?

Drug has relatively narrow window of concentrations (exposures) that produce therapeutic versus toxic effects

Low/ narrow therapeutic

window?

Schumacher GE, ed. Therapeutic drug monitoring. Norwalk, CT: Appleton and Lange, 1995.Ensom et al. Clinical Pharmacokinetics in the 21st century. Clin Pharmacokin 1998;34:265-79

Dosing cannot be easily optimized by routine laboratory tests, clinical observation, or empiric dose adjustments-i.e. no other means of assessing pharmacodynamics

TDM most practical strategy? ESCMID eLibrary

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Prescribed Drug

treatment

Drug

concentration

Adverse effects /

toxicity

Effective

Treatment

Selection of

Drug

Resistance

Actual drug

intake

Adherence

Pharmacokinetics

Effect

Pharmacodynamics

#

“The clinical pharmacological view of anti-infective treatment”

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Tängdén T et al, ICM 2017

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TDM of antimicrobial agents

Slide from Prof de Waele from pro – con debate on TDM in the ICU Bruggemann – de Waele

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We could give all patients the highest possible dose of voriconazole

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Why do we need TDM

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• Populations with altered PK• Pediatrics / obese / ICU

• Impaired renal or hepatic function

• Impaired oral bioavailability:• Mucositis/ stomatitis / diarrhea

• Acid suppression therapy

• Altered drug distribution, protein binding

• Interacting medication

• Suspected breakthrough infection

• Suspected toxicity

Clinical scenario’s where TDM is needed

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How do we use TDM

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Options for optimized dosing

• Depends on pharmacodynamic index

• Higher dosages / more frequent dosing

• Extended infusion vs continuous infusions

• Therapeutic drug monitoring

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DiagnosisStandard

empirical (Product Information) dose

Drugconcentrationdetermination

(TDM)

Dose adjusted basedon nomogram

New doseimplementation

Conventional dosing with or without therapeutic drug monitoring (TDM)

Steady state has to be reached for best dose advice, which can cause a substantial delay.

DiagnosisIndividualisedempirical dose

Drugconcentrationdetermination

(TDM)

Dose adjustedbased on

population PK and patient factors

New doseimplementation

Enhanced chance of reaching PD target with additionaldrug concentration measurements and dose optimisation.

Empirical dose based on population PK model and patient factors.

Individualised dosing with therapeutic drug monitoring (TDM)

Enhanced chance ofreaching PD target early.

Dose unchanged withouttherapeutic drug monitoring.

Tängdén T et al, ICM 2017

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Sampling times• In the absence of model informed dosing:

• Timing of the sample is very crucial for adequate interpretation.

• Measure direct after loading dose or at steady-state.

• Timing of the sampling is dependent on the defined target concentrations.

• Sampling for peak samples should be done in relation to the distribution of the drug.

• Review from literature: Up to 50% of the sampling is done incorrect. ESCMID eLibrary

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Analysis

• Type of assay

LC-MSMS HPLC / UPLC Bioassay

• Precision of the immuno-assay versus chromotography Crossreactivity for immuno-assays

• Validation of the assay internal QC

external QC program

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Interpretation and reporting

• Therapeutic concentrations reflect a chance for efficacy or absence of toxicity(probabilistic concept of the therapeutic range)

• Target concentration: population vs individual patient • Individual for sure does not reflect the population

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ECIL 6 charges:

• Identify key questions concerning azole therapeutic drug monitoring (TDM) in patients with haematological malignancies /allogeneic HSCT

• Provide evidence-based recommendations or expert opinion addressing key questions (ESCMID/EFISG scoring system)

Pharmacology Haematology /Infectious diseases

Clinical reference laboratory

Russell Lewis (Italy)Roger Brüggemann (Netherlands)Christophe Padoin (France)

Johan Maertens (Belgium)Oscar Marchetti (Switzerland)Andreas Groll (Germany)

Elizabeth Johnson (UK)Maiken Arendrup (Denmark)

http://www.live-sante.com/ecil/

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Parameter Substantial PK variability?

Therapeutic range defined in humans?

Narrow therapeutic

window?

Fluconazole ✔ yes ✔ yes ✘ no

Itraconazole ✔ yes ✔ yes ✔ yes

Voriconazole ✔ yes ✔ yes ✔ yes

Posaconazole * ✔ yes ✔ yes ?not well defined

Isavuconazole ** ✔ yes ✘ no ?not well defined

*Limited data for new posaconazole formulations **Limited data

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Posaconazole concentration- prophylaxis efficacy

Pharmacology: What target levels are recommended?

• Pharmacokinetic analysis of two pivotal prophylaxis trials utilizing suspension did not report significant concentration-effect relationships 1,2

• Median posaconazole 0.61 mg/L (breakthrough IFI) vs. 0.92 mg/L (no breakthrough)

• FDA pharmacodynamic analysis:3

• Inverse relationship between POS plasma levels and clinical failure by logistic regression

• Proposed efficacy target: 0.7 mg/L• Definition of clinical failure used in this analysis has been

debated (composite efficacy endpoint→ greater number of treatment failures than reported in original trials)

1. Krishna G et al. Pharmacotherapy:2008; 28: 1223–1232.2. Krishna G, et al. Journal of Clin Pharmacol 2007; 27: 1627–1636.3. Jang SH et al. Clinical Pharmacology & Therapeutics 2010; 88: 115–119.4. Dolton et al. Antimicrob Agents Chemother 2012;56:2806-2813.

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Posaconazole concentration- prophylaxis efficacy

Pharmacology: What target levels are recommended?

• Other monocentric studies reported concentration-response relationship between posaconazole plasma trough levels and risk of breakthrough infection 1-5

> 0.5 to 0.7 mg/L

1. Lebeaux D. Antimicrob Agents Chemother 2009; 53: 5224–5229.2. Bryant AM, . Int J Antimicrob Agents 2011; 37: 266–269.3. Eiden C, Eur J Clin Microbiol Infect Dis 2012; 31: 161–167.4. Hoenigl M, Int J Antimicrob Agents 2012; 39: 510–513.5. Cattaneo et al. Mycoses 2015; 58, 362–367

Recommendation: prophylaxis target: > 0.7 mg/L (BII)

Use of tablet formulation (or IV formulation) isrecommended to maximize probability of achieving target (AII)

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Posaconazole concentration- toxicity

Pharmacology: What target levels are recommended?

• No relationship between adverse effects and plasma concentrations for oral suspension 1-3

• Pharmacokinetic bridging studies for gastroresistant tablet and IV formulation used an upper plasma target of 3.75 mg/L3

1. Jang SH et al. Clinical Pharmacology & Therapeutics 2010; 88: 115–119.2. Cantanzaro et al. Clinical Infectious Diseases 2007;45:562-568.3. European Medicine Agency. Assessment report: Noxafil. 2014. Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000610/human_med_000937.jsp&mid=WC0b01ac058001d124. Accessed 30 April 2015.

Recommendation: At present, insufficient data to recommendtarget trough for safety further data are needed

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Azole resistance in 2017

Med Mycol. (in press); slide courtesy of Paul Verweij

Red: reported azole resistance White: unknown!

TR34/L98H and TR46/Y121F/T289A ESCMID eLibrary

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Acquired resistance frequency in A. fumigatus 2013 - 2016

2013 7.1%2014 8.7%2015 15.7%2016 15.3%

2013 19.2%2014 13.3%2015 16.3%2016 20.5%

2013 4.3%2014 3.8%2015 …..%2016 12.9%

2013 4.9%2014 4.9%2015 8.3%2016 9.5%

2013 7.1%2014 9.4%2015 6.7%2016 12.1%

www.swab.nl: Netmap 2016:128-31Slide courtesy of Prof. Paul Verweij

131 isolatesTR34/L98H 74%TR46/Y121F/T289A 9%Point mutations 2%WT Cyp51A 15%

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A.F.A.D. Schauwvlieghe, ECCMID 2018Seyedmousavi, Drug Resistance Updates 2014

0.5 mg/L

High Dose posaconazole to target High concentration 16 patients with an intended target of > 3 mg/L 25 patients with spontaneous high dose posaconazole with a median Ctrough of 4,3 mg/L No relations could be identified so far between exposure and toxicity ESCMID eLibrary

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Voriconazole concentration-efficacy relationship

• Prospective studies have identified target trough concentrations of ≥ 1.5-2 mg/L are associated with nearmaximal clinical response in treatment of IFI 1-6

• Post-hoc analysis of Phase II/III clinical trials:4

• Vori C avg /MIC target > 2, or vori plasma 2-5 mg/L• Response rate: 74%

1. Pascual A,et al. Clin Infect Dis 2012; 55: 381–390.2. Pascual A, et al. Clin Infect Dis 2008; 46: 201–211.3. Park WB et al. Clin Infect Dis 2012; 55: 1080–1087.

Recommendation: voriconazole prophylaxisand treatment target: > 1-2 mg/L (AII);higher troughs (> 2) are recommended for severe infectionsor treatment of pathogens with elevated MICs (e.g., >0.25 mg/L)7

4. Troke PF, et al. Antimicrob Agents Chemother 2011; 55: 4782–475. Trifilio S et al. Bone Marrow Transplant 2007; 40: 451–456.6. Dolton MJ et al. Antimicrob Agents Chemother 2012; 56: 4793–47997. Siopi et al. Antimicrob Agent Chemother 2014;69:1611-9.

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Voriconazole concentration-toxicity relationship

• Patients with voriconazole trough concentrations > 5-6 mg/L have a higher probability of neurotoxic events and visual hallucinations during voriconazole therapy 1-4

• Post-hoc phase II/III safety data analysis:5

• Some evidence of relationship between increased risk of hepatotoxicity at higher voriconazole exposures

• No reliable upper “cut-off” concentration can be identified to minimize risk of hepatotoxic effects1,5

• Possible exception: Japanese patients hepatotoxicity was more common (34.5%) if voriconazole trough concentrations ≥ 3.9 mg/L6-8

1. Pascual A,et al. Clin Infect Dis 2012; 55: 381–390.2. Pascual A, et al. Clin Infect Dis 2008; 46: 201–211.3. Dolton MJ et al. Antimicrob Agents Chemother 2012; 56: 4793–47994. Zonios D et al. J Infect Dis 2014;209:1941-1948.

5. Tan K et al. J Clin Pharmacol 2006; 46: 235–243.6. Matsumoto K, et al. Int J Antimicrob Agents 2009; 34: 91–94.7. Suzuki Y,et al.Clin Chim Acta 2013; 424: 119–122.8.Atsushi et al. J Ped Oncol 2013;35:p e219–e223

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The Dutch Experience

• Multicentre (n=10), prospective cluster randomised cross-over clinical trial.

• Patients aged ≥ 18 years with a haematological malignancy or an allogeneic stem cell transplant and had a clinical diagnosis of IA treated with VCZ.

• In total 192 patients should be included, based on an expected failure rate of 40% in the non-TDM group and a failure rate of 20% in the non-TDM

group.

• Composite endpoint of response to treatment at day 28 and toxicity

A. Veringa, ECCMID 2018

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Isavuconazole-concentration efficacy

https://www.us.astellas.com/docs/cresemba.pdf

TDM is indicated for patients receiving tablets or IV formulation in the setting of breakthrough or infection unresponsive to treatment, treatment of pathogens with reduced susceptibility, or in the setting of drug interactions (BIII) additional data are needed

Isavuconazole package labelling:

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Desai et al. Antimicrob Agents Chemother. 2017 Nov 22;61(12).Maertens et al. Lancet. 2016 Feb 20;387(10020):760-9.

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There was only a small sample subset of patients with both pharmacokinetic (PK) parameters and pathogen susceptibility data available (n 36)

PK done with total drug concentrations (like in all other studies)

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a values from a chromatography assay: i.e. high performance liquid chromatography (HPLC), liquid chromatography mass spectroscopy (LC/MS) of LC/MS/MSb patients without symptoms of clinical toxicity may not warrent dosage adjustmentC higher troughs (≥ 2) are advocated for severe infectionsor treatment of pathogens with elevated MICs (> 0.25 mg/L)

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Summary of routine TDM recommendations – modified slide

Triazole Efficacy target(mg/L) a

Toxicity target(mg/L)a,b

SOR Timing of first trough sample

VoriconazoleProphylaxisTherapy

> 1.5-2c

> 1.5-2c

< 5-6< 5-6

AII (efficacy)AII (toxicity)

After 2-5 days;(repeat sampling recommended)

PosaconazoleProphylaxisTherapy

> 0.7> 1.0

No recommend.No recommend.

BII (efficacy)AII (efficacy)

Tablet/IV: after3 days:

Suspension: 5-7 days.*

IsavuconazoleTherapy(personal viewpoint)

Average population exposure 2- 4

No recommend.

*earlier sampling possible and may be desirable during treatment.

* Earlier sampling possibleusing lower targets

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Criticism on TDM

• Animal models – clear signals

• Humans have a very heterogenic background of disease and infection

• Unidirectional – only focussing on drug concentrations

• Focussing on total drug concentration rather then free drug

• Over the past decade limited advances

• Need for incorporation in phase III trials.

• No solid outcome markers other than fever and HR-CT

• Some use GM

• Time for new markers of response

• Time for disease progression modelling ESCMID eLibrary

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Take home message

• Azoles exhibit different pharmacokinetics and safety profiles and have different target concentrations

• TDM is a must for voriconazole• TDM for posaconazole and isavuconazole requires further investigations

• ECIL Guideline available at http://www.live-sante.fr/ecil/ • ESCMID Guideline recently published includes section in TDM

• Questions that arise: • Do we need to do it in every patient? • How often do we need to repeat sampling?• Does everybody has access to good facilities with short turn-around-

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mycology@radboudumc.nl

Center of Expertise in Mycology Radboudumc / CWZ

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