Which TDM in 2018?- The support of the pharmacology lab

Prof. Antonio D'AvolioLaboratory of Clinical Pharmacology and Pharmacogenetics

Department of Medical Sciences, University of Turin, ASL Città di Torino, Amedeo di Savoia Hospital, Turin, ItalyWeb Site: www.tdm-torino.org ; e-mail: info@tdm-torino.org; PHASE I A.I.F.A., UNI EN ISO 9001:2008; 13485:2012 CERTIFIED LABORATORY

Sottogruppo di Studio SIBIOC “Therapeutic Drug Monitoring (TDM) e Personalizzazione della Terapia”

Antonio D’Avolio Disclosure/Conflict of Interest

Grant/Research Support: none

Consultant/Advisor: Shimadzu, HDC

Sponsored Lectures: Merck-Millipore

Sponsored Writing: Novartis

Shareholder Company: CoQua Lab srl

from last 5 years to date

The right drug

The right amount of the right drug

The right amount of the right drug to the right person

Resistance Testing TDM Pharmacogenomics

The Role of Diagnostics for anti-infectives

From Prof. David Back 2003

It was an indication how the laboratory needed to be equipped and implemented

TDM Laboratory Evolution

2003 2018

The pharmacology laboratory evolution probably has been dependent by guidelines…

…we developed methods with few drugs to quantify…

... the number of drugs increased (need for more

complex methods or methods with more complex

instruments… LC-MS)

Immunosuppressant are only as an example.

Indications were given to dose the concomitant drugs that could be influenced by antiretrovirals

XX

Ribavirin TDM

(haemolytic anaemia)

No TDM for DAAs……but you have manage the possible (many)

interactions…

Proportion of Patients on Co-Medication with Potential DDI to at

Least One of Chronic HCV Treatment

Comorbidities, Comedication and Potential DDIs in CHC Patients in Spain

• HCV infection is associated with high comorbidity and use of concomitant medication, especially in older

patients. Due to differences in DDI potential among HCV regimens, prescribers need to carefully select

the appropriate DAA.

Potential Contraindications According to Antiviral Therapy Received

Sicras et al 2016. EASL 2016. Poster SAT-116

Currently research interest has been extended beyond measuring only plasma concentrations, because it has been realized that this may not be representative of the drug that is present at the site of

action or tissue of Interest

Currently, with the advancement in HCV therapies and increased rate of HIV/HCV coinfection being simultaneously treated, new

drug–drug interactions have become a concern. The effects may manifest in changes in systemic or tissue exposure of the DAA or

ARV. Potentially this could cause increases in exposure, resulting in

adverse or toxic effects, or decreases in efficacy.In addition, these interactions could extend to concomitant

medications commonly used in this patient population, such as antihypertensives, statins, and opioid maintenance therapy.

…but what is more important?

PK of DAAs?• Toxicity - Simeprevir• Response - Sofosbuvir (metabolite)

• SVR > 90-95%

PK co-administered drugs? es. Amiodarone?es. Dabigatran?

Coadministration has not been studied but may increase amiodaroneconcentrations due to mild inhibition of intestinal CYP3A4 by simeprevir. Mild increases in simeprevirconcentrations may occur due to inhibition of CYP3A4 by amiodarone. Caution is warranted and therapeutic drug monitoring for amiodarone and/or clinical monitoring (ECG etc.) is recommended.

Coadministrationhas not been studied and is not recommended due to the potential for serious and/or life-threatening adverse events such as cardiac arrhythmias.

FDA Drug Safety Communication: FDA warns of serious slowing of the heart rate when antiarrhythmic drug amiodarone is used with hepatitis C treatments containing sofosbuvir (Harvoni) or Sovaldi in combination with another Direct Acting Antiviral drug

U.S. Food and Drug Administration10903 New Hampshire Avenue

Silver Spring, MD 209931-888-INFO-FDA (1-888-463-6332)

Our review of submitted postmarketing adverse event reports found that patients can develop a serious and life-threatening symptomatic bradycardia when either Harvoni or Sovaldi combined with another direct-acting antiviral is taken together with amiodarone. The reports included the death of one patient due to cardiac arrest and three patients requiring placement of a pacemaker to regulate their heart rhythms.

In 6 of the 9 patients, symptomsoccurred within 24 hours after the first dose of

therapyfor hepatitis C virus (HCV) infection;

in the other 3 patients between 2 and 12 days.

All patients were on amiodarone; 7 of them also took a b-blocker.

HCV therapy consisted of sofosbuvir in all 9 cases towhich was added

daclatasvir in 5, ledipasvir in 3,

simeprevir in 1.

November 2015Volume 149, Issue 6, Pages 1315–1317

TDM Laboratory Evolution

2003 2018

From the antivirals…………………………. to the co-administered drugs

Quantified drugs in the Laboratory of Clinical Pharmacology and

Pharmacogenetics, «Amedeo di Savoia» Hospital, Turin (Italy)

…do you remember?

Limitations to TDM

Several factors limit the routine use of TDM:

• the absence of prospective studies that demonstrate the usefulness of TDM in improving clinical outcomes.

• the absence of a defined therapeutic range, or uncertain cut-off/thresholds of activity (with not many exceptions).

• the great intra- and inter-patient variability in drug concentrations achieved.

• the lack of experts to help in the evaluation of the results, and apply them by modifying the therapeutic regimen.

• a lack of commercial laboratories to perform real time quantitation of ARV concentrations.

• high costs for shipping to (few) qualified centers/laboratory (with know-how and certifications).

• the speed of reporting (absence of automation [if immuno-enzymatic systems are not used], with few exceptions).

FAQ and Answers

• Which is the best shipping condition for the sample?

– To close laboratory: The primary tube has to come as quickly as possible to the laboratory to process the tube, collect the plasma and analyze or frozen it immediately.

– To external Laboratory: The best condition (Gold Standard) for shipping, for all antivirals TDM, is frozen plasma samples, with dry ice.

Future solutions for Dried Blood Spots (DBS) and Dried Plasma Spots (DPS)

DSSD

Lab. Pharmacology, Osp. Amedeo di Savoia (TO) ITALY

News about samples shipping

• Which is the best shipping condition for the samples?

– New way with Dried Plasma Spots (DPS) and Dried Blood Spots (DBS) with delivery at room temperature and low-cost.

• Safe system (CDC Atlanta -> DBS = non-infectious!)

• Not for all drugs, but ONLY for thermostable drugs.

DPS

DBS

ADVANTAGES

• They do not require sample

centrifugation

DISADVANTAGES

• Correction for the hematocrit

is often necessary

• Clinical studies refer to

plasma levels

OPTIMAL

• Pediatric samples

ADVANTAGES• Correction for the hematocrit is

not necessary

• Better stability of drugs

DISADVANTAGES• They require the

centrifugation of the sample (not always)

• Measurement of a volume (not always)

• OPTIMAL• Elasticity of use and scope

DRIED BLOOD SPOTS

(DBS)

DRIED PLASMA SPOTS

(DPS)

DBS vs DPS

Dried Sample Spots Device (DSSD)

Laboratory of Clinical Pharmacology and Pharmacogenetics,

«Amedeo di Savoia» Hospital, Turin (Italy)

Antiretrovirals (Nevirapine,

Efavirenz, Etravirine, Raltegravir,

Maraviroc, Atazanavir, Nelfinavir,

Darunavir, Amprenavir, Indinavir,

Lopinavir, Ritonavir, Saquinavir,

Tipranavir, Elviltegravir,

Dolutegravir, Rilpivirine)

Antivirals (Ribavirin)

Antifungals (Voriconazole,

Posaconazole, Itraconazole,

Isavuconazole)

Antibiotics (Daptomycin,

Linezolid)

Anticancer (TKI; Ponatinib,

Dasatinib, Nilotinib, Imatinib)

Antitubercolars (Rifampicin,

Isoniazide, Pyrazinamide,

Ethambutol)

Soon… Antihypertensive

drugs …and many other

thermostable drugs…

Clinicians and researchers have become very enthusiastic about the potential applications of

dried blood spot based mass spectrometric applications.

LC-MS allows to detect and quantify many analytes (co-administered drugs) simultaneously.

Wagner M, Tonoli D, Varesio E, Hopfgartner G. Theuse of mass spectrometry to analyze dried blood spots.Mass spectrometry reviews. 2016;35(3):361-438.

LC-MS is the future of TDM and

clinical analysis

LC-MS is the future (in the present)

Optimal instrumentation for “Multiple-TDM”

Conclusions• From 2003… TDM is not routinely necessary for ARVs and DAAs or

required by treatment guidelines➢ Rationale only for selected drugs or settings

• Today… TDM is very useful for the management (measurements) of DDIs (co-administered drugs to antivirals)➢ Daily evidence emerges on interactions (expected and

unexpected) with other concomitant drugs, in real life

• Future… “Multiple-TDM”: as simultaneously measurements of ARVs/DAAs and co-administered drugs? (LC-MS?)

• Use of DBS or DPS as a tool to encourage widespread of TDM➢ Key points (thermostable drugs only and turnaround time [?])

University of Turin

Acknowledgement

Prof. Giovanni Di PerriProf. Stefano Bonora

Prof. Francesco Giuseppe De RosaAndrea Calcagno

Maria Cristina TettoniLaura Trentini

Letizia MarinaroGiuseppe CaritiLucio Boglione

Chiara CardellinoSilvia Corcione

www.tdm-torino.org

Laboratory of Clinical Pharmacology and Pharmacogenetics

PHASE I A.I.F.A, UNI EN ISO 9001:2015 and 13485:2012 (CE-IVD) Certified Laboratory

The Laboratory TeamMauro SciandraJessica Cusato

Amedeo De NicolòValeria Avataneo

Marco SimieleSarah Allegra

Giovanna FatigusoCristina Tomasello

Chiara CarcieriIlaria Zedda

Miriam Antonucci…and the students

Scientific PartnersMassimo Tempestilli (Roma)

Marco Cantù (Bellinzona, SUI)Antonello Di Paolo (Pisa)

www.coqualab.it