the role of clinical pharmacology in supporting the clinicians · 2018-12-10 · mate1 inhibition,...

The role of clinical pharmacology in supporting the clinicians

Letizia Marinaro

Clinica Universitaria di Malattie InfettiveOspedale Amedeo Di Savoia-Torino

The key concept of Therapeutic Drug

Monitoring (TDM) is to individualise

drug dosage to attain certain target

plasma concentrations

TDM in Antiretroviral Therapy

The rationale for TDM of antiretrovirals points on two main features:

a) Relationships between drug concentration and immunovirologicalbenefit - and in some cases, toxicity - have been established;

a) Available clinical data show significant interpatient variability atequal dose intake

TOXICITY

LACK OF EFFICACY

Desired concentration

interval

Scenarios for use of TDM (DHHS 2017, Italian Guidelines 2017, BHIVA 2016)

↗ Clinically significant drug-drug or drug-food interactions.

↗Persons of >50 years old treated with polipharmacy at higher risk of DDI.

↗ Pathophysiological states that may impair GI, hepatic, or renal function, potentially altering PK.

↗ Pregnant women at risk for virological failure as a result of their PK characteristics.

↗ Treatment experienced persons.

↗ Unusual combination regimens.

↗ Concentration-dependent toxicities.

↗ Lack of expected virological response, compliance issues

TDM CONs

↗ Lack of large prospective studies demonstrating that TDM improves clinical and virologic outcomes.

↗ Lack of established therapeutic range of concentrationsfor certain ARV drugs.

↗ Intrapatient variability in ARV drug concentrations.

↗ Lack of widespread availability of clinical laboratories and shortage of experts to assist interpretation of ARV concentration data..

TDM role in 2018?

Yesterday Today

Narrow therapeutic ranges (unboostedPI, EFV, NVP)

Wide therapeutic range (INSTI, PI/cobi, RPV)

Single drug formulations and multiple tablets (EFV, fosAPV, ATV, LPV, DRV)

Single tablet formulations

Concentration-dependant toxicity Optimal tolerability and no concentration dependant-toxicityclearly stated

TDM still useful un 2018?

↗ Data gap of certain ARV associations

↗ Unespected effects of concomitant drugs on ARV

↗ TDM of concomitant drugs

ARV Mechanism that may affect absorption

Enzymes that metabolize or are induced or inhibited by ARV Other mechanisms of drug interactions

P-glyco-protein CYP Substrate CYP Inhibitor CYP inducer UGT1A1

COBICISTAT Inhibitor 3A4 3A4, 2D6 --- --- BCRP, OATPs, MATE1 inhibition, only weak PXRactivation

RITONAVIR SubstrateInhibitor

3A4, 2D6 3A4, 2D6 1A2,2B6,2C9,2C19,2C8

Inducer BCRP, OATPs, MATE1 inhibition, PXRactivation

a key difference

• Drugs glucuronated and/or metabolized by inducible CYPs but not by CYP3A are predicted to be decreased by RTV and not affected by COBI.

• Drugs glucuronated and/or metabolized by inducible CYPs to a larger extent than CYP3A are predicted to be decreased by RTV and moderatly increased by COBI.

• Drugs subject to induction or inhibition are predicted to be decreased or increased by RTV but only increased by COBI1.

1C Marzolini et Al. JAC 2016

from RTV to Cobi-1

↗ P.R. male, 54-year-old

↗ Previous multiple regimen changes due to tolerability and selection of multiclass resistancemutations (R to all NRTIs and NNRTIs; minor mutations for PIs)

↗ DRV/r 800/100+ DTG 50 mg QD

↗ BUT…

ARV Mechanism affecting absorption

Enzymes that metabolize or are induced or inhibited by ARV

Other mechanisms of drug interactions

P-glyco-protein

CYP Substrate

CYP Inhibitor

CYP inducer

UGT1A1

COBICISTAT Inhibitor 3A4 3A4, 2D6 --- --- BCRP, OATPs, MATE1 inhibition, only weak PXR activation

RITONAVIR SubstrateInhibitor

3A4, 2D6 3A4, 2D6 1A2,2B6,2C9,2C19,2C8

Inducer BCRP, OATPs, MATE1 inhibition, PXR activation

DOLUTEGRAVIR Substrate 3A4 (minor)

Substrate

ELVITEGRAVIR 3A4 2C9

ARV-ARV interactions

Efficacy, tolerability and pharmacokinetics of dual therapy based on dolutegravir (DTG) and darunavir/ritonavir (DRV/r) qd in the clinical setting M. Ferrara, L. Marinaro, et al. ICAR 2017

•PBMC-to-plasma ratio was higher as compared toDTG with other PI (0.3 vs 0.1).

•This finding suggests that DTG decrease observed inplasma is counterbalanced by a high degree ofintracellular penetration, accounting for the antiviralefficacy of the regimen.

1.Tivicay US Prescribing Informations, ViiVHealthcare, August 2013

from RTV to Cobi-1

PCR HIV> 20 copies/ml

DRV/RTV + DTG 50 mg

After few months, with DRV/COBI available, the patient switched to

DRV/COBI + DTG 50 mg.

TDM: Reference1,2

DRV Ctrough ng/mL 898 2041 (368-7242) geomean (IQR)

DTG Ctrough ng/mL 250 830 (26) geomean(CV%)

TDM: Reference


DTG Ctrough ng/mL 786 830 (26) geomean(CV%)

1. Prezista FDA Prescribing informations, 2. Min S et Al. AIDS 2011

from RTV to Cobi-1

Gervasoni C, Riva A, Cozzi V, Capetti A, Rizzardini G, Clementi E, Cattaneo D. Effects of ritonavir and cobicistat on dolutegravirexposure: when the booster can make the difference.J Antimicrob Chemother. 2017

from RTV to Cobi-2

↗ G.G., female, 73 years old,

↗ Multitreated patient (R to NRTIs, harbouring 1 DRV-RM)

↗ DRV/r 800/100 + ETV 400 qd + RAL 400 bid

↗ She asked for simplification to DRV/cobi (GI intolerance, triglycerides increase)

↗ TDM-controlled switch was planned

from RTV to Cobi and back

PCR HIV< 20 copies/ml

DRV/RTV+ETV 400 qd+ RAL

DRV/COBI+ETV 400 qd+ RALTDM: Reference1


TDM: Reference1


1. Prezista FDA Prescribing informations

Due to therapeutical and virological history, the patient was switched back to DRV/RTV

Pharmacokinetics of darunavir/cobicistat and etravirine alone and co-administered in HIV-infected patientsJosé Moltó et al. JAC 2017

CONCOMITANT DRUG ARV

Lower dolutegravir plasma concentrations in HIV-positive patients receiving valproic acid. A. Palazzo et Al. J Antimicrob Chemother 2017

With intravenous valproic acid, DTG AUC 82% lower

than the mean reference AUC value for dolutegravir

q12h (75.1 lgh/mL),

with oral valproic acid 500 mg q8h it was 87% lower

with oral valproic acid 250mg q8h it was 90.5%lower.

• Dolutegravir absorption may be limited from

excipients such as magnesium stearate.

• Enzymatic induction of dolutegravir

metabolizing enzymes (such as CYP3A4 and

UGT1A1) or dolutegravir-transporting enzymes

(such as P-glycoprotein)

ARV CONCOMITANT DRUG

↗ M.F., male, 50-year-old

↗ HIV/HCV since 1993

↗ Previous IVDU, alchool abuse

↗ Long therapeutic history, frequent interruptions


Comorbidities and treatments

• Hypotiroidism ✓ Levotiroxine 100 mcg

• Osteoporosis ✓ Risedronate

• Peripheral neuropathy ✓ Pregabalin 300 mg

• Hypogonadism ✓ Topical testosterone

• Prostate adenoma ✓ Terazosine 2 mg

• Substitutive therapy ✓ Methadone 25 mg

• Sleeping disorders ✓ Flurazepam 15 mg

• Bipolar disorder ✓ Quetiapine 200 mg

RALTEGRAVIR+

DARUNAVIR 800/COBICISTAT


“ Doctor, I’m doing quite well but I’m disappointed, can’tunderstand this weight gain, I’m almost 20 Kg extra since I take allthose drugs together, I used to be an handsome guy. I’m toolazy…”

Quetiapine + DRV/COBI: quetiapine primarly methabolized by CYP3A4, interaction not studied but based on expected COBI/RTV effect quetiapine is not recommended by European medicine Agency and US Prescribing Information recommends thatquetiapine should be reduced to one sixth of the original dose.


Quetiapine main side effect: extrapyramidal symptoms, tardive

dyskinesia, hyperglycemia, weight gain, dyslipidemia, hyperprolactinemia, orthostatic hypotension, blood pressure increases, hypotiroidism, QT prolongation.


Quetiapine main side effect: extrapyramidal symptoms, tardive

dyskinesia, hyperglycemia, weight gain, dyslipidemia, hyperprolactinemia, orthostatic hypotension, blood pressure increases, hypotiroidism, QT prolongation.

QUETIAPINE TDM: 970 ng/mL (expected target range 100-500 ng/mL, alert level 1000 ng/mL)

M. Grundmann et Al. Acta Pharm. 64 (2014) 387–401, Simon A. et Al. Ther Adv Psychopharmacol. 2013 Jun;3(3):129-37.


↗ A.R. 76-year-old

↗ DTG + DRV 800 mg/RTV

↗ eGFR 60 mL/min

↗ Asks for an ARV simplification to DRV/COBI

↗ Atrial fibrillation: which oral anticoagulant?

The Effect of Dabigatran Plasma Concentrations and Patient

Characteristics on the Frequency of Ischemic Stroke and Major Bleeding in

Atrial Fibrillation Patients-The RE-LY Trial (Randomized Evaluation of

Long-Term Anticoagulation Therapy). Reilly et al. JACC, 2014

• The efficacy and safety of dabigatran etexilate were

demonstrated in the RE-LY (Randomized

Evaluation of Long-Term Anticoagulation Therapy)

trial, but a therapeutic concentration range has not

been defined

• Ischemic stroke and bleeding outcomes were

correlated with dabigatran plasma concentrations.

Age was the most important covariate. Individual

benefit–risk might be improved by tailoring

dabigatran dose after considering selected patient

characteristics.

• However, there is large variability in the plasma

concentrations achieved with any given dose,

depending on absorption, renal function, and other

patient factors.


DABIGRATAN WARFARIN

Dosing Once or twice daily Once daily

Monitoring Not required (but really not necessary? Tromboplastin Time, TDM)

PT/INR

Bleeding risk comparable comparable

Reversal agent Idarucizumab vitamin K, FFP, PCC, rFVIIa

Methabolism/transport P-gp, MATE-1 S-enantiomer (more potent) CYP2C9, R-enantiomer CYP1A2, CYP3A4, CYP2C19

Effect of RTV DHHS: The extent of interaction of PI/r + dabigratran is unknown. Consider alternative ARV or warfarin. If coadministered, take dabigatran and PI/r simultaneously.

warfarin reduced, required dose increaseCYP2C9 induction. DHHS: Monitor INR closely when stopping or starting PI/r and adjust warfarin dose accordingly.

Effect of COBI dabigatran AUC ↑ 110%–127%P-gp and MATE-1 inhibitionDHHS: Coadministration is notrecommended. Consider alternative ARV or warfarin.

no significant effect, dose adjustment required if switched from RTV boosteddue to possible increase in warfarin exposures.


1 DRV/RTV + DABIGRATAN:

• Dose 110 mg bid in >75 years, avoid if eGFR < 30 ml/min.

• Large interpatients variability (5.5-fold variation) in plasma exposure,

• Plasma exposures in patients administered with ATV/RTV and LPV/RTV similar to those

reported in RE-LY trial. Caution in co-somministration, better if concomitant.

• Tromboplastin Time test.

• TDM monitoring to avoid risk of lack of anticoagulant effect or bleedind.

2 DRV/RTV + WARFARIN:

• RTV CYP2C9 induction, warfarin exposure reduced, difficult to reach and maintain

desired INR target

• Frequent clinical assessmentes required.

• DHHS: Monitor INR closely when stopping or starting PI/r and adjust warfarin dose

accordingly.

3 DRV/COBI + WARFARIN:• no significant effect expected, monitor INR closely and dose adjustment if switched from

RTV boosted due to possible significant increase in warfarin exposures and consequent

bleeding risk.Reilly et al. JACC 2014, DHHS Guidelines for the Use of Antiretroviral Agents in Adults

and Adolescents Living with HIV 2017, Tseng et al. Ann Pharmacother 2017

Conclusions

↗ Drug exposures are not always predictable in certain situations:

• in case of unconventional ARV combinations and switch from RTV to COBI boosting;

• in elderly patients more prone to be treated with multiple drugs;

• in case of unexpected ARV effect on concomitant drugs or viceversa.

Conclusions

↗ A comprehensive analysis of all interactive drugs and conditions to which the single patient is exposed is nowadays required.

↗ TDM requirement is shifting from ARV to concomitant drugs exposures study to provide a better description of the complex interplay between different treatment elements.

A special thanks to all the Staff of the InfectiousDiseases Unit and of the Clical PharmacologicalLaboratory , University of Turin, Ospedale Amedeo Di Savoia.

Acknowledgments

the role of clinical pharmacology in supporting the clinicians · 2018-12-10 · mate1 inhibition,...

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