The role of clinical pharmacology in supporting the clinicians · 2018-12-10 · MATE1 inhibition,...
Transcript of 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
DRV Ctrough ng/mL 987 2041 (368-7242) geomean (IQR)
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
DRV Ctrough ng/mL 282 2041 (368-7242) geomean (IQR)
TDM: Reference1
DRV Ctrough ng/mL 986 2041 (368-7242) geomean (IQR)
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
TDM still useful un 2018?
↗ Data gap of certain ARV associations
↗ Unespected effects of concomitant drugs on ARV
↗ TDM of concomitant drugs
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)
TDM still useful un 2018?
↗ Data gap of certain ARV associations
↗ Unespected effects of concomitant drugs on ARV
↗ TDM of concomitant drugs
ARV CONCOMITANT DRUG
↗ M.F., male, 50-year-old
↗ HIV/HCV since 1993
↗ Previous IVDU, alchool abuse
↗ Long therapeutic history, frequent interruptions
ARV CONCOMITANT DRUG
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
ARV CONCOMITANT DRUG
“ 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.
ARV CONCOMITANT DRUG
Quetiapine main side effect: extrapyramidal symptoms, tardive
dyskinesia, hyperglycemia, weight gain, dyslipidemia, hyperprolactinemia, orthostatic hypotension, blood pressure increases, hypotiroidism, QT prolongation.
ARV CONCOMITANT DRUG
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.
ARV CONCOMITANT DRUG
↗ 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.
ARV CONCOMITANT DRUG
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.
ARV CONCOMITANT DRUG
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