Pharmacology considerations when choosing...

Pharmacology considerations when choosing INSTIs

David Back

University of Liverpool

Salvador – August 2019

Disclosures

• Honoraria received for advisory boards and lectures from AbbVie, BMS, Gilead, Merck, ViiV, Janssen, Teva

• Educational grants for www.hiv-druginteractions.org, www.hep-druginteractions.org, and www.cancer-druginteractions.orgfrom AbbVie, BMS, Gilead, Janssen, Merck, ViiV, Astellas, AstraZeneca, Boehringer Ingelheim, BMS, Ipsen, Janssen, Pfizer, Roche, Sanofi

http://www.hiv-druginteractions.org/

http://www.hep-druginteractions.org/

http://www.cancer-druginteractions.org/

Google images

Since Salvador 2018!

Copa Americana Champions League

1. What are the Key Pharmacological Characteristics of

Integrase Inhibitors?

Google images

Spot the difference!

The Integrase Inhibitors – similar but different! STRUCTURE

Mg

Mg

Integrase

Inhibitor

Mechanism of Binding

White K,, CROI 2017 and Back D

The Integrase Inhibitors – similar but different! BINDING

Mg

Mg

Integrase

Inhibitor

Mechanism of Binding

White K,, CROI 2017 and Back D

Dissociation of INSTI from wild type IN-DNA Complexes

Note: A different method for estimating the dissociation half-life (by exponential decay) gives higher values (see Hightower et al AAC 2011; 55: 4552-4559.

The Integrase Inhibitors – similar but different! HALF LIFE

Podany A et al Clin Pharmacokinet 2017; 56: 25-40

Integrase Inhibitor Elimination Half-Life (hours)

Bictegravir ~18

Dolutegravir ~14

Raltegravir ~9

Elvitegravir/c ~12Time

Dru

g C

on

cen

trat

ion

in

Pla

sma

0 24(h)

Elimination half life

IQ = The number of times Ctrough is above the PA EC95

Time

Ctrough Ctrough

Dru

g C

on

ce

ntr

ati

on

in

Pla

sm

a

PA EC95

PA EC95

IQ

Drug Concentration Time-Curve at Steady State

Kabagambe et al. BHIVA 2019, O08; Podany AT et al Clin Pharmacokinet 2-17; 56: 25-40

Integrase Inhibitor Inhibitory Quotient (IQ)

Raltegravir 8

Elvitegravir/c 10

Bictegravir 16.1

Dolutegravir 17.0

The Integrase Inhibitors – similar but different! INHIBITORY QUOTIENT

The Integrase Inhibitors – similar but different! FORGIVENESS

Elliot E et al JAIDS 2016; 71:1031-1036

Dolutegravir

Elvitegravir

RALTEGRAVIR ELVITEGRAVIR DOLUTEGRAVIR BICTEGRAVIR

DOSE 400 mg BID*1200 mg QD

150 mg QD with cobi in FDC with F/TDF or F/TAF

50 mg QD alone or in FDC with ABC/3TC; also FDC with RPV

50 mg QD in FDC with FTAF

1. Isentress SmPC 29th Nov 2018; 2. Stribild SmPC 15th Nov 2018; 3. Tivicay SmPC 14th Feb 2019; 4. Biktarvy SmPC 2nd Nov 2018.

Other Key Pharmacological Characteristics of the Individual Integrase Inhibitors - 1

BID, twice daily; QD, once daily. CYP3A, cytochrome P450 3A4; UGT1A1; uridine glucuronyl transferase 1A1.






METABOLISM UGT1A1 CYP3A (major), UGT1A1/3 (minor)

UGT1A1 (major), CYP3A (minor)

UGT1A1 and CYP3A (equal)









METABOLISM UGT1A1 CYP3A (major), UGT1A1/3 (minor)

UGT1A1 (major), CYP3A (minor)

UGT1A1 and CYP3A (equal)

DRUG INTERACTION POTENTIAL (DDI)

Least Highest (due to booster)

Slightly greaterthan RAL

Slightly greater than RAL




Comparative Tablet Size for Integrase Inhibitor-Containing Fixed Dose Regimens

Gaur A et al CROI 2018; Abs 844; Boston. USA

B/F/TAF 275 mg*; with or without food

E/C/F/TAF 510 mg*; with food

DTG/ABC/3TC 950 mg*; with or without food

*Active Drug

2. Are drug interactions really an issue in the Integrase era?

Antiretroviral Drug Approval 1987-2019

The Integrase Era

Back D; Personal communication

… when co-administration leads to safety, efficacy or tolerability issues greater than when drugs are administered alone.

When are Interactions of Concern?

Back DJ, personal communication

≈ 780 co-meds

No interaction Potential weak interaction

Interaction of clinical relevance Drugs should not be co-administered

n ≈ 780 Co-medications

Efavirenz Rilpivirine Doravirine

Boosted ARV BictegravirRaltegravir Dolutegravir

Etravirine

Interaction Profile of Antiretroviral Drugs: www.hiv-druginteractions.org

Available at: www.hiv-druginteractions.org.

▪ Retrospective, non-interventional cohort study.▪ DDI considered if ‘Do not co-administer’ statement in www.hiv-druginteractions.org▪ Annual healthcare costs were $16,219 for those without DDI and $19,784 for those

with DDI; unadjusted difference of $3564

Open Forum Infectious Diseases 2019 Mar 22;6(3):ofz051;.

Risk and Cost

Mechanisms of Interactions of Integrase Inhibitors

GI, gastrointestinal; P-gp, P-glycoprotein; BCRP, breast cancer resistance protein; OAT, organic anion transporter; MRP, multidrug resistance-associated protein; UGT, UDP-glucuronosyltransferase; PI, protease inhibitor; /r, ritonavir; /c, cobicistat.

Enzyme = CatalystTransporter = PumpVictim drugsPerpetrator drugs

Drug

Metabolite, M

Metabolite glucuronide, MG

Gut Lumen

Enterocyte

Portal Blood Hepatocyte Bile Duct

pH

BCRP

OATP1B1

OATP1B3

MRP3

MRP3

OATP1B3

OATP1B1

MRP2

MRP2

BCRP

P-gp

P-gp

BCRP

P-gp

CYP3A4

BCRP

P-gp

CYP3A4

M

M

CYPs M

UGTsMG

CYPsM

UGTs

MGChelation with

CationsIntegrase inhibitors

Induction, Inhibition of Hepatic Transporters; CYPs & UGTs

BIC, RAL; DTG; EVG

Induction, Inhibition of GITransporters, & CYP Enzymes

eg TAF + Rifampicin


Some DDIs can Occur in the Kidney

OAT, organic anion transporter; OCT, organic cation transporter; MRP, multidrug resistance-associated protein; MATE, multidrug and toxin extrusion protein.

Song IH, et al. J Acquir Immune Defic Syndr 2016; 72(4):400–407;Custodio J, et al. Open Forum Infect Dis 2017; 4(Suppl1):S249.

Active tubular secretion

Basolateral(Blood) Apical

(Urine)

Tenofovir (TFV)

Creatinine

DolutegravirBictegravir

Mitochondria

OAT-1

OAT-3

OCT-2

MRP2

MRP4

MATE1

CobicistatRitonavir

Proximal tubule

Metformin

M e t f o r m i n i n P l a s m a

T i m e , h

Me

tf

or

min

C

on

ce

nt

ra

tio

n, n

g/m

L

0 4 8 1 2 1 6 2 0 2 4

1 0

1 0 0

1 0 0 0

1 0 0 0 0

P l a c e b o

B / F / T A FAUC + 39%

Bictegravir on Metformin

Dolutegravir on Metformin

AUC + 79%

Agent USPI

Dofetilide Contraindicated

Carbamazepine 50 mg twice daily in INSTI naive

Oxcarbazepine Should be avoided

Phenobarbital Should be avoided

Phenytoin Should be avoided

SJW Should be avoided

Rifampicin 50 mg twice daily in INSTI naive

Efavirenz 50 mg twice daily in INSTI naive

Fosamprenavir/r 50 mg twice daily in INSTI naive

Cation containing antacids DTG 2 h before or 6 h after

Oral iron/calcium

supplements

DTG 2 h before or 6 h after

Etravirine Should not be used without

ATV/r, DRV/r, or LPV/r

Metformin Close monitoring; limit total daily

dose

Tivicay USPI; Tivicay SmPC; Tivicay JPI (all accessed January 2019);recommendations where there is known/considered interaction.

Dolutegravir is a VICTIM of interactions

except dofetilide and metformin

* Or absence of integrase resistance; ** Japan label differs from the USPI and the SmPC;SJW, St. John’s Wort; /r, ritonavir; INSTI, integrase strand transfer inhibitor; DTG, dolutegravir; ATV, atazanavir; DRV, darunavir; LPV, lopinavir; bPI, boosted-protease inhibitors.

Established and Other Potentially Significant DDIs: Dolutegravir

Note: ORANGE means an interaction of potential clinical relevance – need to do something! It does not mean do not give!

Agent USPI SmPC

Dofetilide Contraindicated Contraindicated

Carbamazepine 50 mg twice daily in INSTI naive 50 mg twice daily in INSTI naive

Oxcarbazepine Should be avoided 50 mg twice daily in INSTI naive

Phenobarbital Should be avoided 50 mg twice daily in INSTI naive

Phenytoin Should be avoided 50 mg twice daily in INSTI naive

SJW Should be avoided 50 mg twice daily in INSTI naive

Rifampicin 50 mg twice daily in INSTI naive 50 mg twice daily in INSTI naive

Efavirenz 50 mg twice daily in INSTI naive 50 mg twice daily in INSTI naive

Fosamprenavir/r 50 mg twice daily in INSTI naive No dose adjustment in INSTI naïve*

Cation containing antacids DTG 2 h before or 6 h after Antacid 2 h after or 6 h before

Oral iron/calcium

supplements

DTG 2 h before or 6 h after Antacid 2 h after or 6 h before



Use 50 mg twice daily without a bPI.

Should not be used without bPI in

INSTI resistant.


dose

Dose adjustment should be considered






Different wording/

recommendation

✓

✓

✓

✓

Agent USPI SmPC Japan PI

Dofetilide Contraindicated Contraindicated Pilsicainide – Caution**

Carbamazepine 50 mg twice daily in INSTI naive 50 mg twice daily in INSTI naive 50 mg twice daily in INSTI naive

Oxcarbazepine Should be avoided 50 mg twice daily in INSTI naive – **

Phenobarbital Should be avoided 50 mg twice daily in INSTI naive Caution**

Phenytoin Should be avoided 50 mg twice daily in INSTI naive Caution**

SJW Should be avoided 50 mg twice daily in INSTI naive Caution**

Rifampicin 50 mg twice daily in INSTI naive 50 mg twice daily in INSTI naive 50 mg twice daily in INSTI naive

Efavirenz 50 mg twice daily in INSTI naive 50 mg twice daily in INSTI naive 50 mg twice daily in INSTI naive

Fosamprenavir/r 50 mg twice daily in INSTI naive No dose adjustment in INSTI naïve* Do not use in InH-resistant pts

Cation containing antacids DTG 2 h before or 6 h after Antacid 2 h after or 6 h before DTG 2 h before or 6 h after

Oral iron/calcium

supplements

DTG 2 h before or 6 h after Antacid 2 h after or 6 h before DTG 2 h before or 6 h after;

BUT with food at same time**




Should not be used without bPI in

INSTI resistant.


Do not use without either ATV/r,

DRV/r, or LPV/r in INSTI resistant.


dose

Dose adjustment should be considered;

particularly in renal impairment

Administer with care; reduce dose

as necessary**


✓





✓

CPT 2019; 105: 505-514

38 drugs selected – approved between 2008-2016;1727 co-meds documented in at least one label (average or 45 per study drug).

Message

DDIs

↑ Pill burden↓ Medication adherence↑ Prescribing cascade errorMultimorbidity

Polypharmacy(Inc non-prescription

drugs/supplements etc)

‘Polydoctory’

Reduced efficacy of HIV agent?

Reduced efficacy of co-medications?

Adverse effect?Perpetrator

Victim

Co-medARV

Cost

• DDIs may still be an issue in some patients on INSTIs – (older patients; polypharmacy; EVG/c).


3. Which co-meds should we be alert for?

Integrase Inhibitors: Contraindications or Do Not Coadminister*

Raltegravir (n=1) Dolutegravir (n = 7) E/C/F/TAF (n= 55) B/F/TAF (n= 15)

Al++/Mg++ antacids Dofetilide; Eslicarbazepine; Oxcarbazepine; Phenobarbitone;Phenytoin; Primidone; St John’s Wort

Dextropropoxyphene;Amiodarone; Disopyramide; Quinidine; Dofetilidie; Rifampicin; Rifapentine; Apixaban; Clopidogrel; Dabigatran; Rivaroxaban; Ticagrelor; Carbamazepine; Phenobarbitone; Phenytoin; Primidone; Astemizole; Terfenadine; Dihydorergotamine; Ergotamine; Halofantrine; Pimozide; Quetiapine; Adefovir; Boceprevir; Elbasvir/Grazoprevir; OBV/PTV/r;OBV/PTV/r + DSV; Simeprevir; Telaprevir; TAF (HBV); Midazolam; Everolimus; Avanafil; Cisapride; Domperidone; St John’s Wort; Aliskiren; Eplerenone; Ivabradine; Lercanidipine; Ranolazine; Sildenafil; Sirolimus; Lovastatin; Simvastatin; Alfuzosin; Fibanserin; Darifenacin; Ergometrine; Budesonide; Fluticasone; Mometasone; Triamcinolone

Dofetilide; Rifabutin; Rifampicin; Rifapentine; Carbamazepine; Oxcarbazepine; Phenobarbitone;Phenytoin; Primidone; St John’s Wort; Adefovir; Boceprevir; Telaprevir;

Relevant prescribing information and www.hiv-druginteractions.org

* Excluding ARV-ARV

Top 20 Global Co-medication Searches 2018: Liverpool database

PPI, proton-pump inhibitor.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Perpetrator Victim

No

of

Qu

erie

s

Statins

PPIs/H2 blockers

Antidiabetics

Analgesics

Antihypertensives

Anti-infectives

Psychotropic drugs

AntiplateletsAnticoagulants

HIV DDIs searched: 2018

Website 3.08M;76%

App955K24%

60,000

50,000

40,000

30,000

20,000

10,000

Top 20 Co-medications Generating the Most DDI Queries in www.hiv-druginteractions.org (MixPanel Analytics).

Relevant for unboosted INI

http://www.hiv-druginteractions.org/

Out of the Top 20 searches – 2 relevant for non-boosted INSTIs

Therefore, we suggest that physicians remain vigilant in monitoring for toxicity and limit the total daily dose of metformin to 1000 mg when metformin is taken concomitantly with dolutegravir, and suggest avoidance of this combination in patients at highest risk for metformin-associated lactic acidosis, such as elderly patients with suboptimal renal function.

Gervasoni C et al JAIDS 2017; 75: e24-26

Cattaneo D et al AIDS 2018; 32: 532-533

Naccarato M et al AIDS 2017; 31: 2176-2177.

#1. Drug Interactions with Statins

ATV, atazanavir; DRV, darunavir; EFV, efavirenz; DOR, doravarine; RAL raltegravir; DTG, Dolutegravir; BIC, bictegravir; EVG, elvitegravir; /c, cobicistat; /r, ritonavir; F, FTC; TAF, tenofovir alafenamide

www.hiv-druginteractions.org.

• Statins are Victims of DDIs.

• Increased exposure (eg boosted regimens) gives potential statin-associated muscle symptoms plus other side effects; reduced exposure (eg EFV) possible loss of efficacy

Agent ATV/r DRV/r DRV/c EFV DOR RAL DTG BIC/F/TAF EVG/c

Atorvastatin

Fluvastatin

Pitavastatin

Pravastatin

Rosuvastatin

Simvastatin

No interaction Potential weak interaction

Interaction of clinical relevance Drugs should not be co-administered

#1. However…

NRTI, nucleoside reverse transcriptase inhibitor; TC, total cholesterol . Myers J, et al. HIV Med 2018; 13:190–192

• Note: raltegravir, dolutegravir, bictegravir, doravarine & NRTIs do not interact with statins.

• Be careful re suboptimal dosing due to concern of DDI.

#2. DDIs with Proton Pump Inhibitors

No interaction Drugs should not be co-administered

Agent ATV/r DRV/r or DRV/c

RPV EFV DOR RAL DTG BIC/F/TAF EVG/c

Omeprazole *

Pantoprazole *

ATV, atazanavir; DRV, darunavir; EFV, efavirenz; DOR, doravarine; RAL raltegravir; DTG, Dolutegravir; BIC, bictegravir; EVG, elvitegravir; /c, cobicistat; /r, ritonavir; F, FTC; TAF, tenofovir alafenamide www.hiv-druginteractions.org.

* But note Dolutegravir/Rilpivirine!

#2. DDIs with Proton Pump Inhibitors + H2 Antagonists




Omeprazole *

Pantoprazole *

Ranitidine *

Interaction of clinical relevance


* But note Dolutegravir/Rilpivirine!

#2. DDIs with PPIs + H2 Antagonists + Antacids




Omeprazole

Pantoprazole

Ranitidine

Antacids

(cations)

Interaction of clinical relevance


• All the integrase inhibitors are affected by cation containing antacids BUT there are different recommendations dependent on the integrase inhibitor and the cations (Al++/Mg++ vs Ca++) and food effect.

• Separation of the antacid by +/- 2 hours (or greater) reduces the interaction for DTG, EVG and BIC but doesnot reduce interaction for RAL (qd). RAL (bid) can be used with Ca++ antacid.

Refer to the USPI or SmPC for full prescribing information

#2. However…

4. What about these drugs?

Gender Affirming Steroids


5. What about these patients?

Case: Clinical Characteristics

Nationality Caucasian

Age 62 years

BMI 20.1

HIV History Recently diagnosed with HIV; VL 105,000 cps/ml

CD4 520 cell/ul

HLA-B*5701 Negative

Chronic HBV No

Any history of drug resistance No

Renal function eGFR 50 ml/min

ComorbiditiesComplex medical history, multiplewell-controlled comorbidities, including hypertension, atrial fibrillation, diabetes, GERD

♂

GERD: Gastroesophageal reflux disease

Case: Co-medications

www.ncmedsoc.org; www.fda.gov.

Calcium channel blockers Amlodipine 10 mg

Lipid-lowering agent Atorvastatin 20 mg

New Oral Anticoagulant Dabigatran 150 mg twice daily

Antiarrthyhmic Digoxin 125µg/day

Antidiabetic Sitagliptin 50 mg

Proton-pump inhibitor Omeprazole 20 mg

Antidepressant Quetiapine 300 mg/day

Are you concerned about the DDIs with a first line integrase based regimen?

Case: Interactions of Integrase Inhibitors with the co-meds

No interaction Interaction of clinical relevance Drugs should not be co-administered

www.hiv-druginteractions.org

44

Case: Interactions of Integrase Inhibitors with the co-meds

▪ Other considerations:

• ABC/3TC/DTG not recommended (renal function);

• Also need to consider abacavir and cardiovascular risk.

• Recommend BIC/F/TAF or DTG + F/TAF or RAL + F/TAF

Expert opinion of the presenter

What would you do?

A 48 year old male has recently been referred to your clinic. His HIV viral load has been

suppressed on DTG/ABC/3TC for more than 1 year. He is receiving the following co-

medications for depressive psychosis; quetiapine, risperidone, olanzapine, mirtazapine,

oxcarbazepine. You immediately note that the recommended dosing for dolutegravir is

bd when oxcarbazepine is present. However his VL is suppressed and there are no

recorded blips. What do you do?

A.Nothing. It’s not broke – no need to fix it!

B.Add an additional DTG so that the regimen is now BID.

C.Consider an alternative to oxcarbazepine.

D.Switch to B/F/TAF

Always refer to the SmPC for all products for recommendations on managing potential DDIs

What would you do?

A 54 year old male with HIV who is well controlled on once daily

Dolutegravir, TAF/FTC has now developed Hansen’s disease and requires

rifampicin once a month. What do you do?

A.Nothing! Maintain HIV regimen without change.

B.Maintain QD DTG but switch TAF/FTC to TDF/FTC

C.Increase the DTG dose to 50 mg twice daily.

D.Increase the DTG dose to 50 mg twice daily for 1 week and then

continue on 50 mg once daily for the rest of the month.

E.Not at all sure!

Hansen’s disease (also known as leprosy) is an infection caused by bacteria called Mycobacterium leprae. These bacteria grow very slowly and it may take up to 20 years to develop signs of the infectionref: https://www.cdc.gov/leprosy/about/about.html accessed July 2019

Advice for Clinicians• DDIs are practically unavoidable in HIV care – there are many more with boosted

regimens and efavirenz.

• Be aware of the relatively few interactions with unboosted integrase inhibitors..

• Older patients particularly at risk: age-related co-morbidities and physiological changes.

• Managing interactions is the key

• Searchable online Drug Interaction checkers are a vital resource.

• Other key areas going forward:

Determine impact of eliminating medications

not essential for quality of life in older PLWH

1

Understand the implications for DDIs of

Long acting ARVs

2

Its all about Teamwork!

Liverpool Website Team & Editorial Board

Katie MossLiverpool

Katie McAllisterLiverpool

Justin ChiongLiverpool

Jasmine MartinLiverpool

Fiona MaraGlasgow

Jonathan SchapiroTel Aviv - Glasgow

Charles FlexnerBaltimore

Mohammed LamordeKampala

David BurgerNijmegen

Mas ChapondaLiverpool

Catia MarzoliniBasel

David BackLiverpool

Saye KhooLiverpool

Sara GibbonsLiverpool

Marta BoffitoLondon

Spanish and Portuguese versions of the website coming SOON

In Numbers: www.hiv-druginteractions.org

• Accessed from 188 countries across the world

• In the past 3 years around 8.5M DDIs have been downloaded,~ 4M in 2018

• Year-on-year increase in usage (+ ~20%)

• UK Standards require every GP letter to carry the URL

• Recommended tool for over 30 national or international HIV guidelines

• Translations: Japanese (HEP) in 2017, Spanish (HIV) version to launchDec 2019 and Portuguese (HIV) in Q1 2020.

• Database linkage for electronic prescribing in Uganda and Australia

Back Ups

Summary of Bictegravir Concentration (C24) Changes After Various Antacid/Supplement Co-administration Conditions

The effects on BIC PK and IQ were limited when antacids/supplements were administered either simultaneously with B/F/TAF under fed conditions or staggered from B/F/TAF administration by ± 2 h under fasted conditions

511. Lutz JD, et al. International Workshop on Clinical Pharmacology of Antiviral Therapy 2018, poster 6. Kabagambe, BHIVA, 2019, O08

0

20

0

25

50

75

100

125

Fasted Fed 2 hBefore

2 hAfter

Fasted Fed Fasted Fed%G

LS

M R

atio

(9

0%

CI)

fo

r B

IC C

24

47

16.1

7.6

Ca + B/F/TAFAI/Mg + B/F/TAF Fe + B/F/TAF

Pre

dic

ted IQ

in H

IV-1–In

fecte

d P

atie

nts

Refer to the SmPC for prescribing advice


RENAL

ELIMINATION

RENAL

ELIMINATION

~32% of dose (mainly glucuronide)

No dose

adjustment

Minimal; ~7%

eGFR > 30 (Genvoya)

eGFR > 70 (Stribild)

~31% of dose(primarily metabolites)

No dose adjust

(DTG)

eGFR > 50

(Triumeq)

~35% of dose (primarily metabolites)

eGFR > 30

(Biktarvy)



BID, twice daily; QD, once daily. CYP3A, cytochrome P450 3A4; UGT1A1; uridine glucuronyl

transferase 1A1.


CSF/Plasma

ratio

0.03a - 0.06b 0.003c 0.02d 0.003e

Semen/Plasm

a ratio

1.6-6.5f

1.8g

0.4h 0.08i No data

Breast Milk

/Plasma ratio

No data No data 0.02k No data

Other Key Pharmacological Characteristics of the Individual Integrase Inhibitors – 2. PENETRATION

aJohnson DH et al; PLOS ONE 2013; 8: e82672; bCalcagno A et al AIS Res Hum Retro 2016; 32: 409-411. c Croteau D et al AAC 2010; 56: 5156-5160; d Greener BN et al JAIDS 2013; 64: 39-44; e Tiraboschi J et al CROI 2019

Abs 474; f Calcagno A et al AAC 2010; 54: 2744-2745; g Le MP et al Pharmacotherapy 2019; [ahead of print]; h Imaz A et al HIV Med 2017; 18: 225-230; i Imaz A et al; JID 2016; 214: 1512-1519; k Kobbe R et al AIDS 2016; 30:

2731-2735;

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