Top DDIs in clinical practice: Still relevant?

Catia Marzolini University Hospital & University of Basel University of Liverpool

Adapted from Roden DM et al. Nat Rev 2002

Absorption

Metabolism

Excretion

Inhibition/induction intestinal CYPs or drug transporters

Change gastric pH

Chelation with mineral supplements

Inhibition of renal drug transporters

Inhibition/induction of hepatic CYPs, glucuronidation, or drug transporters

Drug-drug interactions potential of antiretroviral drugs

integrase inhibitors

atazanavir rilpivirine

maraviroc doravirine rilpivirine bictegravir tenofovir prodrugs

victim drugs perpetrator drugs

maraviroc doravirine rilpivirine bictegravir dolutegravir raltegravir

tenofovir bictegravir dolutegravir cobicistat ritonavir

PI/ritonavir PI/cobicistat EVG/cobicistat PI/ritonavir

PI/cobicistat EVG/cobicistat efavirenz etravirine nevirapine

Drug-drug interactions profiles of antiretroviral drugs

www.hiv-druginteractions.org

Efavirenz Rilpivirine Doravirine

no interaction potential weak interaction interaction of clinical relevance deleterious interaction

n ≈ 700 comedications

boosted ARV Bictegravir Raltegravir Dolutegravir

Etravirine

-

10.000

20.000

30.000

40.000

50.000

60.000

www.hiv-druginteractions.org

Top 25 comedications generating the most DDIs queries in www.hiv-druginteractions.org (MixPanel analytics)

……………………..…………… 50……………….…….100…………………….……200……

statins

PPIs/H2 blockers

antidiabetics

analgesics

antihypertensives

anti-infectives

psychotropic drugs

antiplatelets

anticoagulants

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

Top global comedications searches in 2018

erectile dys. agents

mineral suppl.

corticosteroids

Differences in magnitude of DDIs with statins explained by different metabolic pathways and affinities to drug transporters

Rosuvastatin + (transporters)

www.hiv-druginteractions.org, Annaert P et al. Xenobiotica 2010

and differences in inhibition of drug transporters among antiretroviral drugs

ATV/c

822%

ATV/r DRV/c DRV/r LPV/r EVG/c

290% 490%

213% 93% 48% 107% 38%

Atorvastatin + (CYP3A4 + transporters)

OATP1B1 inhibition

ATV > LPV > DRV > RTV, Cobi 242%

Atorvastatin + ATV/c Rosuvastatin + ATV/c

CYP3A4

# 1 – DDIs with statins

Management of DDIs with statins

www.hiv-druginteractions.org

ATV ATV/r ATV/c DRV/r DRV/c LPV/r EVG/c EFV ETV

Atorvastatin not recommended

Use lowest dose Max dose 10 mg

Use lowest dose Max dose 40 mg

Use lowest dose Max dose 20 mg

Use lowest dose Max dose 40 mg

Adjust dose based

on response

Fluvastatin Use lowest dose

Use lowest dose

Use lowest dose

Use lowest dose

Pitavastatin Use lowest dose

Use lowest dose

Use lowest dose

Pravastatin Use lowest dose

Use lowest dose

Use lowest dose

Adjust dose based

on response

Rovuvastatin Use lowest dose Max dose 10 mg

Use lowest dose Max dose 20 mg

Use lowest dose Max dose 10 mg

Simvastatin

Adjust dose based on response

Bictegravir, doravirine, dolutegravir, NRTIs do not interact with statins

# 2 – DDIs with antidepressants

Metabolism by several CYPs

Gutierrez MM et al. Clin Ther 2003, Aarnoutse RE et al. Clin Pharmacol Ther 2005, Spina E et al. Clinical Therapeutics 2008, Park J et al. J Clin Pharmacol 2010, Stader F et al. AAC 2018

mitigate DDIs magnitude RTV booster weak inhibitor of CYP2D6 and weak inducer of CYP2B6

Escitalopram metabolized by CYP3A4, 2C19, 2D6

Desipramine metabolized by CYP2D6

Bupropion metabolized by CYP2B6

www.hiv-druginteractions.org, Cattaneo D et al. World J Biol Psychiatry 2018

Larger proportion of PLWH with subtherapeutic antidepressants levels compared to uninfected individuals suggesting deliberate lower dosing of antidepressants as clinicians fear DDIs with antiretroviral drugs.

Drugs Reference range (ng/ml)

Cmin levels (ng/ml)

Subtherapeutic levels

Cmin levels (ng/ml)

Subtherapeutic levels

Citalopram 50-110 65 + 67 60% 73 + 58 34%

Duloxetine 30-120 32 + 35 63% 68 + 41 32%

Fluoxetine 120-500 204 + 190 50% 250 + 160 21%

Paroxetine 20-65 22 + 20 54% 150 + 116 33%

Sertraline 10-150 20 + 12 20% 47 + 43 6%

Venlafaxine 100-400 223 + 52 0% 288 + 239 23%

PLWH treated with ARV (n = 55) Uninfected individuals (n = 233)

Antidepressants levels in PLWH vs uninfected individuals

• no a priori dosage adjustment needed for several antidepressants when starting boosted regimens • caution warranted when combining ATV, ATV/c, ATV/r, LPV/r (avoid SQV/r) and antidepressants with potential to

prolong QT interval • avoid St John’s Wort as may substantially decrease the exposure of ARVs thus leading to loss of therapeutic effect • avoid tricyclic antidepressants in elderly as more sensitive to anticholinergic side effects (delirium, orthostatic hypotension)

# 3 – DDIs with PrEP and Chemsex

PEPT1 OATP2B1 OATP1A2 BCRP MRP2

MRP3 OCT1 MRP1

Intestine

P-gp

Tenofovir disoproxil fumarate

www.hiv-druginteractions, Moss D & Marzolini C. In: Drug Interactions in Infectious Diseases 2018

Inhibitors of P-gp or BCRP increase absorption of TDF and thereby systemic exposure of tenofovir monitor renal function:

Amiodarone Ketoconazole SOF/VEL Ciclosporin Quinidine SOF/VEL/VOXI Clarithromycin Ranolazine Verapamil Itraconazole SOF/LDV

PrEP

MRP4

OAT1

OAT3

urine

Tenofovir

Kidney

Drug interactions at intestinal level

Drug interactions at renal level

Inhibitors of renal transporters decrease elimination of tenofovir. Nephrotoxic comedications: additive risk for nephrotoxicity monitor renal function:

Adefovir (avoid) Antivirals Lithium AINS Carboplatin Methotrexate Aminoglycosides Cisplatin Oxaliplatin

Antoniou T et al. Ann Pharmacother 2002, Urbina A et al. Recreational drugs and HIV, a guide for clinicians 2014, Bracchi M et al. AIDS 2015

Higher potential for DDIs with ritonavir or cobicistat containing regimens Low potential for DDIs with bictegravir, dolutegravir, raltegravir, doravirine, rilpivirine, maraviroc and NRTIs

Recreational drugs Metabolism, theoretical DDIs with RTV/Cobi Signs of toxicity Recommendations

Methamphetamine CYP2D6: RTV/cobi as boosters limited CYP2D6 inhibition Cave: non linear PK + large variability in actual amount and presence of other substances

Hypertension, seizure, hyperthermia, arrhythmia, tachycardia, teeth grinding

• Avoid combination if possible • If unavoidable, start with 1/4-1/2 of the

usual amount and watch for toxicity signs MDMA (ecstasy)

Mephedrone CYP2D6: RTV/cobi limited CYP2D6 inhibition Tachycardia, agitation • Use lower dose, inform about toxicity signs

GHB GHB dehydrogenase, CYP? : Risk DDIs unknown Cave: narrow therapeutic index

Seizure, bradycardia, respiratory depression

• Caution, use lower dose, inform about toxicity signs

Cocaine CYP3A4 (minor): low-moderate risk of DDIs Tremor, paranoia, seizure, headache, hyperthermia

• Clinical relevance unknown, inform about toxicity signs

Ketamine CYP3A4: high potential for DDIs Respiratory depression, hallucinations • Avoid combination if possible otherwise start with 1/3-1/2 of the usual amount

Benzodiazepines CYP3A4: high potential for DDIs Drowsiness, disorientation • Avoid midazolam, triazolam • Caution with other BZD, use lower dose

Fentanyl CYP3A4: high potential for DDIs Pinpoint pupils, extreme sleepiness • Avoid as risk of fatal respiratory depression

Sildenafil, tadalafil, vardenafil

CYP3A4: high potential for DDIs

Chest pain, nausea, irregular heart beat • Lower dose: sildenafil 25mg/48h, tadalafil: 10mg/72h, vardenafil: 2.5 mg/72h

Nitrites (poppers) Non CYP mediated: no DDIs Dizziness, hypotension

DDIs with Chemsex

• when possible switch to antiretroviral drugs with low DDIs potential • if not possible: inform about risk of DDIs, toxicity signs and provide recommendations to limit harm

# 4 – DDIs with antihypertensives

www.hiv-druginteractions.org

boosted regimens EFV/ETV RPV BIC/DOR DTG/RAL

ACE inhibitors

Angio. antagonists

valsartan

adjust dose based on BP

B-blockers metoprolol

*

no a priori dose adjust.

Cal. channel inhibitors

amlodipine

diltiazem, verapamil

lacidipine, nifedipine

lercanidipine

*

reduce amlodipine by 50%

adjust dose based on BP *

start at low dose, monitor BP

adjust dose based on BP ARV

no need to adjust dose ARV

no need to adjust dose

*

start at low dose, monitor BP

adjust dose based on BP

adjust dose based on BP

Diuretics

eplerenone

adjust dose based on BP

* Risk of PR prolongation with ATV, ATV/r, ATV/c, LPV/r, SQV/r

# 5 – DDIs with metformin

Metformin is excreted unchanged in urine via active secretion

MATE2 OCT2

urine

Metformin

MATE1

+ dolutegravir + bictegravir

Song I et al. JAIDS 2016, Zhang H et al. IWCPT 2017

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 F

T i m e , m i n

La

cta

te

, m

gl/

dL

0 6 0 1 2 0

0

5

1 0

1 5

2 0

A f t e r M e t f o r m i n

B e f o r e M e t f o r m i n

T i m e , m i n

La

cta

te

, m

gl/

dL

0 6 0 1 2 0

0

5

1 0

1 5

2 0

A f t e r M e t f o r m i n

B e f o r e M e t f o r m i n

Dolutegravir QD Dolutegravir BID

metformin AUC + 79%

metformin AUC + 145%

Bictegravir QD

metformin AUC + 39%

Plasma lactate concentrations

bictegravir placebo

Stades AM et al. J Intern Med 2004, Eppenga WL et Al. Diabetes Care 2014

• Metformin-induced lactic acidosis rare • Cases: related to underlying conditions (no correlation with metformin levels) • Risk increased with impaired renal function (eGFR < 60) and high dose metformin (>2 gr/day)

• DTG: close monitoring and consider dose adjustment when starting/stopping DTG (avoid high dose metformin) • BIC: no dose adjustment in patients with normal renal function, close monitoring and consider dose adjustment in

patients with moderate renal impairment

# 6 – DDIs with PPIs, antacids and mineral supplements

www.hiv-druginteractions.org, Iwamoto M et al. Clin Infect Dis 2009, Patel P et al. JAC 2011, Griessinger JA et al. Drug Dev Ind Pharm 2016

PPIs

Raltegravir pill dissolution improved when decreasing gastric pH

Atazanavir & rilpivirine absorption reduced when decreasing gastric pH

antacids: 2 h before or 4 h after RPV H2 blockers: 12 h before or 4 h after RPV

antacids: ARV 2 h before or after antacid H2 blockers: ATV: max equiv. 20 mg BID famotidine ATV/r: max equiv. 40 mg BID famotidine (ttt naive) or 20 mg BID famotidine (ttt experienced). Adm. simultaneous or >10h after H2 blocker

Antacids & mineral supplements and INIs

Dolutegravir + antacid 2h later

Dolutegravir alone

0 10 20 30 40 50 80 60 70

2.0 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2

0 Mea

n D

TG

con

cent

ratio

n (µ

g/m

L)

26%

74%

Time (hrs)

Dolutegravir +antacid

Binding of integrase inhibitors

integrase inhibitors

alternatives

alternatives

Mg Mg

Extent of chelation varies depending on type and amount of divalent cation

DTG alone

+ aluminium (AL)

+ calcium (CA)

+ iron (IR)

+ magnesium (MG)

+ zinc (ZN)

mo

re c

hel

atio

n

more AL more CA more IR more MG more ZN

Recommendations

Integrase inhibitor Antacids Mineral supplements

Bictegravir 2 h before antacid under fasting conditions simultaneously with food

Dolutegravir 2 h before or 6 h after antacid 2 h before or 6 h after mineral suppl. or simultaneously with food

Elvitegravir/cobicistat separate intake from antacid by > 4 h separate intake from mineral suppl. by > 4 h

Raltegravir 400 mg BID

not recommended with AL- MG- containing antacid BUT possible with CA- containing antacid

separate intake from mineral suppl. by > 4 h

Raltegravir 1200 mg QD not recommended with AL- MG- CA- containing antacid use 400 mg BID

not recommended use 400 mg BID

www.hiv-druginteractions.org, Patel P et al. JAC 2011, Ramanathan S et al. JAIDS 2013, Krishna R et al. J Pharm Pharmacol 2016

# 7 – DDIs with rifampicin NRTIs:

TDF: TAF: dose 25 mg BID

T im e (h )

Me

an

(S

D)

TF

V C

on

c (

ng

/mL

)

0 4 8 1 2 1 6 2 0 2 4

1

1 0

1 0 0T A F B ID + R IF

T A F Q D

www.hiv-duginteractions.org, Custodio J et al. EACS 2017, Cerrone M et al. JAC 2019, Khalilieh S et al. J Clin Pharmacol 2018, Atwine D et al. BJCP 2018, Cerrone M et al. Clin Infect Dis 2018

IC Tenofovir AUC ↑76% (TAF + RIF vs TDF)

Similar systemic TFV + intracellular TFV-DP

NNRTIs:

DOR: alternative rifabutin + DOR 100 mg BID (keep this dose for at least another 2 weeks following cessation

rifabutin due to persisting inducing effect)

ETV: alternative rifabutin 300 mg + ETV (with no PI)

NVP: alternative rifabutin

RPV: rifabutin

EFV:

EFV 400 alone EFV 400 + RIF (1 month) EFV 400 + RIF (3months)

Note: TAF QD + RIF vs TDF alone

Note: EFV 400 mg + RIF (10 mg/kg) possible Concentrations still within range ENCORE study

n = 21

Time hr 0 5 10 15 20 25

Mean PBMC Concentrations of TFV By treatment group

Mea

n T

FV c

on

cen

trat

ion

in

PB

MC

(fm

ol/

mill

ion

-ce

lls)

1000

200

0 3

000

400

0 5

000

600

0

DDIs with rifampicin PIs:

PI/r: alternative rifabutin 150 mg QD

PI/c: alternative rifabutin 150 mg every other day

www.hiv-duginteractions.org, Taburet AM et al. Clin Infect Dis 2015, Dooley K et al. JAIDS 2013, Dooley K et al. CID 2019, Custodio J et al. CROI 2018

INIs:

DTG: dose at 50 mg BID

EVG/c: alternative rifabutin 150 mg every other day

BIC: rifabutin

BIC BID dosing is not sufficient to compensate rifampicin inducing effect (BIC AUC 60%)

RAL 1200 mg QD + RIF: not recommended use RAL 400 mg BID or 800 mg BID

RAL: dose at 400 mg BID or 800 mg BID

Drug properties that minimize risk of CS (inhaled/intranasal corticosteroids)

• Low glucocorticosteroid relative receptor binding affinity (RRA) • Higher plasma protein binding (limits drug diffusion) • Shorter half-life • Lower lipophilicity (limits drug diffusion)

beclomethasone meets most of the properties

# 8 – DDIs with corticosteroids

Corticosteroids mostly CYP3A4 metabolism

+ PI/r , PI/c adrenal insufficiency, Cushing’s syndrome EVG/c (risk with oral, eye, intra-articular, topic administration)

Schwarze-Zander C et al. Infection 2013, Hyle EP et al. JAIDS 2013, Daley-Yates P et al. Br J Clin Pharmacol 2015, Elliot ER et al. Clin Med 2016, Lopez-Centeno B et al. Glasgow HIV Conference 2018

DDI with corticosteroid are common: DDI analysis in a large spanish HIV Cohort n = 22’945 overall 3% (n = 729) red flag DDIs, mainly between boosted regimens and corticosteroids

Management of DDIs with corticosteroids

www.hiv-druginteractions.org, Elliot ER et al. Clin Med 2016

• change PI/r, PI/c, EVG/c to antiretroviral treatment with no inhibitory effects on CYP3A4 if possible (note: dose reduction of corticosteroid does not eliminate CS risk)

• if not possible, substitute corticosteroid with a more favorable one with periodic control of cortisol

+ document presents algorithm for clinical monitoring in case of suspected DDI

acenocoumarol: substrate CYP2C9 (major), CYP1A2, CYP2C19

phenprocoumon: substrate CYP2C9, CYP3A4

apixaban, rivaroxaban: substrates CYP3A4, P-gp, BCRP

dabigatran: prodrug substrate P-gp, mainly eliminated renally

warfarin: CYP2C9 (S-enant.); CYP3A4, CYP1A2, CYP2C19 (R-enant.)

when switching PK booster:

ritonavir induces CYPs but cobicistat does not

edoxaban: substrate P-gp, eliminated renally and through biliary secretion

# 9 – DDIs with anticoagulants

EACS Guidelines v 9.1 2018, www.hiv-druginteractions.org, Marzolini C et al. JAC 2016

Vit

amin

K

anta

gon

ists

D

irec

t ac

tin

g an

tico

agu

lan

ts

legend: induction, strong induction, strong inhibition

Fulco P. Pharmacother 2008 Hughes CA. CMAJ 2007 Welzen ME Antivir Ther 2011 Tseng AL. AIDS 2017 Liedtke MD. Ann Pharmacother 2012 Bonora S. CID 2008

Cases reporting DDIs between anticoagulants and boosted regimens/NNRTIs

Botond L. Swiss Med Wkly 2014 Corallo CE. Drug Saf Case Rep 2015 Bates D. Can J Hosp Pharm 2013 Yoong D. Ann Pharmacotherapy 2017

INR monitoring

no monitoring of coagulation effect possible

Switch from ATV/r QD to DRV/c reduction of warfarin dose by 60%

Tseng A et al. AIDS 2017, Kumar P et al. AAC 2017

PK/PD study for dabigatran + RTV or Cobi

PK

PD

RTV: mixed inhibitory/inducing effect on P-gp Cobi: only inhibitory effect on P-gp

dabigatran alone dabigatran adm 2 h before Cobi dabigatran adm together with Cobi

dabigatran alone dabigatran adm 2 h before RTV dabigatran adm together with RTV

Anticoagulants + ritonavir or cobicistat boosting

• boosted regimens: use vitamin K antagonists and monitor INR or use heparin derivatives • boosted regimens: avoid rivaroxaban, apixaban. Possible to coadminister PI/r with dabigatran (dosage adjustment

might be needed in patients with mild or moderate renal impairment), consider dose adjustment with edoxaban

www.pharmgkb.org, Marsousi N et al. Clin Pharmacokinet 2018

Clopidogrel activation pathway

induction by RTV

inhibition by RTV, Cobi

Prasugrel activation pathway

Liver cell

Platelet

Prasugrel

Active metabolite

irreversible

P2RYI12

CES

CYP3A4

CYP2B6

CYP2C9

CYP2C19

Thiolactone int. metabolite

≈15%

net PK/PD effect difficult to predict

# 10 – DDIs with antiplatelet agents

Ticagrelor

Boosted regimen

Aspirin

All ARVs

www.hiv-druginteractions.org

In clinical trials, prasugrel has demonstrated greater platelet inhibition compared to clopidogrel possibly due to a more efficient bioactivation and higher concentrations of the active metabolite.

Question

Which antiplatelet agent(s) can be used without efficacy or toxicity concerns in patients treated with a boosted regimen?

1) clopidogrel

2) prasugrel

3) both antiplatelet agents can be used

PK/PD DDI between boosted regimens and clopidogrel or prasugrel

Clopidogrel active metabolite

Prasugrel active metabolite

antiplatelet drug alone

antiplatelet drug + RTV/Cobicistat boosted regimen

AUC -69% AUC -52%

PK effect

Marsousi N et al. Clin Pharmacokinet 2018; Itkonen MK et al. Clin Pharmacol Ther 2018, Bravo I et al. BJCP 2018

Second independent clinical study: clopidogrel + RTV clopidogrel active met. AUC -49%

PD effect (platelet receptor blockade measured with VerifyNow®)

Second independent clinical study: platelet aggregation inhibition: 51% (clopidogrel alone) vs 31% (clopidogrel + RTV)

Clopidogrel Prasugrel

healthy volunteers HIV patients

44% HIV patients did not achieve platelet inhibition

platelet inhibition remains adequate in all patients

efficient p

latelet inh

ibitio

n

• avoid ticagrelor and clopidogrel with boosted HIV regimens • use prasugrel unless patient has a clinical condition (e.g. history of stroke or transient ischaemic attack) which contraindicates its use in which case an alternative HIV regimen should be considered

Cases reports of the deleterious DDI between clopidogrel and boosted regimens start to emerge

DDIs not covered in this talk

• HCV drugs: www.hep-druginteractions.org

• Cancer drugs: www.cancer-druginteractions.org

www.hiv-druginteractions.org

Outcomes of drug-drug interactions in real-life

www.clinicalcasesDDIs.com

The page can be used for: - Reporting new clinical cases on drug combinations - Searching for information on specific combinations. - Share information on real-life experience about drug combinations that may be used in

the clinic.

Summary

• DDIs are practically unavoidable in HIV care but mostly manageable. • Potential for DDIs to be considered systematically when selecting an antiretroviral

regimen or when adding new medications to an existing HIV treatment with particular attention to adjust dosage or perform clinical monitoring when needed.

• Searchable online drug interactions databases constitute valuable tools to recognise

and manage unwanted DDIs in clinical practice.

Acknowledgements

Manuel Battegay Felix Stader Marcel Stoeckle

David Back Saye Khoo Liverpool HIV drug interactions website team members