Molecular mechanism of HIV-1 integrase inhibition by Raltegravir ...
Top DDIs in clinical practice: Still relevant? · , Iwamoto M et al. Clin Infect Dis 2009, Patel P...
Transcript of Top DDIs in clinical practice: Still relevant? · , Iwamoto M et al. Clin Infect Dis 2009, Patel P...
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