The Pharmacology of INSTIs - Virology Educationregist2.virology-education.com/presentations/2019/... · The Pharmacology of INSTIs David Back University of Liverpool Tokyo –May

The Pharmacology of INSTIs

David Back

University of Liverpool

Tokyo – May 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/

Disclosures

https://www.ddi.ncgm.go.jp/

2017: NCGM Launch Hep Website with an Interface linking to Liverpool

Overview

Background: Pharmacological Characteristics

Comorbidities and Polypharmacy

Evaluating the Interaction Potential of a Drug

Which Interactions are of Concern?

A Case

1

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5

Overview





What About DDIs and Long Acting?

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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

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

UGT1A1 (major), CYP3A (minor)

UGT1A1 and CYP3A (equal)

Renal Elimination

Renal Impairment

~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)

Drug Interaction(DDI) Potential

Least Highest (due to booster)

Slightly greaterthan RAL

Slightly greater than RAL

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

Key Pharmacological Characteristics of the Individual Integrase Inhibitors - 1

*Approved in Japan March 2019;BID, twice daily; QD, once daily. CYP3A, cytochrome P450 3A4; UGT1A1; uridine glucuronyl transferase 1A1.

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






Renal Impairment

No dose adjustment eGFR > 30 (Genvoya)eGFR > 70 (Stribild)











Renal Impairment

No dose adjustment eGFR > 30 (Genvoya)eGFR > 70 (Stribild)






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

UGT1A1 (major), CYP3A (minor)

UGT1A1 and CYP3A (equal)

Drug Interaction(DDI) Potential

Least Highest (due to booster)

Slightly greaterthan RAL

Slightly greater than RAL

Integrase Inhibitor Inhibitory Quotient

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

Overview





A Case

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5

The Prevalence of Comorbidities & Other Age-Related Conditions is Higher in People Living with HIV (PLWH)

Negredo E, et al. Biomed Res Int 2017; 2017:5897298; Wong C, et al. Clin Infect Dis 2018; 66(8):1230–1238;Pelchen-Matthews A, et al. AIDS 2018; 32(16):2405–2416; Allavena C, et al. PLoS One 2018; 13(9):e0203895; Guaraldi G, et al. BMC Geriatr 2018; 18(1):99.

Reference Age, yearsPolypharmacy

(At Least 5 Non-ARV Drugs)

Courlet P, et al.CROI 2019; Abs Poster 466

≥ 65 46%

Guaraldi G, et al.BMC Geriatr 2018; 18(1):99

≥ 65 37%

Justice A, et al. AIDS 2018; 32(6):739–749

≥ 65 43%

Núñez-Núñez M, et al.Farm Hosp 2018; 42(4):163–167

≥ 50 48%

Ssonko M, et al.BMC Geriatr 2018; 18(1):125

≥ 50 15%

Ruzicka DJ, et al.BMJ Open 2018; 8: e019985

≥ 50 34.6%

O’Halloran M, et al. Antivir Ther 2019 (Epub ahead of print)

≥ 50 30%

Ware D, et al*.PLoS One 2018; 13(9):e0203890

≥ 50 38.4–46.8%*

Lopéz-Centeno B, et al.HIV Drug Therapy, Glasgow 2018; Abstract P211

≥ 50 47%

Potential Limitations• Recall bias• Under-reporting• OTC consistency• Different populations

Polypharmacy is more Prevalent Among PLWH; Particularly ≥ 50 Years Old

*Study period 2004–2016;PLWH, people living with HIV; OTC, Over The Counter.

Polypharmacy in Acute Care Hospitals in Japan

.Ruzicka D et al BMJ Open 2018; 8: e019985

▪ PLWH, aged ≥ 18 years with a diagnosis of HIV and a prescription record of ARVs between Jan 2010 and Dec 2015

▪ Data on 1445 patients extracted from the Medical Data Vision(MDV) database

Polypharmacy in Acute Care Hospitals in Japan

0

5

10

15

20

25

30

35

40

45

50

18-29 30-39 40-49 50-59 60-69 >70

Ruzicka DJ et al, J Infect Chemother 2019; 25: 89-95

Age years

% o

f p

atie

nts

HIV negatives (N = 14,450)

HIV positives (N = 1445)

% of patients with polypharmacy (≥ 5 co-meds);

8% 2% 11% 4% 23% 7% 31% 11% 35% 17% 45% 18%

Key Message 1

• Polypharmacy brings many challenges in treating PLWH, particularly older patients

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

Age-related Pharmacokinetic & Pharmacodynamic

changes‡

Overview





A Case

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Evaluating the Interaction Potential of a Drug (DDIs)

Available at: https://www.fda.gov/downloads/drugs/guidances/ucm292362.pdf; https://www.ema.europa.eu/documents/scientific-guideline/guideline-investigation-drug-interactions_en.pdf.

Preclinical Studies(including in vitro)

Clinical DDI Studies (plausible mechanisms & potential co-meds in target population)

Real-World DataPopulation PKCase Reports

PBPK, physiologically based pharmacokinetic.

PBPK Modelling (systems pharmacology approach

requiring physicochemical and in vitro data) - at different

stages of drug development)

Evaluating the Interaction Potential of a Drug (DDIs)

Available at: https://www.fda.gov/downloads/drugs/guidances/ucm292362.pdf; https://www.ema.europa.eu/documents/scientific-guideline/guideline-investigation-drug-interactions_en.pdf. https://www.pmda.go.jp/english/

Preclinical Studies(including in vitro)

Clinical DDI Studies (plausible mechanisms & potential co-meds in target population)

Real-World DataPopulation PKCase Reports

PBPK, physiologically based pharmacokinetic.

DRAFT GUIDANCE; October 2017, Clinical Pharmacology

PBPK Modelling (systems pharmacology approach

requiring physicochemical and in vitro data) - at different

stages of drug development)

https://www.ema.europa.eu/documents/scientific-guideline/guideline-investigation-drug-interactions_en.pdf

https://www.pmda.go.jp/english/

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

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 Administer with care; reduce dose

as necessary**


✓





✓

✓

DDIs of BictegravirAgent USPI SmPC Japan PI

Rifamipicin Contraindicated Contraindicated Contraindicated

Dofetilide Contraindicated - Pilsicainide - Caution

SJW Not recommended Contraindicated Contraindicated

Atazanavir - Not recommended Administer with care

Carbamazepine Alternatives should be considered Not recommended Contraindicated

Ciclosporin - Not recommended

Oxcarbazepine Alternatives should be considered Not recommended

Phenobarbital Alternatives should be considered Not recommended Contraindicated

Phenytoin Alternatives should be considered Not recommended Contraindicated

Rifabutin Not recommended Not recommended Administer with care

Rifapentin Not recommended Not recommended

Macrolides - Caution

Verapamil - Caution

Dronaderone - Caution

Glecaprevir/Pibrentasvir - Caution

Methadone - Caution

Mg++ or Al++ Antacids BIC can be taken fasting 2h before antacid BIC at least 2h before or with food 2h after BIC at least 2h before

Iron supplements Can be taken together with food BIC at least 2h before or together with food Can be taken together with food

Metformin Refer Prescribing information for Metformin Close monitor patients with moderate RI Monitor patients closely

Biktarvy USPI Feb 2018

Biktarvy SmPC Nov 2018

✓

CPT 2019; 105: 505-514

1727 co-meds listed (average or 45 per study drug).

Key Message 2

• Product labels summarise essential clinical pharmacology but there can be differences in interpretation of DDI data and also gaps which make other resources essential.

• Understanding mechanisms of DDIs is critical. Most are Pharmacokinetic (PK) but Pharmacodynamic (PD) interactions (egsynergistic QT prolongation1) can be important.

1https://www.crediblemeds.org ; Waters L, HIV Glasgow 2018: oral presentation O234;.

Overview





A Case

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

Which Antiretroviral Interactions are of Concern?

Back DJ, personal communication

≈ 750 co-meds

No interaction Potential weak interaction

Interaction of clinical relevance Drugs should not be co-administered

n ≈ 750 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.

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

Top Global Co-medication Searches 2018: Liverpool database

PPI, proton-pump inhibitor. Data from: www.hiv-druginteractions.org.

……………………………50………………….100……………….……200……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 Japan Co-medication Searches 2018: Liverpool database

Data from www.hiv-druginteractions.org

0

50

100

150

200

250

No

of

Qu

eri

es

Statins

Anti-infectives

Antidiabetics

Antihypertensives

Psychotropic drugs

Anticancer

Top 10 Co-medications Generating the Most DDI Queries in www.hiv-druginteractions.org (MixPanel Analytics).


Top 10 Co-medications in PLWH – Japan Hospital Claims Database

J Infect Chemother 2019; 25: 89-95

Top 10 most common medications PLWH (n = 1445)

Antacids; anti-ulcer 458 (31.7%

Antibacterials 321 (22.2%)

Psycholeptics 318 (22.0%)

Systemic antihistamines 268 (18.5%)

Lipid-regulators 249 (17.2%)

Anti-inflammatory 224 (15.5%)

Antidiarrheals 175 (12.1%)

Antihypertensives 160 (11.1%)

Vitamins 148 (10.2%)

Cough/cold preparations 138 (9.6%)

#1. Drug Interactions with Statins

ATV, atazanavir; /c, cobicistat; AUC, area under the curve; Atorvastatin SmPC; Rosuvastatin SmPC; Pravastatin SmPC (all accessed April 2019); Busti AJ, et al. J Cardiovasc Pharmacol 2008; 51:605–610; www.hiv-druginteractions.org.

Hepatocyte

OATP1B1/3

BCRP

CYP3A

RosuvastatinPravastatinFluvastatinPitavastatin

All statins;+ gi effects

Simvastatin Atorvastatin

X

XX

MRP2; P-gp

Statin ATV/c EVG/c

Atorvastatin AUC 822% Not studiedExpect increase

Rosuvastatin AUC 242% Not studiedExpect increase

Pravastatin AUC Not studiedPossible increase

Not studiedExpect increase

• 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

• Difference in extent of interaction with different statins

• PK changes inform label recommendations

#1. However…

NRTI, nucleoside reverse transcriptase inhibitor; TC, total cholesterol . Myers J, et al. HIV Med 2018; 13:190–192. Cattaneo D et al World Journal of Biological Psychiatry 2019 [Epub ahead of print]

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

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

#2. Interactions of Integrase Inhibitors with Antacids

Raltegravir Elvitegravir/c Dolutegravir Dolutegravir/Rilpivirine

Bictegravir

Omeprazole No dose adjustment required

No dose adjustment required


Contraindicated due to decreasein RPV


Pantoprazole No dose adjustment required



Contraindicated due to decreasein RPV


Cation containing Antacids

www.hiv-druginteractions.org;Isentress SmPC accessed April 2019; Genvoya SmPC accessed April 2019; TriumeqSmPC accessed April 2019; Juluca SmPC accessed

April 2019; Biktarvy SmPC accessed April 2019; www;hiv-druginteractions.org.

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

Decreased absorption - Caution! Not recommended/separate depending on the

integrase inhibitor and the cation (ie AL/Mg; Ca; Fe)

Some Key Questions in Interpreting a Pharmacokinetic Drug Interaction

What is the magnitude of the change?

What is the clinical significance of an increase of 2-or 5-fold or decrease of 50 or 80%? (think in terms of a dose change!)

What is the appropriate management strategy for the DDI?

Drugs with a Narrow Therapeutic Index1,2 or working at the margins of their activity cause greatest concern

1 Blix HS, et al. Pharm Pract (Granada) 2010; 8(1):50–55. 2https://www.drugbank.ca/categories/DBCAT003972

Key Message 3: Advice for Clinicians

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

• It may be necessary to:

– Change a co-medication to an alternative or modify dose

– Change the ARV or modify the dose

– Alter the timing of administration of the drugs

• It is necessary to use a drug interaction checker (avoid inappropriate use)

• It is necessary in elderly for Periodic Medication Review and check for inappropriate use of drugs (Beers and STOPP criteria*)

* EACS Guidelines v 9.1;

Overview





A Case

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Case: Clinical Characteristics

Nationality Japanese

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

♂

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

Case: Interactions of Integrase Inhibitors with the co-meds

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

Other considerations:• Triumeq not recommended (renal function); also abacavir and cardiovascular risk.• Recommend BIC/F/TAF or DTG + F/TAF

Summary

• DDIs are practically unavoidable in HIV care, but mostly manageable.

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

• Searchable online Drug Interaction checkers are a vital resource. Translations?

• Other key areas going forward:

Determine impact of eliminating medications

not essential for quality of life in older PLWH

Greater consistency in Prescribing Information;

Gain confidence in understanding Drug

Interactions of LA formulations

1 32

Grateful Thanks

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

Antiretroviral Therapy: Past, Present & Future

1983 19961987 2006 2012/13 2019ff

HIV-1 discovered

Zidovudine monotherapy

Triple drug therapy

Single tablet regimens

The Integraseera

iii. New Delivery Systems

ii. 2 Drug Regimens (2DR)

i. New Drugs

1991

Dual NRTI therapy

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

441. 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

▪ European B/F/TAF SmPC recommendations1:

– Al/Mg: B/F/TAF should be administered at least 2 hours before, or with food 2 hours after antacids containing Al or Mg

– Iron: Take B/F/TAF at least 2 hours before iron supplements, or take together with food

– Calcium: Can be taken together, without regard to food

‡

1. Bictegravir/emtricitabine/tenofovir alafenamide SmPC via medicines.org.uk accessed 30/3/19; Kabagambe et al. BHIVA 2019, O08

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

Since g.i. absorption is by-passed focus on hepatic interactions of LA (injectable/implant).

Cabotegravir/Rilpivirine and Rifampicin

• Importance of PBPK modeling to predict the interactions of Long Acting drugs (intramuscular, implants etc)

AUC ↓ 59%

Actual Oral Data

(single dose CAB)

0

0,5

1

1,5

2

2,5

0 7 14 21 28

Co

nce

ntr

atio

n (

mg/

L)

CAB alone

CAB + RIF

Simulated LA Data (PBPK)

(single dose CAB)

AUC ↓ 25%

(> at multiple dose)

What About DDIs with Long Acting Formulations?

Siccardi M & Rajoli R, personal communication;Ford SL, et al. Antimicrob Agents Chemother 2017; 61(10):e00487-17; Rajoli R, et al. CROI 2018; Abstract 485. CAB, cabotegravir; RIF, rifampicin; PBPK, physiologically based pharmacokinetic.

CAB (n=15)CAB + RIF (n=15)

Hepatic Vein

SystemicCirculation

Portal Vein

Hepatic artery

Intestinal Tract

Oral Medication

Time days

• Elderly particularly at risk of DDIs due to an increase in

age related co-morbidities and age related physiological

changes which impact the risk-benefit ratio of many

drugs.

• However the magnitude of a DDI in an older person (vs

a younger person) is not well described and requires

further study.

Documents

The Pharmacology of INSTIs - Virology Educationregist2.virology-education.com/presentations/2019/... · The Pharmacology of INSTIs David Back University of Liverpool Tokyo –May