Saye Khoo

University of Liverpool, UK

Clinical Pharmacology of Integrase Inhibitors

Declaration of Interestswww.hiv-druginteractions.org & www.hep-druginteractions.org

Receives sponsorship from AbbVie, Merck, BMS, Janssen, Gilead, ViiV.Editorial content remains independent.

Research funding, travel grants, speakers bureau from Gilead, AbbVie, ViiV, Merck, Janssen

See https://www.liverpool.ac.uk/translational-medicine/staff/saye-khoo/external-engagement/

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▪ Pharmacology of InSTIs (RAL, EVGc, DTG, BIC)

▪ Special Populations, with focus on pregnancy

▪ Drug Interactions

▪ RAL od versus bd

Integrases - Pharmacology

RAL EVGc DTG BIC

Dose 400mg bd or

1200mg od

150mg qd with

booster

50mg qd or bd

(experienced)

50mg od

Food Effect Significant

C12 66-100%) with

mod-high fat

food variability

No restrictions

Significant

AUC 36-91% with

mod-high fat

Take with food

Moderate

AUC 33-41% with

mod-high fat

Take with food if

TE, or DDI

Mild-Moderate

AUC 24% with mod/high

fat

No restrictions

Metabolism UGT1A1 CYP3A

UGT1A1/3

UGT1A1

(CYP3A 10-15%)

>90% metabolised

Substrate of CYP3A,

UGT1A1

Protein binding 83% 99% 99% 99%

Half life 9h 12.9h 14h 17.3h

Pharmacogenetics UGT1A1 *28/*28

AUC 41% C12 91%

Effect unlikely UGT1A1 PM

AUC 41%

Significant effect

unlikely

Integrases – Special Populations

RAL EVGc DTG BIC

Effect on eGFR V small (5mL/min)

reduction in eGFR

(cobi effect) Modest (13-15mL/min)

reduction in eGFR

(OCT-2 inhibition)

Modest reduction in

eGFR

(OCT2 / MATE1

inhibition)

Renal Impairment No adjustment FDC - eGFR

Genvoya >30

Stribild >70

No adjustment FDC eGFR >30

No data <15ml/min

(<1% renal excretion)

Hemodialysis No data; avoid

dosing before

dialysis

FDC – avoid No data, no difference

expected

No data

Cirrhosis (CPT A/B) No adjustment No adjustment No adjustment No adjustment

Severe (CPT C) Caution Not recommended Caution Not studied

Integrases – Special Populations

RAL EVGc DTG BIC

Swallowing Chewable tablets,

granules

(bioavailability)

Cannot be

chewed or

crushed

Crushable, can be

given with NG feeds

Granule being

developed

( bioavailability)

Not recommended

Children Licensed from 4

weeks

Not licensed <18,

avoid <6

Not licensed <12 Insufficient data

<18y

Pregnancy Reasonable data;

Preferred

(DHHS 2017)

Limited data;

Not recommended

(DHHS 2017)

Preliminary Data;

WOCBP – use

contraception

(FDA/EMEA 2018)

No data

www.hiv-druginteractions.org

Integrases – Special Populations

RAL EVGc DTG BIC

Swallowing Chewable tablets,

granules

(bioavailability)

Cannot be

chewed or

crushed

Crushable, can be

given with NG feeds

Granule being

developed

( bioavailability)

Not recommended

Children ≥ 4 weeks ≥ 6y of age

(≥ 25kg)

≥ 6y of age ≥ 18 years

Pregnancy Reasonable data;

Preferred

(DHHS 2017)

Limited data;

Not recommended

(DHHS 2017)

Preliminary Data;

WOCBP – use

contraception

(FDA/EMEA 2018)

No data

ARV exposure in Pregnant Mothers and their Infants

MOTHERchanges in drug

exposure (T3)

MOTHERBM penetration

of ARVs

BABYAntepartum & peripartum

exposure of ARV

BABYARV exposure through

breastfeeding

Third Trimester Exposures (vs PP) of HIV Drugs

Stek et al . JIADS 2015;70:33

Colbers et al AIDS 2013,27:739

Moodley et al JID 1998; 178: 1327

Le et al. AVT 2015;20:507

Mirochnick et al CPK 2004;43:1071

Blonk et al. Clin Infect Dis. 2015;61:809

Colbers et al CID 2015:61:1582

Else et al. AAC 2012:56(2):816

Best et al. HIV Med 2015;16:502

Mulligan et al. CROI 2016

Best CROI 2017

Rimawi et al. AC 2017

ABC

FTC

TDF

ETR

EFV

NVP

ATV

DRV (od)

DRV (bd)

FPVr

LPVr (sgc)

LPVr (tab)

RTV (LPV)

MVC

RAL

EVG

Cobi

DTG

REDUCED in T3 INCREASED in T3

0.5 0.75 1.51.0

0.43

0.58

Elvitegravir and Cobicistat in Pregnancy

Cord blood: maternal plasma concentrations

0% 50% 100%

* unbound

Schalwijk et al. AIDS 2015;30:1239

Fayet-Mello Antivir Ther. 2013;18(2):171

Yeh et al AAC 2009 Jun;53(6):2367

Cressey et al . JAIDS 2012 Mar 1;59(3):245

Mulligan et al. Front Pharmacol 2016 Aug 4;7:239

Watts et al. JAIDS 2014 Dec 1;67(4):375

Blonk et al. Clin Infect Dis. 2015;61:809

NVP 50-80%

RPV 55%EFV

49%

ETR52%

3TC100%

TFV~100%

ZDV86%

ABC100%

FTC~100%

ATV 15%

DRV18%

FPV27%

LPV*41-57%

RTV15-55%

SQV 3%

IDV65%

RAL / DTG>=100%

MVC30%

T202%

UGT1A1 activity in neonates –Delayed Washout of RAL & DTG, but not EVG

▪ N = 19

▪ Cord: maternal ratio 1.48

▪ Highly variable elimination

▪ Median T½ 26.6h (9.3 – 184)

▪ (adult T½ typically 9h)

▪ N = 10

▪ Median T½ 34.5h (IQR 28.6-39.9)

▪ (adult T½ typically 14h)

RALP1097

DTGP1026s

Clarke et al, JAIDS 2014 Nov 1;67(3):310

Mulligan et al CROI 2016

Best CROI 2017

EVGcP1026s

▪ N = 16

▪ Median T½ 7.4h (IQR 3.1-7.5)

▪ Similar to typical adult T½

Delayed initiation of ART in Pregnancy

• PMTCT programmes report significant

rates of delayed ART initiation (3rd

trimester or labour)

• Most often relates to delayed diagnosis

• Study from Yunnan Province

• N = 1548 HIV+ pregnanciesARV in T1 or T2 63%

ARV in T3 17%

L&D or no ARV 20%

• Adverse impact on infant mortality

• Strong case for use of INSTI

0

1

2

3

4

5

0,1 1 10Adjusted RR of transmission

T1 or T2

T3

L&D or

no ART

7.01

7.55

Meyers et al. . PLoS ONE 2015;10(9): e0138104

RAL EVGc DTG BIC

Metabolism UGT1A1 CYP3A

UGT1A1/3

UGT1A1

(CYP3A 10-15%)

CYP3A & UGT1A1

Perpetrator of

DDIs

No effect on CYPs,

UGT or PgP

Cobi – inhibits

CYP3A +++,

(CYP2D6 & MATE1)

EVG –induces

CYP2C9

No effect on CYPs,

UGT or PgP

OCT2 - metformin

No effect on CYPs, or

UGT1A1

OCT2 - metformin

Divalent cations Al/ Mg contraindicated

Ca- not clinically

meaningful

Al/Mg antacids- ±2h

Multivits ±4h

Al/Mg/Ca/Fe/Multivits

take -6h or +2h

Fe – take with food

Al/Mg antacids-

take +2h. (EMEA – 2h

before BIC (with food)

Fe and Ca++ take with

food

Gastric pH pH dependent solubility

absorption with OMP

(+39%) / FAM (+45%);

no dose adjustment

No DDI expected No DDI expected No DDI expected

Integrases – Drug Interactions

** BIC unlicensed, data from published abstracts etc

Differences between RAL twice and once-daily

Rizk et al. CROI 2014

RAL 600mg reformulation (vs 400mg)

• Higher relative bioavailability

• Similar systemic PK thereafter

• Less variability

• Food effects similar/smaller

• Any potential impact on DDIs or special

groups ?

Differences between RAL twice and once-daily

RAL 400bd RAL 1200od Notes

Rifabutin ◆* ◆ * RBT (300od): RAL Cmin 20%

Rifapentine ◼* ◼* RPT weekly: RAL AUC 71%,

* RPT daily: RAL Cmin 41%

Rifampicin ◼ Not recommended

Carbamazepine ◼ Not recommended

Phenytoin ◼ Not recommended

Phenobarbitone ◼ Not recommended

Pregnancy ◆

BD dosing required

(DHHS Nov 2017)

T3: AUC 29%,

Cmin probably

Metformin, OCT2 and Dolutegravir / Bictegravir

• Both DTG and BIC are inhibitors of OCT2• Metformin is excreted unchanged in urine, mainly through OCT2

0,1

1,0

10,0

0 4 8 12

Co

nce

ntr

atio

n,

µg/

mL

Nominal Time, h

Metformin Alone, Period 1

Metformin + DTG 50 mg q24h

Metformin Alone, Period 3

0,1

1,0

10,0

0 4 8 12

Co

nce

ntr

atio

n,

µg/

mL

Nominal Time, h

Metformin Alone, Period 1

Metformin + DTG 50 mg q12h

Metformin Alone, Period 3

MET AUC +79%

DTG qd DTG bd

MET AUC +145%

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

B/F/Taf od

MET AUC +39%

• Metformin-induced lactic acidosis rare

• Many cases (particularly fatalities) related to underlying conditions rather than metformin risk of LA with impaired GFR (<60ml/min; HR 6.37) particularly with high doses (>2g/d; HR 13.0) are also used

• Close monitoring when starting/stopping DTG

• Avoid high Metformin doses (eg 2g/day), especially in patients with eGFR<60COSMIC Study; Cryer Diabetes 2003

Stades J Int Med 255:179–187, 2004

Eppenga. Diabetes Care 2014

DDIs between HIV drugs and Hormonal Contraception

www.hiv-druginteractions.org/printable_charts

ATV/r DRV/r LPV/r EFV ETV NVP RPV RAL EVGc DTG BIC ABC XTC TDF

Estrogen Ethinylestradiol ↓19% ↓44% ↓42% ↔ ↓20% ↓25%

Progestins (COC)

Desogestrel ↑ ↑ ↑ ↓ ↓ ↓ ↑

Drospirenone ↑ ↑ ↑ ↓ ↓ ↓ ↑

Gestodene ↑ ↑ ↑ ↓ ↓ ↓ ↑

Levonorgestrel ↑ ↑ ↑ ↓ ↓ ↑ ↑

Norethisterone/-thindrone ↑ ↓14% ↓17% ↓ ↓19% ↑

Norgestimate ↑85% ↑ ↑ ↓64% ↓ ↓ ↑126%

Norgestrel ↑ ↑ ↑ ↓ ↓ ↑29% ↑

Progestins (POP)

Desogestrel ↑ ↑ ↑ ↓ ↓ ↓ ↑

Levonorgestrel ↑ ↑ ↑ ↓ ↓ ↑ ↑

Norethisterone (Norethindrone) ↑50% ↑50% ↑50% ↓ ↓ ↓ ↑

Progestins (Non-oral)

Etonogestrel (implant) ↑ ↑ ↑52% ↓63% ↓ ↓ ↑

Etonogestrel (CVR) ↑ ↑ ↑ ↓ ↓ ↓ ↑j

Levonorgestrel (IUD)

Levonorgestrel (implant) ↑ ↑ ↑ ↓57% ↓ ↑14% ↑

Medroxyprogesterone (depot)

Norelgestromin (patch) ↑ ↑ ↑83% ↓ ↓ ↓ ↑

Norethisterone/ -thindrone (depot)

Emergency

Levonorgestrel (emergency) ↑ ↑ ↑ ↓58% ↑

Mifepristone ↑ ↑ ↑ ↓ ↓ ↓ ↑

Ulipristal ↑ ↑ ↑ ↓ ↓ ↓ ↑

Interactions with Rifampicin

Time after dose (hours)

7

6

5

4

3

2

1

0

DT

G c

on

cen

trat

ion

(µ

g/m

L)

0 4 8 12 16 20 24

DTG 50 mg QD1,2

DTG 50 mg BID1,2

DTG 50 mg BID

+ RIF 600 mg QD1,2

REFLATE: HIV/TB coinfected

• RIF + RAL 400bd – slightly lower exposures(C0 0.46)

• RIF + RAL 800bd - overcompensated

RIFRAL (HIV-) RIF 3x/w + RAL

• HIV+ Rif (3x/w) Cmin 60%, restored by 800mg RAL

bd

RAL + RIF

• HIV- AUC 54% Cmin 72%

• DTG 50 bd + rif comparable Cmin

INSPIRING (CROI 2018) – 24w outcomes with

coinfection

DTG + RIF

Taburet et al. Clin Infect Dis. 2015 Oct 15;61(8):1328

Dooley et al. J Acquir Immune Defic Syndr 2013; 62:21–7

Reynolds et al. JAC 2015 Feb;70(2):550-4

Dooley et al. CROI 2018

DOSE at 50mg bd

DOSE at 400 or 800mg bd

Interactions with Rifampicin

BIC + Rif in healthy volunteers

• Even with bid dosing, BIC AUC 60%, Ctrough

~80%,

• A proportion of patients may fall below the paEC95

(target)

• Well-tolerated (FTC exposure approx doubled)

• BFTaf bid with RIF not recommended

BIC + RIF

BIC + Rifampicin not recommendedCustodio et al. CROI 2018 34

Interactions with TB medications

DTG EVGc RAL BIC EFV RPV DRVr ATVr TDF ABC (X)TC

Rifabutin ◆ ◼ ◆ ⚫ ◼ ⚫ ◼ ◼ ◆ ◆ ◆

Rifampicin ◼ ⚫ ◼ ⚫ ◼ ⚫ ⚫ ⚫ ◆ ◼ ◆

Rifapentine ◼ ⚫ ◼ ⚫ ◼ ⚫ ◼ ◼ ◆ ◆ ◆

Streptomycin ◆ ◼ ◆ ◆ ◆ ◆ ◆ ◆ ◼ ◆ ◆

Isoniazid ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆

Pyrazinamide ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆

Ethambutol ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆

Capreomycin ◼ ◼ ◼ ◼ ◆ ◆ ◆ ◆ ◼ ◆ ◼

Amikacin ◆ ◼ ◆ ◆ ◆ ◆ ◆ ◆ ◼ ◆ ◼

Kanamycin ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◼ ◆ ◼

Moxifloxacin ◆ ◆ ◆ ◆ ◼ ◼ ◆ ◼ ◆ ◆ ◆

Levofloxacin ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◼

Ethionamide ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆

Cycloserine ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆

PAS ◆ ◼ ◆ ◼ ◆ ◼ ◆ ◆ ◼ ◆ ◼

Bedaquiline ◆ ◼ ◆ ◆ ◼ ◼ ◼ ◼ ◆ ◆ ◆

Clofazimine ◆ ◆ ◆ ◆ ◆ ◼ ◼ ◆ ◆ ◆ ◆

Integrases and DDIs

▪ InSTI as PERPETRATORS: EVGc > DTG/BIC > RAL

▪ InSTI as VICTIMS:

Inducers eg Rifampicin, antiepilepticsDTG – consider 50bdEVG – avoidBIC – likely to be significantly affected (note Taf + Rif data from EACS)

InhibitorsATV or ATVr – will increase DTG, BIC, RAL exposures

▪ Managing DDIs

FDC (eg E/C/F/Taf, or B/F/Taf) ?DTG dosing with inducer AND InSTI-experienced ?

** BIC unlicensed, data from published abstracts etc

Summary

InSTIs likely to replace EFV in preferred regimens

• Efficacy & tolerability

• DDIs

• (cost)

Important needs to be addressed

• Pediatric use

• Pregnancy

• TB

• 2DR

• IRIS and CNS toxicity

Optimal deployment to maximise the useful therapeutic lifespan

• Prevention of resistance

• Transition from EFV-based regimens in LMIC