Pharmacological Considerations in

Optimal Integrase Inhibitor Clinical Care

David Back

University of Liverpool

UK David Back

November 2016

Disclosures

• Honoraria received for advisory boards and

lectures from AbbVie, BMS, Gilead, Merck,

ViiV, Janssen, Teva

• Educational grants for www.hep-

druginteractions.org and

www.hiv-druginteractions.org from AbbVie,

BMS, Gilead, Janssen, Merck, ViiV

Overview

Integrase Inhibitors: An Overview1

2

3

4

Eron J – CROI 2016

Antiretroviral Therapy: Past, Present &

Future

Recommended Regimens: International

GuidelinesGuidelines Year NNRTI INSTI PI/r

WHO 2016 TDF/FTC (or 3TC) + EFV TDF/FTC (or 3TC) +

DTG

NA

EACS (v8.1)¥ 2016 TAF/FTC/RPV or

TDF/FTC+RPV*

TAF/FTC or TDF/FTC

with EVG/c Or RAL

or DTG

ABC+3TC with DTG

TAF/FTC or

TDF/FTC+DRV/r

or DRV/cobi

IAS-USA 2016 TAF/FTC+RPV* (or EFV) if

INSTI not appropriate

TAF/FTC with EVG/c

Or RAL or DTG

ABC+3TC with DTG

TAF/FTC+DRV/r

(if INSTI not

appropriate)

DHHS 2016 TDF/FTC with EVG/c

Or RAL or DTG

TAF/FTC with EVG/c

or RAL or DTG

ABC+3TC with DTG

TDF/FTC+DRV/r

TAF/FTC+DRV/r

WHO 2016: http://www.who.int/entity/hiv/pub/arv/arv-2016/en/index.html

EACS v8: http://www.eacsociety.org/files/guidelines_8.0-english-revised_20160610.pdf

IAS-USA 2016: http://jama.jamanetwork.com/article.aspx?articleid=2533073

DHHS 2016: https://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf

* In viral loads <100K copies/mL

¥ Guideline update Oct 2016TDF, tenofovir disoproxil fumarate; TAF, tenofovir alafenamide; FTC,

Emtricitabine; 3TC, Lamivudine; ABC, Abacavir; DRV/r,

Darunavir/ritonavir, RPV, rilpivirine; EFV, efavirenz; EVG/c,

elvitegravir/cobicistat; RAL, raltegravir; DTG, dolutegravir; NNRT, non-

nucleoside reverse transcriptase inhibitor; PI/r, boosted protease

inhibitor; INST, integrase inhibitor

CONFIDENTIAL – NOT FOR DISSEMINATION

Dolutegravir1–3 Raltegravir4 Elvitegravir5,6

Clinical dose 50 mg QD (INI-naïve),

50 mg BID (INI-resistant)

400 mg BID* 150 mg QD boosted

(quad pill)

t1/2 ~14 hours ~9 hours ~12.9 hours (boosted)

PK variability Low to moderate High Low (with boosting)

Food effect No food restriction No food restriction, but fat

content affects absorption and

increases PK variability

Taken with food

Protein binding High: ≥98.9% Moderate: 83% High: 98–99%

Metabolism and

excretion

UGT1A1 (major), CYP3A

(minor), renal elimination <1%

UGT1A1, renal elimination ~9% CYP3A (major), UGT1A1/3

(minor), renal elimination 6.7%

PK/PD relationship Yes, Ctrough-driven efficacy Yes, Ctrough-driven efficacy QD

No (for bd dose)

Yes, Ctrough-driven efficacy

1. Tivicay US Prescribing Information. ViiV Healthcare, August 2013; 2. Min S, et al. Antimicrob Agents Chemother 2010;54:254–8

3. Min S, et al. AIDS 2011;25:1737–45; 4. Isentress prescribing information (June 2013)

5. Stribild prescribing information (October 2013); 6. Ramanathan S, et al. Clin Pharmacokinet 2011;50:229–44

Key Pharmacology of Integrase Inhibitors:

Pharmacokinetics

* QD 1200 mg Currently under review by EMA

Higher potential Moderate

Potential

Lower Potential

Boosted PIsPerpetrators – enzyme and

transporter Inhibition

Victim - absorption (ATV);

induction

RilpivirineVictim of enzyme

inhibition and induction.

Also absorption.

RaltegravirVictim of few induction

and absorption

interactions

EVG/cobiPerpetrator – enzyme and

transporter inhibition

Victim - absorption;

induction

(Maraviroc)Victim of enzyme

inhibition and induction.

Most NRTIsVictim of some

transporter mediated

interactions

Efavirenz, (Nevirapine,

Etravirine)Perpetrators – enzyme and

transporter induction

Interaction Potential of Integrase Inhibitors

Based on www.hiv-druginteractions.org

Dolutegravir

Victim of enzyme

induction and absorption

interactions

Perpetrator of renal

interaction

Key Pharmacology of Integrase Inhibitors:

Structure and Binding

From Tivicay: www.viivhealthcare.com

From Tivicay www.viivhealthcare.com

Overview

Integrase Inhibitors: An Overview

Raltegravir: What’s New

1

2

3

4

ONCEMRK: RAL 1200 mg QD vs

400 mg BID + TDF/FTC in ART-Naive Pts

• Multinational, randomized, double-blind phase III trial

– Primary endpoint: Wk 48 HIV-1 RNA < 40 copies/mL

– Reformulated RAL 600 mg tablets allow 1200 mg QD dosing

RAL 1200 mg* QD +

TDF/FTC

(n = 533)

RAL 400 mg BID +

TDF/FTC

(n = 269)

ART-naive adults

with HIV-1 RNA

≥ 1000 copies/mL

(N = 802)

96 wksRandomized 2:1 48 wks

Pts

followed for

14 days

*Two 600-mg tablets

Baseline HIV-1 RNA > 100,000 copies/mL: 28.1% to

28.6%

Cahn P, et al. AIDS 2016. Abstract FRAB0103LB.

ONCEMRK: RAL 1200 mg QD Noninferior

to RAL 400 mg BID at Wk 48

100

80

60

40

20

0

88.388.786.583.578.2

51.9

53.5

76.382.1 87.4 87.2 88.9

0 4 8 12 16 20 24 28 32 36 40 44 48

Treatment Wk

RAL 1200 mg QD + TDF/FTC

RAL 400 mg BID + TDF/FTC

• Wk 48 HIV-1 RNA < 40 copies/mL in pts with BL HIV-1 RNA > 100,000 copies/mL:

RAL QD, 86.7%; RAL BID, 83.8% (∆ 2.9; 95% CI: -6.5-14.1)

• RAL QD associated with overall safety profile similar to RAL BID

Cahn P, et al. AIDS 2016. Abstract FRAB0103LB.

Pts

Wit

h H

IV-1

RN

A

< 4

0 c

op

ies/m

L (

%)

Impact of Efavirenz on 1200 mg RAL QD

Mean ±SD plasma concentration profile of raltegravir following single dose

administration of 1200 mg without and with multiple dose efavirenz (600 mg qd)

for 14 days in healthy adults (n=21)

GMR

(RAF+EFV/RAL

AUC 0.86

Ctrough 0.94.

Krishna R et al Biopharm Drug Dispos 2016 [epub ahead of print]

Impact of Efavirenz on 1200 mg RAL QD

A trough target has been based on the exposure-

response relationship of QD RAL previously

described, below which significantly lower antiviral

responses could be anticipated.

Considered that the absence of a clinically relevant

difference in the efficacy of RAL 1200 mg QD is

anticipated when reductions in the Ctrough are < 25%.

So lower bound of 90% CI of Ctrough GMR should be >

0.75.

However Efavirez is mild/moderate inducer of

UGT1A1. What about RIFAMPICIN?

Krishna R et al Biopharm Drug Dispos 2016 [epub ahead of print]

Co-administered

drug

Dolutegravir1 Raltegravir BD2 E/C/F/TDF3 or

E/C/F/TAF4

Mg++ or Al++

containing antacid

Take

antacid/supplement

a minimum of 2h

after or 6 h before

Co-administration

not recommended

Separate by at least

4 h

Calcium antacid/

supplements

Take

antacid/supplement

a minimum of 2h

after or 6 h before

No dose adjustment

of RAL required

(Ctrough ↓32%)

Not stated

Multivitamins Take

antacid/supplement

a minimum of 2h

after or 6 h before

Not stated Separate by at least

4 h

Integrase Inhibitors and Cation

Containing Antacids: Recommendations

1, Tivicay SmPC Oct 2015; 2. Isentress SmPC July 2015; 3. Stribild SmPC Sept 2016; 4, Genvoya SmPC Oct 2016.

Impact of Antacids on 1200 mg RAL QD

Treatment A: 1200 mg RAL alone

Treatment B: 1200 mg RAL + 3 tabs of TUMS US (Ca carbonate) – given

together

Treatment C: 1200 mg RAL + 20 ml Maalox (Al++ /Mg++) given 12 h after RAL

Treatment D: 1200 mg RAL + 3 tabs of TUMS given 12 h after RAL

Krishna R et al J Pharm Pharmacol 2016; 68: 1359-1365)

PK Parameters of RAL after administration

of 1200 mg with/without antacids

Treatment N AUC (h.µM) and GMR C24 (nM)

A (RAL

alone)

20 53.7 75.6

B (Ca++)

together

19 14.8 (0.28) 39.6 (0.52)

C (Al++/Mg++)

Separated

19 46.3 (0.86) 32.0 (0.42)

D (Ca++)

separated

19 48.5 (0.90) 32.4 (0.43)

Krishna R et al J Pharm Pharmacol 2016; 68: 1359-1365)

Given the C24h values are all < 0.75 – the co-administration of

Calcium carbonate and Mg++/Al++ with RAL 1200 mg is not

recommended.

Impact of Atazanavir on 1200 mg RAL QD

Mean ±SD plasma concentration profile of raltegravir following single dose administration

of 1200 mg without and with multiple dose atazanavir (400 mg qd) for 9 days in healthy

adults (n=21)

Krishna R et al Biopharm Drug Dispos 2016 [epub ahead of print]

Overview

Integrase Inhibitors: An Overview

Raltegravir: What’s New

1

2

Dolutegravir: What’s New3

4

Dolutegravir: What’s New

Treatment Simplification

Pharmacokinetic tail

Real life tolerability

Switch study

‘Tail’ study in subjects stopping either

DTG or EVG/cobi

Elliott et al. 16th PK Workshop, Washington May 2015

PA IC90

64 ng/ml

SPRING-1: Phase IIb, dose-ranging study in INI-naïve subjects1–3

Once-daily dose

N2,3

HIV-1 RNA <50 c/mL at

Week 96 (%)2,3

C

(µg/mL)1,

3

IQ*,1,3

EFV 600 mg

50 72 – –

DTG 10 mg 53 79 0.30 (71) 4.7

DTG 25 mg 51 78 0.54 (67) 8.4

DTG 50 mg 51 88 1.20 (62) 19

Lower boundary: in SPRING-1, a 75% reduction in DTG C with DTG 10 mg vs 50 mg QD (from 1.20 to 0.30) was not deemed clinically significant based on efficacy at Week 96 and IQ3

Upper boundary (toxicity): no dose-limiting toxicities identified3

C values are geometric means (CV%) at Week 20 5

Post-dose time (hours)

10

1

Mea

n D

TG c

on

cen

trat

ion

(µ

g/m

L)

0.1

10 15 20 25

10 mg QD3

25 mg QD3

50 mg QD3

PA-IC90 0.064 µg/mL

*Inhibitory quotient is defined as C/PA-IC90

1. Adapted from van Lunzen J, et al. Lancet Infect Dis 2012;12:111–8 2. Adapted from Stellbrink H-J, et al. CROI 2012. Abstract 102LB

3. Adapted from Song I, et al. IWCP 2012. Abstract O07

The Concept of IQ: DTG Exposure

SPRING-1: ARV naïve (dose ranging and vs EFV)

SPRING-2: ( ARV naïve (vs RAL)

CDER Clinical Pharmacology Review 2013. NDA 204,790)

Percentage of subjects achieving virologic

success (< 50 cps/ml, left) & virologic failure

(right) vs DTG Cmin from SPRING I & SPRING II

Relationship between dolutegravir trough

concentration and viral load reduction

c/mL, copies/mL; Emax, maximum effect

Adapted from Min S, et al. AIDS 2011; 25:1737–45

DTG has a well characterised exposure-response relationship

Phase IIa, dose-ranging, placebo-controlled, 10-day monotherapy study

Placebo

10 mg OD

50 mg OD

Model fit: Emax = –2.6, IC50 – 0.036 µg/mL

C (µg/mL)

Day

11

log 1

0vi

ral l

oad

chan

ge f

rom

bas

elin

e –3.5

–3.0

–2.5

–2.0

–1.5

–1.0

–0.5

0

0.5

1.0

0 0.4 0.6 0.8 1.0 1.4

Subjects with

HIV-1 RNA <50 c/mL

are represented by

orange-bordered

circles

Open circles with lines

denote mean standard

deviation

0.2 1.2

C: Trough concentration

EC90EC50

CDER Clinical Pharmacology Review 2013. NDA 204,790)

SAILING: ARV experienced, INH naïve patients

Percentage of subjects achieving virologic

success (< 50 cps/ml) vs DTG Cmin from SAILING

Category GM C0 (h)

µg/ml

Response

(%)

DTG (all)(n=335)

0.85 79%

DTG

(no inducer;

no BLQ)(n=286)

1.04 81%

DTG (BLQ)(n=28)

0.24 57%

DTG (EFV)(n=13)

0.20 62%

Pharmacodynamic Characteristics of

Integrase InhibitorsParameter DTG EVG RAL

IC50 ng/ml 16 7.2 NA

IC90/95 ng/ml 64 44.9 14.7

EC50 ng/ml 36 14 NA

EC90 ng/ml 324 126 NA

IQ

(Ctrough /IC90/95)

17 10 8

IC50/90/95 protein binding adjusted conc inhibiting viral replication by 50/90/95%Podany AT et al Clin Pharmacokin 2016 (Epub ahead of print)

Higher rates of neuropsychiatric adverse events leading

to dolutegravir discontinuation in women and older

patients

Sabranski M et al HIV Glasgow 2016; Abs O214

Relationship between DTG plasma trough concentration,

UGT1A1 polymorphisms and side-effects of the CNS in

Japanese HIV-1 infected patients

N = 101

UGT1A1 *6 and *28 studied

Median DTG Ctrough was

significantly higher in patients

with CNS side effects

However, no difference in

CNS AEs in terms of genetic

polymorphisms

Yagura H et al HIV Glsagow 2016; Abs P312.

Dolutegravir Distribution and CSF

Penetration

Plasma Protein Binding > 98%1

A Phase IIIb study assessed the distribution of DTG in

CSF2

13 ART-naïve subjects received DTG 50 mg +

ABC/3TC 600/300 mg QD

DTG concentrations in CSF at week 2 and 26

averaged 18 ng/ml and exceeded the non-protein

binding corrected IC50 against WT virus (0.2 ng/ml)2 for

all subjects

Median decrease in CSF HIV RNA (-3.42 log) at wk 16

were similar to those observed in plasma (3.04 log).

1. Tivicay SmPC; 2. Letendre S et al CROI 2013 Poster 178LB

Population PK of DTG alone and following

treatment switch from efavirenz

ALONE WK1 WK2 WK3 WK40

20

40

60

80

Weeks after switch

DT

G A

UC

0-2

4(m

g.h

/L)

ALONE WK1 WK2 WK3 WK40.0

0.5

1.0

1.5

2.0

Weeks after switch

DT

G C

24

(mg

/L)

STUDY1* STUDY2

Parameter ALONE WK1 WK2 WK3 WK4

n 17 17 14 14 39

AUC0-24 (mg.h/L)56.9

(53.0-62.4)

40.8

(38.5-43.8)

34.2

(31.5-38.0)

48.3

(45.1-52.5)

49.0

(47.2-51.7)

C24 (mg/L)1.27

(1.17-1.45)

0.75

(0.69-0.84)

0.51

(0.46-0.59)

1.02

(0.93-1.15)

1.04

(1.00-1.11)

PA IC90

Dickinson L et al Glasgow 2016 P094

PK data from healthy volunteer study and HIV+ patient study were combined to develop DTG

model. Effect of residual EFV on DTG CL/F post-switch (study 2) determined using DTG alone

from healthy volunteers as reference (study 2)

• Predicted PK parameters significantly reduced following

EFV switch, particularly C24 (↓33%, 53%, 18% at WK1,

WK2, WK4 vs. alone)

• All predicted C24 were above the PA-IC90 of 0.064 mg/L for

DTG, which is comparable to other reports1. One C24 was

at the EC90 value of 0.32 mg/L

• Adds support that DTG dose adjustments are not

necessary following switch from EFV in virologically

suppressed patients.

1 Wet et al. 17th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy 2016. Washington DC, USA. Abstract O_23

Overview

Integrase Inhibitors: An Overview

Raltegravir: What’s New

1

2

Dolutegravir: What’s New3

Elvitegravir: What’s New4

Approved TAF-containing regimens

Genvoya® (Elvitegravir 150mg/cobicistat 150mg/emtricitabine 200mg/tenofovir alafenamide 10mg) (EVG/Cobi/FTC/TAF)

Odefsey® (Rilpivirine 25mg/emtricitabine 200mg/tenofovir alafenamide 25mg) (RPV/FTC/TAF)

Descovy® (FTC 200mg, TAF 10 and 25 mg – EMEA approved; (FTC 200 mg, TAF 25 mg – FDA approved)

Not recommended for pts with CrCl < 30 mL/min• No dose adjustment necessary CrCl ≥ 30 mL/min; FTC/TDF requires dose adjustment

CrCl 30-49 mL/min

Not yet indicated for patients co-infected with HBV. TAF is active against HBV but clinical efficacy not yet fully established Descovy 200/10mg & 200/25mg SmPCs; available at: https://www.medicines.org.uk/emc/medicine/31764 OR

https://www.medicines.org.uk/emc/medicine/31765 Truvada SmPC: https://www.medicines.org.uk/emc/medicine/15826

Absorption of Tenofovir (TFV), TenofovirDisoproxil Fumarate (TDF) and Tenofovir

Alafenamide (TAF)

† T1/2 based on in vitro plasma data.

1. Lee W et. Antimicr Agents Chemo 2005;49(5):1898-1906. 2. Birkus G et al. Antimicr Agents Chemo 2007;51(2):543-550. 3. Babusis D, et al. Mol Pharm 2013;10(2):459-66.

4. Ruane P, et al. J Acquir Immune Defic Syndr 2013; 63:449-5. 5. Sax P, et al. JAIDS 2014. 2014;67(1):52-8. 6. Sax P, et al. Lancet 2015;385:2606-15.

HIV TARGET CELL

AMIDATE

ESTER

DIANION

GI TRACT

Tenofovir

alafenamide

(TAF)

Tenofovir

disoproxil

fumarate

(TDF)

Tenofovir

(TFV) Parent

Nucleotide

T1/2 = 90

min†

T1/2 = < 5 min†

PLASMA

TAF25 mg

or 10 mg*

TDF 300 mg

TFV

TFV

TFV

• 91% lower plasma TFV levels after E/C/F/TAF than E/C/F/TDF

administration – TFV AUC is 290 vs 3308 ng.h/ml for Genvoya vs Stribild

TFV HIV

Gupta SK, et al. IAS 2015. Vancouver, CA; #TUAB0103.FDA Center for Drug Evaluation and Research. Clinical Pharmacology & Biopharm Rev 2014

AVT 2014; 19: 687-692

‡

Virologic Efficacy

Overall Virologic Efficacy at Week 144

36

Studies 104 and 111: ART-Naïve Adults with patients randomised to E/C/F/TDF or E/C/F/TAF. N = 1733.

Favours E/C/F/TAF

HIV

-1 R

NA

<50

c/m

L, %

Treatment Difference (95% CI)

Favours E/C/F/TDF

Virologic Success Virologic Failure No Data

E/C/F/TAF E/C/F/TDF

Week 144

% %

Week 144

• For patients ≥ 50 , treatment difference: 11.8% (95% CI: 1.3-22.2)• At Week 144, E/C/F/TAF was statistically superior in efficacy to

E/C/F/TDF

Ward, D. et al. HIV and Aging 2016. Washington, DC. #33; Sax PE et al Lancet 2015; 385: 2606-2615

‡

Overall Week 144: Renal Events Leading to Discontinuation

37

Reason for Treatment Discontinuation

E/C/F/TAF

n

E/C/F/TDF

n

Total Renal Event Discontinuations 0 12

Creatinine increased and GFR decreased 0 1

Reduced GFR 0 1

Fanconi syndrome + glycosuria 0 1

Nephropathy 0 1

Proteinuria 0 1

Renal failure 0 2

Renal tubular disorder 0 3

Creatinine increased + bone density decreased 0 1

Bladder spasm 0 1

Ward, D. et al. HIV and Aging 2016. Washington, DC. #33

On the E/C/F/TAF arm through 144 weeks there were

– No cases of renal tubulopathy (including Fanconi Syndrome)

vs. 2 for E/C/F/TDF

– No discontinuations due to renal AE

vs. 12 for E/C/F/TDF (p<0.001)

Studies 104 and 111: ART-Naïve Adults with patients randomised to E/C/F/TDF or E/C/F/TAF. N = 1733.

Differences in the DDI Profile of E/C/F/TDF

and E/C/F/TAF

E/C/F/TDF E/C/F/TAF Potential Mechanism

Aspirin NSAIDS and Renal

Celecoxib NSAIDS and Renal

Diclofenac NSAIDS and Renal

Ibuprofen NSAIDS and Renal

Mefenamic acid NSAIDS and Renal

Naproxen NSAIDS and Renal

Nimesulide NSAIDS and Renal

Acetazolamide Renal transport

Cefalexin Renal transport

Dacarbazine Renal transport

Flucloxacillin Renal transport

Mycophenolate Renal transport

Probenecid Renal transport

Oxaliplatin Renal toxicity

Penicillamine Renal toxicity

Zoledronic acid Renal dysfunction

www/hiv-druginteractions.org – accessed Nov 17th 2016

Differences in the DDI Profile of TDF & TAFTDF TAF Potential Mechanism

Rifabutin NR Induction of P-gp

Rifampicin NR Induction of P-gp

Rifapentine NR Induction of P-gp

Carbamazepine NR Induction of P-gp

Oxcarbazepine NR Induction of P-gp

Phenobarbitone NR Induction of P-gp

Phenytoin NR Induction of P-gp

St John’s Wort NR Induction of P-gp

Fluconazole Dose 10 mg TAF Inhibition of P-gp

Itraconazole Dose 10 mg TAF Inhibition of P-gp

Ketoconazole Dose 10 mg TAF Inhibition of P-gp

Cyclosporin Dose 10 mg TAF Inhibition of P-gp

Boceprevir NR Stops intracellular activation

Telaprevir NR Stops intracellular activation

www/hiv-druginteractions.orgNR = Not Recommended

N = Could argue could be red (personal communication, David Back Nov 16)

J Hepatology 2016;

DDIs:Are not going away!

AgeingPolypharmacy

Increased

OTC

Less Clinic

visits?

Online access drugs

Different prescribers

Recreational drugs

More patients

starting tx

Adapted from Okoli C - with permission

Take home points.5

There are important pharmacological considerations in relation to

Integrase Inhibitors:

Disposition and PK profile; QD, dose, boosting; tail.

STR and backbone

TAF v TDF

Pharmacodynamics (binding to integrase)

Differential DDI profile

Pregnancy

Sanctuary site penetration

ConsiderationPotential Choice

ABC/3TC FTC/TAF FTC/TDF

Pt might benefit from STR vs

MTR (adherence or

preference)

Pt has high CVD risk

Confidence in high VL Only with DTG

Pt is HLA-B*5701 positive

Pt has osteopenia or

osteoporosis

Pt has renal impairment *

If INSTIs are generally preferred in guidelines,

need to choose between backbones

*DTG/ABC/3TC not recommended for pts with CrCl < 50 mL/min as 3TC dose adjustment required.

DTG/ABC/3TC [package insert]. September 2015. FTC/TAF [package insert].

April 2016. FTC/TDF [package insert]. April 2016.Personal Communication, David Back 2016

Guideline-recommendations for first-line likely to evolve to FTC/TAF +

INSTI or DRV/RTV or DTG/ABC/3TC

Thank You

Drug Distribution into the Genital Tract

DTG is present in both female and male genital tract1

AUC in CVF, cervical tissue and vaginal tissue is 6-10%

of plasma concentrations1,2

AUC in semen was 7% and in rectal tissue was 17% of

plasma concentration1,3

1. Tivicay SmPC; 2. Adams Jl et al Antiviral Therapy 2013; 18: 1005-1014; 3. Greener BN et al. JAIDS 2013; 64: 39-44

Dolutegravir and Darunavir in CSF, Male

and Female Genital Tract

Matrix DTG

ng/ml

DTG

Ratio to BP

DRV

ng/ml

DRV

Ratio to BP

CSF 18 0.02 16 0.01

Semen 58 0.07 390 0.17

Rectal Tissue 139 0.17 6730 ~3-fold

CVF 93* 0.06-0.10 170

AUC

0.09 (Case)

~1.5-fold

VT 78 0.06-0.10 NR NR

CT 149 0.17 NR NR

Tivicay SmPC; Adams Jl et al Antiviral Therapy 2013; 18: 1005-1014; Greener BN et al. JAIDS 2013; 64: 39-44; Calcagno A et al CID 2015;

60: 311-317; Else LJ et al AVT 2011; 16; 1149-1167; Brown K et al. JAIDS 2012; 61: 138-144. Paterson K et al. AAC 2011; 55: 1120-1122.

Distribution of Tissue Penetration Ratios:

Cervical or Vaginal Tissue or CVF

Thompson CG et al AIDS Research and Human Retroviruses 2014; 30: 1058-1065

Persistence of HIV during apparently

suppressive therapy

Special Patient GroupsDolutegravir Elvitegravir Raltegravir

Swallowing Granule being

developed

Cannot be chewed

or crushed

Chewable tablets,

granules

(suspension)

Children Not licensed < 12 Not licensed < 18;

avoid < 6

Licensed from 4

wks

Pregnancy Limited data; FDA

Cat B

Limited data; FDA

Cat B.

Some data in pts;

FDA Cat C*

Renal Impairment No adjustment(exposure decreased by

40% in severe RI)

FDC not < 70;

stop < 50 ml/min;

No adjustment

HD No data, no

difference

expected

FDC - avoid No data; avoid

dosing before

dialysis

Hepatic Impairment

- CPA

- CPB/C

No adjustment

Caution

No adjustment

Not recommended

No adjustment

Caution

• Avoid SmPC;

Data from Tivicay SmPC, Oct 2015; Stribild SmPC May 2016; Isentress SmPC July 2015.

Podany AT et al Clin Pharmacokinetics 2016; [Epub ahead of print]

DHHS Recommendations: ART in

Pregnant Women

DHHS

Guidelines[1] PIs NNRTIs NRTIsEntry

Inhibitors

Integrase

Inhibitors

RecommendedAtazanavir/RTV*

Darunavir/RTV*Efavirenz*†

ABC/3TC

TDF/FTC

TDF + 3TC

ZDV/3TC

Raltegravir*

Alternative Lopinavir/RTV* Rilpivirine*

Insufficient data

to recommendFosamprenavir

RPV/TAF/

FTC[2]TAF/FTC[3]

Maraviroc

Dolutegravir

EVG/COBI/TDF/

FTC

EVG/COBI/TAF/

FTC[2]

Not

recommended

Indinavir/RTV

Nelfinavir

Ritonavir

Saquinavir/RTV

Tipranavir/RTV

Etravirine

Nevirapine

ABC/3TC/ZDV

d4T

ddI

Enfuvirtide

1. DHHS Perinatal Guidelines. April 2015. 2. EVG/COBI/TAF/FTC

[package insert]. 2015. 3. RPV/TAF/FTC [package insert]. 2016.

4. TAF/FTC [package insert]. 2016.

*In addition to 2-NRTI backbone. †May be initiated after first 8 wks of pregnancy.

Slide credit: clinicaloptions.com

CDER Clinical Pharmacology Review 2013. NDA 204,790)

Geometric DTG C0h and response rate for subjects

from SAILING according to whether subject

received an inducer or had a BLQ determination

STUDY11

n=17

-----------------------------

DTG 50 mg qd(10 days)

Serial sampling:

0-216 h after final

dose

NONMEM

(v. 7.3)

PK data from healthy volunteer STUDY11 and HIV-infected patient STUDY22 were combined to

develop the DTG model. Effect of residual EFV on DTG CL/F post-switch (STUDY2) was

determined using DTG alone from healthy volunteers as a reference (STUDY1)

Influence of EFV on DTG-----------------------------------------------------------

Covariates:

Age, weight, sex, ethnicity

HIV status, food intake

DTG Predicted PK parameters:AUC0-24, Cmax, C24

WK1, 2, 3, 4 post-switch vs. aloneGMR 90% CI

1 Elliot et al. J Antimicrob Chemother 2016; 71 (4): 1031-36; 2 Bracchi et al. HIV Drug Therapy Glasgow 2016. Glasgow, UK. Abstract P209

STUDY22

n=39

(18 immediate/

21 delayed switch)

----------------------------

Switched from EFV to

DTG 50 mg qd

Random sampling:

WK1, 2, 3, 4 post-

switch (1-25.75 h post

dose)

Population PK of DTG alone and

following treatment switchDickinson L et al Glasgow 2016

P094

FDA Center for Drug Evaluation and Research. Clinical Pharmacology & Biopharm Rev 2014

Tenofovir exposure following administration of E/C/F/TAF and E/C/F/TDF (studies GS-104 and GS-111; PK sub-study)