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)
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