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Key Pharmacology of Integrase Inhibitors: Pharmacokinetics

Key Pharmacology of Integrase Inhibitors: Pharmacokinetics

Pharmacological Considerations in Optimal 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

1 Integrase Inhibitors: An Overview

2

3

4 Antiretroviral Therapy: Past, Present & Future

Eron J – CROI 2016 Recommended Regimens: International Guidelines Guidelines Year NNRTI INSTI PI/r

WHO 2016 TDF/FTC (or 3TC) + EFV TDF/FTC (or 3TC) + NA DTG EACS (v8.1)¥ 2016 TAF/FTC/RPV or TAF/FTC or TDF/FTC TAF/FTC or TDF/FTC+RPV* with EVG/c Or RAL TDF/FTC+DRV/r or DTG or DRV/cobi

ABC+3TC with DTG IAS-USA 2016 TAF/FTC+RPV* (or EFV) if TAF/FTC with EVG/c TAF/FTC+DRV/r INSTI not appropriate Or RAL or DTG (if INSTI not appropriate) ABC+3TC with DTG DHHS 2016 TDF/FTC with EVG/c TDF/FTC+DRV/r Or RAL or DTG TAF/FTC with EVG/c TAF/FTC+DRV/r or RAL or DTG

* In viral loads <100K copies/mL ABC+3TC with DTG ¥ Guideline update Oct 2016 TDF, fumarate; TAF, ; FTC, ; 3TC, ; ABC, ; DRV/r, /, RPV, ; EFV, ; EVG/c, WHO 2016: http://www.who.int/entity/hiv/pub/arv/arv-2016/en/index.html /; RAL, ; DTG, ; NNRT, non- EACS v8: http://www.eacsociety.org/files/guidelines_8.0-english-revised_20160610.pdf nucleoside reverse transcriptase inhibitor; PI/r, boosted protease IAS-USA 2016: http://jama.jamanetwork.com/article.aspx?articleid=2533073 inhibitor; INST, integrase inhibitor DHHS 2016: https://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf CONFIDENTIAL – NOT FOR DISSEMINATION Key of Integrase Inhibitors: Pharmacokinetics

Dolutegravir1–3 Raltegravir4 Elvitegravir5,6 Clinical dose 50 mg QD (INI-naïve), 400 mg BID* 150 mg QD boosted 50 mg BID (INI-resistant) (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 Taken with food content affects absorption and increases PK variability

Protein binding High: ≥98.9% Moderate: 83% High: 98–99% Metabolism and UGT1A1 (major), CYP3A UGT1A1, renal elimination ~9% CYP3A (major), UGT1A1/3 excretion (minor), renal elimination <1% (minor), renal elimination 6.7%

PK/PD relationship Yes, Ctrough-driven efficacy Yes, Ctrough-driven efficacy QD Yes, Ctrough-driven efficacy No (for bd dose) * QD 1200 mg Currently under review by EMA

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 Interaction Potential of Integrase Inhibitors Higher potential Moderate Lower Potential Potential Boosted PIs Rilpivirine Raltegravir Perpetrators – enzyme and Victim of enzyme Victim of few induction transporter Inhibition inhibition and induction. and absorption Victim - absorption (ATV); Also absorption. interactions induction EVG/cobi () Most NRTIs Perpetrator – enzyme and Victim of enzyme Victim of some transporter inhibition inhibition and induction. transporter mediated Victim - absorption; interactions induction Dolutegravir Efavirenz, (, Victim of enzyme ) induction and absorption Perpetrators – enzyme and interactions transporter induction Perpetrator of renal interaction

Based on www.hiv-druginteractions.org Key Pharmacology of Integrase Inhibitors: Structure and Binding

From Tivicay: www.viivhealthcare.com From Tivicay www.viivhealthcare.com Overview

1 Integrase Inhibitors: An Overview

2 Raltegravir: What’s New

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

Randomized 2:1 48 wks 96 wks

RAL 1200 mg* QD + TDF/FTC ART-naive adults (n = 533) Pts with HIV-1 RNA followed for ≥ 1000 copies/mL RAL 400 mg BID + 14 days (N = 802) TDF/FTC (n = 269)

*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 88.9 82.1 87.4 87.2 76.3 80 88.7 88.3 83.5 86.5

78.2 1 RNA RNA 1

- 60 53.5 RAL 1200 mg QD + TDF/FTC 51.9 RAL 400 mg BID + TDF/FTC

40 < 40 copies/mL (%) copies/mL < 40 Pts With HIV With Pts 20

0 0 4 8 12 16 20 24 28 32 36 40 44 48 Treatment Wk • 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. Impact of Efavirenz on 1200 mg RAL QD

GMR (RAF+EFV/RAL

AUC 0.86

Ctrough 0.94.

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)

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] Integrase Inhibitors and Cation Containing Antacids: Recommendations

Co-administered Dolutegravir1 Raltegravir BD2 E/C/F/TDF3 or drug E/C/F/TAF4

Mg++ or Al++ Take Co-administration Separate by at least containing antacid antacid/supplement not recommended 4 h a minimum of 2h after or 6 h before Calcium antacid/ Take No dose adjustment Not stated supplements antacid/supplement of RAL required a minimum of 2h (Ctrough ↓32%) after or 6 h before

Multivitamins Take Not stated Separate by at least antacid/supplement 4 h a minimum of 2h after or 6 h before

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 20 53.7 75.6 alone) B (Ca++) 19 14.8 (0.28) 39.6 (0.52) together C (Al++/Mg++) 19 46.3 (0.86) 32.0 (0.42) Separated D (Ca++) 19 48.5 (0.90) 32.4 (0.43) separated

 Given the C24h values are all < 0.75 – the co-administration of Calcium carbonate and Mg++/Al++ with RAL 1200 mg is not recommended.

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

1 Integrase Inhibitors: An Overview

2 Raltegravir: What’s New

3 Dolutegravir: What’s New

4 Dolutegravir: What’s New

Treatment Simplification

Pharmacokinetic tail

 Real life tolerability

 Switch study ‘Tail’ study in subjects stopping either DTG or EVG/cobi

PA IC90 64 ng/ml

Elliott et al. 16th PK Workshop, Washington May 2015 The Concept of IQ: DTG Exposure

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

3 ) 10 10 mg QD 3 HIV-1 RNA C mL 25 mg QD  Once-daily 2,3 *,1,3 50 mg QD3 N <50 c/mL at (µg/mL)1, IQ

(µg/ dose Week 96 (%)2,3 3 EFV 600 50 72 – – 1 mg DTG 10 mg 53 79 0.30 (71) 4.7

DTG 25 mg 51 78 0.54 (67) 8.4

Mean DTG concentration concentration Mean DTG 0.1 PA-IC90 0.064 µg/mL DTG 50 mg 51 88 1.20 (62) 19

0 5 10 15 20 25 C values are geometric means (CV%) at Week 2 Post-dose time (hours)

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

1. Adapted from van Lunzen J, et al. Lancet Infect Dis 2012;12:111–8 *Inhibitory quotient is defined as C /PA-IC  90 2. Adapted from Stellbrink H-J, et al. CROI 2012. Abstract 102LB 3. Adapted from Song I, et al. IWCP 2012. Abstract O07 Percentage of subjects achieving virologic success (< 50 cps/ml, left) & virologic failure (right) vs DTG Cmin from SPRING I & SPRING II

SPRING-1: ARV naïve (dose ranging and vs EFV) SPRING-2: ( ARV naïve (vs RAL)

CDER Clinical Pharmacology Review 2013. NDA 204,790) Relationship between dolutegravir trough concentration and viral load reduction

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

EC50 EC90 C (µg/mL) 0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 –3.5 –3.0 Subjects with –2.5 HIV-1 RNA <50 c/mL are represented by –2.0 orange-bordered –1.5 Placebo circles –1.0 10 mg OD Open circles with lines

viral load change load change viral frombaseline –0.5 50 mg OD 10 0 denote mean standard Model fit: Emax = –2.6, IC50 – 0.036 µg/mL 0.5 deviation

Day 11 log Day 11 1.0

DTG has a well characterised exposure-response relationship

C: Trough concentration c/mL, copies/mL; Emax, maximum effect Adapted from Min S, et al. AIDS 2011; 25:1737–45 Percentage of subjects achieving virologic success (< 50 cps/ml) vs DTG Cmin from SAILING

Category GM C0 (h) Response µg/ml (%) DTG (all) 0.85 79% (n=335) DTG 1.04 81% (no inducer; no BLQ) (n=286) DTG (BLQ) 0.24 57% (n=28) DTG (EFV) 0.20 62% (n=13)

SAILING: ARV experienced, INH naïve patients

CDER Clinical Pharmacology Review 2013. NDA 204,790) Pharmacodynamic Characteristics of Integrase Inhibitors Parameter 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 17 10 8

(Ctrough /IC90/95)

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

80 2.0

60 1.5

/L)

mg.h

(

(mg/L) 24

- 1.0 24

0 40 DTG C DTG

DTG AUC DTG 20 0.5

PA IC90 0 0.0 ALONE WK1 WK2 WK3 WK4 ALONE WK1 WK2 WK3 WK4 Weeks after switch Weeks after switch

STUDY1* STUDY2 Parameter ALONE WK1 WK2 WK3 WK4 n 17 17 14 14 39 56.9 40.8 34.2 48.3 49.0 AUC (mg.h/L) 0-24 (53.0-62.4) (38.5-43.8) (31.5-38.0) (45.1-52.5) (47.2-51.7) 1.27 0.75 0.51 1.02 1.04 C (mg/L) 24 (1.17-1.45) (0.69-0.84) (0.46-0.59) (0.93-1.15) (1.00-1.11) 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) Dickinson L et al Glasgow 2016 P094 • 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 1 DTG, which is comparable to other reports . 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

1 Integrase Inhibitors: An Overview

2 Raltegravir: What’s New

3 Dolutegravir: What’s New

4 Elvitegravir: What’s New 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 Descovy 200/10mg & 200/25mg SmPCs; available at: https://www.medicines.org.uk/emc/medicine/31764 OR efficacy not yet fully established https://www.medicines.org.uk/emc/medicine/31765 Truvada SmPC: https://www.medicines.org.uk/emc/medicine/15826 Absorption of Tenofovir (TFV), Tenofovir Disoproxil Fumarate (TDF) and Tenofovir Alafenamide (TAF)

GI TRACT PLASMA Tenofovir HIV (TFV) Parent TFV TARGET CELL Nucleotide DIANION TFV

Tenofovir disoproxil TDF fumarate 300 mg † (TDF) ESTER T1/2 = < 5 min TFV HIV T1/2 = 90 TAF † Tenofovir min alafenamide 25 mg (TAF) or 10 mg* TFV AMIDATE

• 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

† 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.

FDA Center for Drug Evaluation and Research. Clinical Pharmacology & Biopharm Rev 2014 Gupta SK, et al. IAS 2015. Vancouver, CA; #TUAB0103. AVT 2014; 19: 687-692 Studies 104 and 111: ART-Naïve Adults with patients ‡ randomised to E/C/F/TDF or E/C/F/TAF. N = 1733. Overall Virologic Efficacy at Week 144

Virologic Efficacy Treatment Difference (95% CI)

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

E/C/F/TAF E/C/F/TDF Week 144

Week 144

1 RNA <50 c/mL, % % c/mL, <50 RNA 1

- HIV

% % Virologic Success Virologic Failure No Data

• 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

36 Ward, D. et al. HIV and Aging 2016. Washington, DC. #33; Sax PE et al Lancet 2015; 385: 2606-2615 Studies 104 and 111: ART-Naïve Adults with patients ‡ randomised to E/C/F/TDF or E/C/F/TAF. N = 1733. Overall Week 144: Renal Events Leading to Discontinuation E/C/F/TAF E/C/F/TDF n n Reason for Treatment Discontinuation 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 . 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) 37 Ward, D. et al. HIV and Aging 2016. Washington, DC. #33 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 & TAF

TDF 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

N = Could argue could be red (personal communication, David Back Nov 16) NR = Not Recommended www/hiv-druginteractions.org J Hepatology 2016; More patients starting tx

Polypharmacy Ageing

Increased DDIs: OTC Are not going away! Different prescribers

Less Clinic visits?

Recreational drugs Online access drugs Adapted from Okoli C - with permission 5 Take home points.

 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 If INSTIs are generally preferred in guidelines, need to choose between backbones

Potential Choice Consideration 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 * 

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

 Guideline-recommendations for first-line likely to evolve to FTC/TAF + INSTI or DRV/RTV or DTG/ABC/3TC

DTG/ABC/3TC [package insert]. September 2015. FTC/TAF [package insert]. April 2016. FTC/TDF [package insert]. April 2016. Personal Communication, David Back 2016 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 DTG DRV DRV ng/ml Ratio to BP ng/ml 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 0.09 (Case) AUC ~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 Groups Dolutegravir Elvitegravir Raltegravir

Swallowing Granule being Cannot be chewed Chewable tablets, developed or crushed granules (suspension) Children Not licensed < 12 Not licensed < 18; Licensed from 4 avoid < 6 wks Pregnancy Limited data; FDA Limited data; FDA Some data in pts; Cat B Cat B. FDA Cat C* Renal Impairment No adjustment FDC not < 70; No adjustment (exposure decreased by stop < 50 ml/min; 40% in severe RI) HD No data, no FDC - avoid No data; avoid difference dosing before expected dialysis Hepatic Impairment - CPA No adjustment No adjustment No adjustment - CPB/C Caution Not recommended 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 Entry Integrase PIs NNRTIs NRTIs Guidelines[1] Inhibitors Inhibitors ABC/3TC Atazanavir/RTV* TDF/FTC Recommended Efavirenz*† Raltegravir* Darunavir/RTV* TDF + 3TC ZDV/3TC Alternative /RTV* Rilpivirine* Dolutegravir EVG/COBI/TDF/ Insufficient data RPV/TAF/ [3] TAF/FTC Maraviroc FTC to recommend FTC[2] EVG/COBI/TAF/ FTC[2] /RTV Etravirine ABC/3TC/ZDV Not Ritonavir Nevirapine d4T recommended /RTV ddI /RTV *In addition to 2-NRTI backbone. †May be initiated after first 8 wks of pregnancy. 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. Slide credit: clinicaloptions.com Geometric DTG C0h and response rate for subjects from SAILING according to whether subject received an inducer or had a BLQ determination

CDER Clinical Pharmacology Review 2013. NDA 204,790) Population PK of DTG alone and following treatment switch

Dickinson L et al Glasgow 2016 STUDY22 P094 n=39 STUDY11 (18 immediate/ n=17 21 delayed switch) ------DTG 50 mg qd NONMEM Switched from EFV to (10 days) (v. 7.3) DTG 50 mg qd Serial sampling: Random sampling: 0-216 h after final WK1, 2, 3, 4 post- dose switch (1-25.75 h post Influence of EFV on DTG dose) ------Covariates: Age, weight, sex, ethnicity HIV status, food intake

DTG Predicted PK parameters:

AUC0-24, Cmax, C24 WK1, 2, 3, 4 post-switch vs. alone GMR 90% CI

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)

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

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

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