Introduction ♦ Bictegravir (BIC)/emtricitabine/tenofovir alafenamide (B/F/TAF 50/200/25 mg)

is a single tablet regimen (STR) approved in Australia, Canada, EU, and USA for treatment of HIV-1 infection in treatment-naïve and virologically suppressed adults without resistance to its components1

– B/F/TAF is a Department of Health and Human Services and International Antiviral Society guidelines-recommended initial regimen for most HIV-1–infected patients2

– B/F/TAF requires qd dosing without regard to food, and has limited testing requirements prior to initiation and few known drug-drug interactions

♦ In five Phase 3 studies of HIV-1–infected patients, B/F/TAF was safe and efficacious, with no development of resistance3-7

♦ A population-based pharmacokinetic (PK) model was developed to understand the clinical covariates of the PK of BIC and TAF in HIV-1–infected patients when administered as B/F/TAF 50/200/25 mg qd

Objectives ♦ To determine the effects of demographic, pathophysiologic, and HIV-1‒related

covariates on the PK of BIC and TAF to better understand clinical factors that may affect exposure in individual patients

Methods Population PK Modeling ♦ Population PK models for BIC and TAF were developed using pooled intensive

and sparse plasma concentration data (8752 and 4201 observations, respectively) from 18 Phase 1 and 3 studies in healthy volunteers (HVs) and patients with HIV-1 infection (BIC: n=1318; TAF: n=1409)

– A nonlinear mixed-effects modeling approach using a 1st-order conditional estimation with interaction method in NONMEM® 7.3 (ICON plc, Dublin, Ireland) was employed

Covariate Effects ♦ Significance covariates were determined using a forward addition and backward

elimination method (based on significance levels of p <0.01 and p <0.001, respectively)

– Demographics: baseline age, sex, race (white vs black or African-American vs Asian vs other), body weight (BW), and HIV-1 status (HVs vs HIV-1–infected patients)

– Pathophysiologic covariates: baseline creatinine clearance, prior treatment experience (naïve vs experienced), and concomitant administration of H2-receptor antagonists (H2RAs) or proton pump inhibitors (PPIs)

– Other covariates: fasting/fed status (never vs sometimes vs always fed) and baseline hepatitis B or C virus (HBV or HCV, respectively) coinfection status

♦ To examine the influence of patient covariates on the steady-state exposures of BIC (area under plasma concentration-time curve over dosing interval [AUC�], maximum plasma concentration [Cmax], and concentration at end of dosing interval [C�]) and TAF (AUC� and Cmax):

– Sensitivity analyses of significant covariates were performed

– Exposures were stratified by covariate and compared

Results ♦ The developed population PK models adequately described BIC and TAF PK

(data on file)

– BIC PK was described using a 1-compartment model, with 1st-order absorption, a lag time, and 1st-order elimination from the central compartment

• Only HIV-1 status, BW, and baseline PPI status were identified as statistically significant covariates

– TAF PK was described by a 2-compartment model with sequential 0- then 1st-order absorption, with 1st-order elimination from the central compartment and redistribution from the peripheral compartment

• Only HIV-1 status and sex on clearance were identified as statistically significant covariates

♦ The sensitivity analysis showed that baseline BW was the greatest contributor to the variability of BIC exposure (34% for AUC� across 90% of plausible range of BW)

♦ The contribution of HIV-1 status or baseline PPI use to the variability in BIC exposure was low (<5%)

♦ Mean BIC exposures in HVs (n=125) and HIV-1–infected patients (n=1193) differed by 12–13%

♦ Mean BIC exposures in highest (n=297) and lowest (n=300) BW quartiles differed by 17–26%

♦ Mean BIC exposures in patients with (n=109) and without (n=1084) concomitant PPI administration differed by <9%

♦ All other demographic and disease covariates demonstrated minimal-to-no effects on BIC exposure

♦ The sensitivity analysis showed that the contribution of HIV-1 status or sex to variability in TAF exposure was low (7–25%), but the combination of both sex and HIV-1 status explained 11–46% of variability in TAF exposure

♦ Mean TAF exposures in HVs (n=202) and HIV-1–infected patients (n=1207) differed by 2–25%

♦ Mean TAF exposures in males (n=439) and females (n=47) differed by 12–15%

♦ All other demographic and disease covariates demonstrated minimal-to-no effects on TAF exposure

References: 1. Biktarvy [package insert]. Foster City, CA: Gilead Sciences, Inc., Feb 2018; 2. AIDsinfo. <https://aidsinfo.nih.gov/news/2044/adult-arv-panel-classifies-bic-taf-ftc-as- recommended-initial-regimen-for-hiv>, 2018; 3. Daar ES, et al. ID Week 2017, abstr LB-4; 4. Gallant J, et al. Lancet 2017;390:2063-72; 5. Kityo C, et al. CROI 2018, abstr 500; 6. Molina J-M, et al. CROI 2018, oral 1918; 7. Sax PE, et al. Lancet 2017;390:2073-82; 8. Lutz JD, et al. International Workshop on Clinical Pharmacology of Antiviral Therapy 2018, poster 6.

Acknowledgments: We extend our thanks to the patients and their families. This study was funded and conducted by Gilead Sciences, Inc.

♦ Considering the favorable B/F/TAF safety profile and high virologic response rates across the Phase 3 program,8 all demographic and disease covariates evaluated were determined to have no clinically relevant impact on BIC or TAF exposure in HIV-1–infected patients

♦ No dose adjustment of BIC or TAF is necessary for the evaluated patient demographic or disease covariates

Conclusions

Presented at HIV Drug Therapy/Glasgow 2018, October 28–31, 2018, Glasgow, UK© 2018 Gilead Sciences, Inc. All rights reserved.

No Clinically Relevant Effect of Patient Demographic or Disease Covariates on the Exposures of Bictegravir and Tenofovir Alafenamide Following

Administration of a B/F/TAF Single-Tablet Regimen to HIV-1‒Infected Patients Justin D. Lutz,1 Brian J. Kirby,1 Yongwu Shao,1 Yuying Gao,2 Erin Quirk,1 Anita Mathias1

1Gilead Sciences, Inc., Foster City, California, USA; 2Certara Strategic Consulting, Menlo Park, California

P262

Gilead Sciences, Inc. 333 Lakeside Drive

Foster City, California, USA 94404 800-445-3235

BIC AUC�, h∙μg/mL BIC C�, ng/mLBIC Cmax, ng/mL

0 1000 2000 3000 4000 5000

90% CI

BW

BW (5%ile)+ PPI use

BW (95%ile)+ PPI use

HIV-1 status

PPI use

0 2000 4000 6000 8000 10,000

90% CI

BW

BW (95%ile)+ PPI use

BW (5%ile)+ PPI use

PPI use

HIV-1 status

0 60 120 180

90% CI

BW

BW (5%ile)+ PPI use

BW (95%ile)+ PPI use

PPI use

HIV-1 status

151 h∙μg/mL

58 kg (+17.8%)113 kg (-16.2%)

63 h∙μg/mL

58 kg + PPI(+17.8%)Base (0%)

Base (0%)113 kg + PPI

(-16.2%)

No (0%)Yes (0%)

HV (0%)

Base=99.2 h∙μg/mL80-kg HIV patient without PPI usage

8752 ng/mL

58 kg (+21.3%)113 kg (-18.6%)

4032 ng/mL

Base (0%)113 kg + PPI

(-22%)

58 kg + PPI(+15.3%)Base (0%)

No (0%)Yes (-4.6%)

HV (+2.8%)HIV (0%)

4275 ng/mL

58 kg (+12.7%)113 kg (-12.4%)

1335 ng/mL

Base (0%)113 kg + PPI

(-10.7%)

58 kg + PPI(+15.2%)Base (0%)

HIV (0%)HIV (-4.2%)

Yes (+2.1%)No (0%)

Base=6088.6 ng/mL80-kg HIV patient without PPI usage

Base=2487 ng/mL80-kg HIV patient without PPI usage

HIV (0%)

BIC Sensitivity Analysis Effect of Covariates on BIC Steady-State Exposure*

*Base (represented by black dotted line and values) refers to predicted steady-state exposure (AUC�, Cmax, or C�) of BIC in typical HIV-1–infected patient with BW of 80 kg and no PPI usage; blue bar with values at each end shows 5th–95th percentile exposure range across entire population; each green bar represents influence of single covariate on steady-state exposure; label at left end of bar represents covariate being evaluated; upper and lower values for each covariate capture 90% of plausible range in population; length of each bar describes potential impact of that covariate on BIC exposure at steady state, with % value in parentheses at each end representing % change of exposure from base; most influential covariate is at top of plot for each exposure parameter. CI, confidence interval.

0 50 100 150 200 250

Base

Sex

HIV-1 status

Sex + HIV-1 status

0 50 100 150 200 250 300

Base

Sex + health status

HIV-1 status

Sex

205 h∙ng/mL

Female HIV (+45.9%)Base (0%)

100 h∙ng/mL

Male HIV (+24.6%)Base (0%)

Female HIV patient (+17%)Base (0%)

Base=134.7 h∙ng/mLMale patient

173 ng/mL

Female HIV patient (+11.2%)Base (0)

50 ng/mL

Base (0)Male HIV (-7.4%)

Female HIV (+4.6%)Base (0)

Base=117.1 ng/mLMale patient

TAF AUC�, h∙ng/mL TAF Cmax, ng/mL

TAF Sensitivity Analysis Effect of Covariates on TAF Steady-State Exposure*

*Base (represented by black dotted line and values) refers to predicted steady-state exposure (AUC� or Cmax) of TAF in typical male HIV-1–infected patient; blue bar with values at each end shows 5th–95th percentile exposure range across entire population; each green bar represents influence of covariates on steady-state exposure; label at left end of bar represents covariate being evaluated; upper and lower values for each covariate capture 90% of plausible range in population; length of each bar describes potential impact of that covariate on TAF exposure at steady state, with % value in parentheses at each end representing % change of exposure from base; most influential covariate is at top of plot for each exposure parameter.

HIV Status Age Sex Race Body Weight Renal Impairment Fed Status TreatmentExperience

Coinfection H2RA Use PPI Use

Health

yHIV

<50 y

≥50 y Male

Female

Whit

eBlac

kAsia

nOthe

rQ1 Q2 Q3 Q4

Normal

Mild

Modera

te

Severe

Never

Someti

mes

Alway

sNaiv

e

HBV and H

CV−

Experi

ence

d

HBV or H

CV+

0

2000

4000

6000

8000

BIC

C�,

ng/

mL

125 1193 1045 148 751 342 28 72 300 300 296 297 955 219 18 1 624 569 1169 24 1155 38 1084 109n= 852 341 355 681 157

0

5000

10,000

15,000

BIC

Cm

ax, n

g/m

L

0

50,000

100,000

150,000

200,000

250,000

BIC

AU

C�,

h∙n

g/m

L

Only HIV-1–Infected Patients (n=1193)

NoYe

s NoYe

s

BIC Exposure Summary in HVs and Phase 3 Population Effect of HIV-1 Infection Status or Demographic Variables on BIC PK in Phase 3 Population (HIV-1–infected patients) Administered B/F/TAF STR*

*Shaded areas represent demographic variables deemed statistically significant in covariate analysis; box and whisker plots depict minimum, 25%, median, 75%, and maximum values. Q, quartile.

HIV Status Age Sex Race Body Weight Renal Impairment Fed Status Coinfection H2RA Use PPI Use

Health

yHIV

<50 y

≥50 y Male

Female

Whit

eBlac

kAsia

nOthe

rQ1 Q2 Q3 Q4

Normal

Mild

Modera

te

Severe

Never

Someti

mes

Alway

s

HBV and H

CV−

HBV or H

CV+

0

100

200

300

TAF

Cm

ax, n

g/m

L

202 1207 439 47 279 159 11 37 122 121 123 120 476 10 475 11 458 28432 48 5 1n= 412 74 113256 117

Only HIV-1–Infected Patients in B/F/TAF Registrational Studies (n=486)

0

100

200

300

400

TAF

AU

C�,

h∙n

g/m

L

NoYe

s NoYe

s

TAF Exposure Summary in HVs and Phase 3 Registrational Studies Effect of HIV-1 Infection Status or Demographic Variables on TAF PK in Phase 3 Registrational Studies (treatment-naïve HIV-1–infected patients) Administered B/F/TAF STR*

*Shaded areas represent demographic variables deemed statistically significant in covariate analysis; box and whisker plots depict minimum, 25%, median, 75%, and maximum values.