Significance of ARV PharmacokineticsSignificance of ARV Pharmacokinetics

Significance of ARV PharmacokineticsSignificance of ARV Pharmacokinetics

Data PresentationData Presentation

0 4 8 12 16 20 24

Time Post-dose (hours)

PK substudy – week 4 data (n=9) (mean ± SD)

DR

V P

lasm

a C

on

c (n

g/m

L)

EC50 = 55 ng/mL for wild-type virus(adjusted for protein binding)

10

100

1,000

10,000

De Jesus E, et al. 47th ICAAC, Chicago, 2007 Abstract 718b.

ARTEMIS: Favorable PK for DRV Once-Daily

ARTEMIS: Predictors of Success

• Sub-analysis of factors associated with successful virologic response demonstrated non-adherent pts did significantly better on DRV/r than LPV/r

Proportion of Patients in ARTEMIS with HIV-1 RNA <50 copies/mL by Average Adherence*

*Adherence based on average % adherence Week 4 through Week 96Nelson M, et al. 16th CROI, Montreal, Canada, 2009. Abst. 575.

100

70

40

10

Adherent Sub-optimallyadherent

LPV/r

Adherent Sub-optimallyadherent

DRV/r

78%(n=252)

53%(n=70)

P<0.000182%

(n=269) 76%(n=55)

P=0.331290

60

30

0

80

50

20

<5

0 c

op

ies

/mL

at

We

ek

96

Intracellular and Plasma Half-lives of ARVs Used in FOTO Study

0

10

20

30

40

50

60

EFV TDF FTC

Intracellular half-life Plasma half-life

Ho

urs

24 hours

Cohen C, et al. 9th ICDTHI, Glasgow, 2008. Abst. O214.

FOTO: Comparison of Continuous Therapy with 5 Days On, 2 Days Off

Pts with HIV RNA <50 copies/mL on TDF / FTC / EFV (N=60)

• No virologic failures seen (due to prolonged ½ life of regimen?)• Number / pattern of “blips” similar• No significant difference in CD4 count changes• Strong pt preference by Likert Scale (9.5/10) for FOTO

Cohen C, et al. 9th ICDTHI, Glasgow, 2008. Abst. O214.

010

20304050

60708090

100110

BL Week 4 Week 12 Week 24

Continuous

FOTO

Continue daily ARV treatment Change to Five days On; Two Off

Primary Outcome: 24 weeks (Missing = Excluded)Primary Outcome: 24 weeks (Missing = Excluded)97% 96%

87% 86% 88% 90% 93% 100%

**P<0.005 to exclude inferiority of FOTO**P<0.005 to exclude inferiority of FOTO

**

• Relationship between adherence and maintenance of virologic suppression evaluated in subset of REACH cohort: homeless or marginally housed with HIV RNA <50 c/mL (n=221)

• VL and adherence by unannounced pill counts measured monthly• ART: NNRTI (38%); Boosted PI (32%)

• With longer duration of viral suppression, adherence >50% becomes more likely to maintain viral suppression

Longer Duration of Virologic Suppression Decreases Risk for Virologic Failure

Rosenblum M, et al. 16th CROI; Montreal, Canada; February 8-11, 2009. Abst. 583.

Number of Consecutive MonthsVirally Suppressed

Pro

ba

bil

ity

of

Vir

olo

gic

Fa

ilu

re

Risk of Virologic Failurewith Adherence Set to 0-49%

Number of Consecutive MonthsVirally Suppressed

Pro

ba

bil

ity

of

Vir

olo

gic

Fa

ilu

re

Risk of Virologic Failurewith Adherence Set to 50-74%

0 2 4 6 8 10 12 0 2 4 6 8 10 12

0.0

0.8

0.4

0.0

0.8

0.4

BENCHMRK: RAL Plasma Pharmacokinetics Are Not Predictive of Response

• RAL Effective Across Range of Trough Levels

• Trough concentrations do not predict RAL effectiveness

• Prolonged pre-integration complex binding may explain the lack of correlation with trough concentration

Miller M, et al. 48th ICAAC/46th IDSA, Washington, DC, 2008. Abst. H-898

% p

atie

nts

wit

h

HIV

RN

A <

400

c/m

L

GM Observed C12hr (nM)

GM Observed C12hr <33 nM (~in vitro IC95)

8 - 125 128 - 254 254 - 545 547 - 91510

20

40

60

80

100

Pharmacokinetic Study of ATV 200, 300, 400 mg BID in Healthy Subjects

• ATV approved doses:• 400 QD (naïve) • 300/100 QD (naïve, experience)

• Open-label, 3-way randomized crossover study with healthy volunteers (n=18)

• Designed to assess the PK, safety and tolerability of ATV 200, 300 and 400 BID without RTV

• Cmin for ATV 300mg and 400mg BID similar to ATV/r 300/100mg QD

10000

1000

100

10

1

-Geometric Mean

10 x EC90

EC90

Historical

ATV 400 mg QD

(N=106)

ATV

200 mg BID

(N=17)

ATV

300 mg BID

(N=17)

ATV

400 mg BID

(N=17)

Historical

ATV/r 300/100

mg QD (N=116)

Ata

zan

avir

Cm

in (

ng

/mL

)

ATV and ATV/r Cmin

Zhu L, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. A-952

ATV Pharmacokinetics:Study Results

ATV 300 mg BID was the most similar to ATV/r 300/100 mg QD based on PK, magnitude of PR prolongation and hyperbilirubinemia.

ATV 200 mg

BID

ATV300 mg

BID

ATV 400 mg

BID

Most Frequent AEs, n (%)

First Degree AV Block 0 1 (5.6) 10 (59)

Prolonged QRS Complex 0 0 5 (29)

Grade ¾ Lab Abnormalities, n (%)

Total Bilirubin, Grade 3 9 (50) 10 (56) 7 (41)

Total Bilirubin, Grade 4 0 4 (22) 9 (53) 0 4 8 12 16 20 24

8000

6000

4000

2000

0

Ata

zan

avir

(n

g/m

L)

300 mg BID AM

300 mg BID PM

Historical ATV/r 300/100 mg QD (N=116)

Time after AM dose (h)

10x EC90

Comparison of PK of ATV 300mg BID with ATV/r 300/100mg QD

Adverse Events

Historical Cmin: ATV/r 300/100 mg

QD (N=116)

Zhu L, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. A-952

PK and Safety of BID ATV 300mg and RAL 400mg in Healthy Subjects

• ATV inhibits UGT1A1 and increases RAL systemic exposure

• 22 subjects dosed with RAL 400 BID (days 1-5) ATV 300 BID (days 6-12) RAL/ATV BID (days 13-26)

• All ATV Cmin were >10 times higher than the EC90 (14ng/mL)

• RAL increased to the extent observed when dosed with ATV/r 300/100mg

• ATV + RAL may provide a nucleoside and RTV-sparing option and a pilot study in naïve patient is currently underway

Mean ATV Plasma ConcentrationsMean ATV Plasma Concentrations

Time (h)Time (h)

Ata

zan

avir

Co

nc

entr

ati

on

s (

ng

/mL

)A

taza

nav

ir C

on

cen

tra

tio

ns

(n

g/m

L) Mean RAL Plasma ConcentrationsMean RAL Plasma Concentrations

Time (h)Time (h)

Ral

tag

rav

ir C

on

cen

trat

ion

s (n

g/m

L)

Ral

tag

rav

ir C

on

cen

trat

ion

s (n

g/m

L)

Zhu L, et al. 16th CROI; Montreal, Canada; February 8-11, 2009. Abst. 696

GS-9350: PK Enhancement without Ritonavir

• GS-9350: Potent, specific inhibitor of CYP3A with no anti-HIV activity

• Boosting of EVG similar to RTV

• GS-9350 (150 mg) maintained EVG trough concentrations 11-fold above the protein binding-adjusted IC95 (44.5 ng/mL)

• Well tolerated with minimal impact on adipocytes or insulin resistance

• Fixed-dosed combination of GS-9350 + EVG + TDF/FTC being explored

Bars represent geometric mean (±95% Cl)

100mg 150mg RTV

GS-9350

Elv

ite

gra

vir

Cta

u (

ng

/mL

)

1200

1000

800

600

400

200

0

Kearnew B, et al. 16th CROI; Montreal, Canada; February 8-11, 2009. Abst. 40.

SPI-452: A Potential Replacement for Ritonavir

• SPI-452: Potent CYP3A inhibitor in preclinical evaluation

• PI boosting similar to RTV• DRV ↑37 fold, ATV ↑12 fold,

and levels remain significantly increased 24 hours after last dose

• Moderate tolerability issues with headache and nausea, diarrhea

• Solubility issues are a concern, as current formulation is a liquid

0

1000

2000

3000

4000

5000

6000

LPV SQV TPV APV ATV NFV DRV IDV

Alone

With SPI-452

With RTV

Maximum achievable levels

PI Enhancement in Human Liver Microsomes

AU

C*

* Based on percent of substrate remaining vs time

Gulnik S, et al. 16th CROI; Montreal, Canada; February 8-11, 2009. Abst. 41.

Low Levels of HIV RNA Associated with Neurocognitive Impairment

• Study to evaluate relationships between HIV RNA in CSF, ARV penetration in CSF and neuropsych performance

• Subjects with HIV RNA in CSF <50 c/mL (n=300)

• Test for HIV RNA with NucliSens EasyQ assay (sensitivity = 2 c/mL)

• Results• 26% of subjects had HIV RNA in CSF

but not in plasma• Detection of low level HIV RNA in CSF

associated with lower ARV CSF Penetration Effectiveness (CPE) score

• Poorer neuropsych performance when HIV RNA detected in CSF but NOT plasma compared to subjects with HIV RNA in CSF and plasma

Relationship Between ARV CNS Penetration and HIV RNA in CSF

Neurocognitive Function and HIV RNA in CSF and Plasma

Proportion 26% 74%CSF >2 c/mL Yes YesPlasma >2 c/mL No Yes

Proportion 26% 74%CSF >2 c/mL Yes YesPlasma >2 c/mL No Yes

P=0.006

9

7

5

3

1

++++G

lob

al R

atin

gG

lob

al R

atin

gd=0.71P=0.006d=0.71P=0.006

OR = 1.7P=0.03

63.5%n = 178

50.8%n = 122

No

Yes

0 0.40 0.45 0.50 0.55 0.60 0.65 0.70CPE Rank, Proportion ≥1.5

0 0.40 0.45 0.50 0.55 0.60 0.65 0.70CPE Rank, Proportion ≥1.5

Letendre S, et al. 16th CROI; Montreal, Canada; February 8-11, 2009. Abst. 484b.

HIV

RN

A in

CN

S >

2 c/

mL

Proposed ARV CNS Penetration-Effectiveness Scores

Letendre S, et al. Arch Neurol 2008;65:65-70; Letendre S, personal communication.

Penetration Rank Score1 NRTIs NNRTIs PIs

OtherClasses

Good 1Abacavir

Zidovudine

Delavirdine

Nevirapine

Indinavir

Indinavir/ritonavir

Lopinavir/ritonavir

Darunavir/ritonaivr

Maraviroc

Fair 0.5

Emtricitabine

Lamivudine

Stavudine

Efavirenz

Amprenavir/ritonavir

Atazanavir

Atazanavir/ritonavir

Raltegravir

Poor 0

Didanosine

Tenofovir

Zalcitabine

Amprenavir

Nelfinavir

Ritonavir

Saquinavir

Saquinavir/ritonavir

Tipranavir/ritonavir

Enfuvirtide

Significance of ARV PharmacokineticsSignificance of ARV Pharmacokinetics

Debate/DiscussionDebate/Discussion