Overview of Drug Interactions Between Brecanavir (BCV) and

Other HIV Protease Inhibitors (PIs)

M Shelton, S Ford, M Anderson, S Murray, J Ng-Cashin

XVI International AIDS Conference, Toronto, Canada, 13-18 August 2006, Abstract TUAB0105

640385 (Brecanavir*, BCV)

• Potent new protease inhibitor• Median IC50 in PBMCs = 0.03 nM

• Range (0.02-0.10 nM)

• Substrate for CYP450 3A4 and p-gp• Bioavailability significantly increased with

RTV 100mg and meals• No significant pharmacokinetic interaction

with TFV, ZDV or 3TC• Generally well tolerated• Currently in Phase II development

*USAN Approved Only

BCV Clinical Development Strategy (I)

• Resistance profile suggests BCV could be highly effective for treatment-experienced HIV patients

• For this population, dual RTV boosted PIs have been evaluated, but robust clinical data is sparse

• Negative interactions observed for dual RTV boosted PI regimens• Tipranavir (TPV): lowered exposure other PI• APV/Kaletra: lowered exposure to both PIs

BCV Clinical Development Strategy (II)• PI interaction studies in healthy subjects

• First drug interactions with CYP substrates

• 3 separate studies were planned:• 1st Lopinavir/ritonavir (LPV/r) – HPR10004*• 2nd Atazanavir (ATV) – HPR10009*• 3rd Tipranavir (TPV) – HPR103377

* Ford S, et al. 7th International Workshop on Clinical Pharmacology of HIV Therapy, Lisbon, Portugal, 20 – 22 April, 2006 (posters 51 and 76)

BCV PI Drug Interaction Studies• Different strategies:

• LPV/r and ATV – hypothesis testing• evaluate combination relative to boosted PI

• TPV – estimation approach• confirm anticipated TPV effects on BCV PK• evaluate higher RTV dose (200mg)

• Different BCV doses (during dose ranging): • LPV/r and ATV - BCV 300mg /RTV 100mg BID• TPV - BCV 600mg /RTV 100mg BID

Study Design for LPV/r & ATV StudiesArm Sample Size Period 1

Days 1-14

Washout 21-28 Days

Period 2 Days 1-14

A 12 PI BCV/r + PIB 12 BCV/r + PI PIC 12 BCV/r BCV/r + PI

D 12 BCV/r + PI BCV/r

Study Design for TPV StudyArm Sample Size Period 1

Days 1-10Period 2 Days 1-10

A 12 BCV/r BCV/r + PI

B 12 BCV/r BCV + RTV 200mg

BCV 300mg

BCV 600mg

Protease Inhibitor PK Comparisons

Drug n

GLS Mean Ratio (90% CI)

AUC(ngh/mL)

Cmax(ng/mL)

C(ng/mL)

LPV/r 23 1.02(0.94, 1.11)

1.01(0.94, 1.08)

1.08(0.94, 1.24)

ATV 16 1.44(1.32, 1.58)

1.21(1.12, 1.30)

2.11(1.81, 2.45)

TPV PK was not evaluated due to premature discontinuation prior to attainment of steady-state conditions for TPV

ATV/r = 300mg/100mg q24hBCV/r + ATV = 300mg/100mg q12h + 300mg q24h

ATV Increased by Addition of BCV to ATV/r

BCV PK Comparisons

Drug nGLS Mean Ratio (90% CI)

AUC(0-)(ngh/mL)

Cmax(ng/mL)

C(ng/mL)

LPV/r 21 0.84(0.75, 0.93)

0.88(0.80, 0.98)

0.86(0.73, 1.02)

ATV/r 18 1.38(1.25, 1.53)

1.48(1.29, 1.71)

1.44(1.25, 1.65)

Extra RTV (200mg total) 11 1.15

(0.99, 1.35)1.10

(0.92, 1.32)1.06

(0.93, 1.20)

TPV Day 5 C ratio 0.53 (non-steady state)

BCV Increased by Addition of ATV to BCV/r

BCV/r = 300mg/100mg q12hBCV/r + ATV = 300mg/100mg q12h + 300mg q24h

Minor Reduction in BCV Combined with LPV/r

BCV/r = 300mg/100mg q12hLPV/r + BCV = 400mg/100mg q12h + 300mg q12h

Time (h)0 2 4 6 8 10 12

Pla

sma

BC

V (n

g/m

L)

50

100

150

200

250

300

BCV/r (C+D)

LPV/r + BCV (C+D)

Hepatic Transaminases in TPV Study

• BCV 600mg + RTV 200mg + TPV 500mg q12h• 7/12 subjects had increased ALT• Maximum DAIDS Toxicity Criteria

• Grade 1 (N=3), Grade 2 (N=2), Grade 3 (N=2)

• Regimen terminated prematurely• low risk tolerance, high probability of interaction

• Elevations returned to baseline following d/c

• BCV 600mg + RTV 200mg q12h • 1/12 subjects with Grade 1 increase in ALT• Regimen completed as planned

Study Safety Summary

LPV/r study (HPR10004):• Combination generally well-tolerated (expected AEs)

ATV study (HPR10009):• No SAEs, clinically significant trends in vitals/ECGs• Total AEs and ocular icterus more common with ATV• Increased bilirubin common with ATV, none with BCV/r• Treatment discontinuations and Grade 4 elevations in total

bilirubin more common for combination

TPV study (HPR103377):• BCV with TPV 500mg + RTV 200mg regimen was discontinued

prematurely due to hepatic transaminase elevations• BCV with RTV 200mg regimen generally well tolerated – no

treatment-related discontinuations

Phase I Summary of Drug Related AEs (5%)*

Adverse EventBCV 300mg/r

N=72BCV 600mg/r

N=32Any Event 31 (43%) 9 (38%)Gastrointestinal 16 (22%) 7 (22%)

Diarrhea 6 (8%) 3 (9%)

Nausea 3 (4%) 3 (9%)

Flatulence 4 (6%) 0Nervous System 9 (13%) 6 (19%)

Headache 6 (8%) 2 (6%)

Dizziness 2 (3%) 3 (9%)

Skin/Subcutaneous 7 (10%) 0

Pruritis 5 (7%) 0

Rash 5 (7%) 0

* Phase I studies conducted in healthy subjects

Conclusions

• BCV may be co-administered with LPV/r without dose adjustment

• For BCV/r + ATV, plasma exposure to both BCV and ATV increased. Clinical significance unknown, but ATV dose reduction may be considered.

• BCV should not be co-administered with TPV/r due to reduced plasma BCV trough concentrations

• Potential for increased hepatic transaminases in patients• RTV 200mg does not significantly increase steady-

state plasma BCV exposure• Dual boosted PI options for BCV include LPV/r and

ATV