Upload
marilyn-howard
View
219
Download
0
Tags:
Embed Size (px)
Citation preview
NDA 21-567 Atazanavir
Kendall A. Marcus, M.D.
Medical Reviewer
Division of Antiviral Drug Products
Presentation Outline
• NDA Submission Overview• Efficacy Summary - Tom Hammerstrom,
Ph.D.• Clinical Virology - Lisa Naeger, Ph.D.• Safety Issues
– Hyperbilirubinemia– Lipid Profiles– Effects on the QT and PR Interval
• Conclusions
NDA Overview
• Submission Date: December 20, 2002• Proposed Dosage: Atazanavir 400 mg
once daily• Proposed Indication: Treatment of HIV
infection
Phase 2 Dose-Finding Studies Treatment Naïve Patients
AI424-007 N=420
• ATV: 200 mg, 400 mg, and 500 mg
• NFV 750 mg tid
Each given with d4T/ddI.
AI424-008 N=467
• ATV: 400 mg and 600 mg
• NFV 1250 mg bid
Each given with d4T/3TC.
Phase 3 Studies
AI424-034 Treatment-naïve subjects (n=810)
• ATV 400 mg daily
• EFV 600 mg daily
Each given with AZT/3TC (Combivir)
AI424-043 Subjects failing PI based regimens (n=300)
• ATV 400 mg daily
• LPV/RTV bid
Optimized background of 2 NRTIs based on phenotypic testing.
Phase 3 Studies
AI424-045* Patients failing at least 2 regimens containing drugs from all three classes (n=358)
• ATV 300 mg/RTV 100 mg once daily
• ATV 400 mg/SQV 1200 mg once daily
• LPV/RTV bid
Background therapy of tenofovir and one NRTI.
*16 week data on roughly 33 patients/arm submitted with initial NDA submission.
Other Supportive Studies
• AI424-041 and AI424-044 – Rollover studies for Phase 2
• PACTG 1020-A– PK and safety study in infants, children, and
adolescents
• AI424-900 - Expanded access protocol
• AI424-009 (N=85)– Small Phase 2 study of treatment experienced patients
comparing ATV/SQV to RTV/SQV
Atazanavir Resistance
Lisa K. Naeger, Ph.D.
Antiviral Advisory Committee Meeting
May 13, 2003
In vitro Selection
Virus strain: mutations
RF: V32I, L33F, M46I, A71V, I84V, N88S
LAI: L10Y/F, I50L, L63P, A71V, N88S
NL4-3: V32I, M46I, I84V, L89M
3 Different Strains of HIV-1 were serially selected with ATV for 4-5 months
(200 - 500 nM)
Fold ATV Resistance
183
93
96
I50L Mutation
• ATV resistance corresponded to the presence of I50L and A71V in the protease of recombinant viruses from 8 clinical isolates.
• 2- to 17-fold decreases in ATV susceptibility were observed in viruses containing the I50L and A71V mutation
I50L Mutation
• Viruses containing the I50L mutation either alone or in combination with A71V remained susceptible to APV, IDV, NFV, and RTV.
• Insertion of the I50L substitution into HIV-1 resulted in replication impaired viruses. The addition of the A71V change with I50L restores some viability.
ATV Clinical Resistance Analyses
• Mutations Associated with ATV-Resistance
– Phenotypic and genotypic analyses of evaluable clinical isolates from patients on ATV-containing regimens who experienced virologic failure or discontinued before suppression from studies 007, 008, 034, 009 and 043
• Baseline Phenotype and Genotype Analysis
• Cross-Resistance
Evaluable Clinical Isolates from Patients on ATV-Containing Regimens who Experienced Virologic
Failure or Discontinued before Suppression
All Studies
Naïve Trials007, 008,
034ARV-ExperiencedTrials 009 and 043
Evaluable isolates 160 93 63Mean 6.6 2.6 12.2
Median 1.4 1.04 2.8
ATV >2.5-fold 50 (31%) 14 (15%) 32 (51%)Mean 18.9 11.7 22.9
Median 9.6 8.7 11
Mutations Associated with ATV-Resistance in Naïve-trials
• 14 ATV-resistant clinical isolates– 11 (79%) developed the I50L
mutation• Median 9-fold change in ATV resistance• 7 of these 11 also developed the A71V
mutation• Development ranged from 2 to 80 weeks (mean = 40 weeks)
Phenotype of ATV-Resistant Isolates that Developed the I50L Mutation In
Naïve Trials
n Baseline*Post-
Baseline*
Fold-changefrom
Baseline P valueATV 10 0.87 9.43 10.9 0.004APV 10 0.69 0.47 0.69 0.11IDV 5 0.88 0.41 0.47 0.005LPV 4 0.98 0.28 0.28 0.06RTV 10 1.06 0.23 0.22 0.0007SQV 10 0.75 0.34 0.45 0.000005NFV 10 1.22 0.71 0.59 0.002
* Average fold-change from reference strain
Mutations Associated with ATV-Resistance in Experienced trials
• 32 ATV-resistant clinical isolates –ATV Treatment (21)
• 5 isolates developed the A71V or T mutation
• 2 isolates developed the I84V mutation (5-fold change from BL)
• 2 developed the N88S or D mutation (4-fold change from BL)
Mutations Associated with ATV-Resistance in Experienced trials
–ATV/SQV Treatment (11)• 5 isolates developed the I84V
mutation (14-fold change from BL)• 4 isolates developed the A71V or T
mutation• 2 isolates developed the L90M
mutation• 2 isolates developed the M46I
mutation
Cross-Resistance of the Virologic Failure Clinical Isolates that were ATV-Resistant from Treatment- Experienced Patients in Trials 009 and 043
ATV APV LPV SQV RTV IDV NFV
%resistantisolates
- 37% 47% 81% 87% 91% 100%
Median fold-change in
ATVsusceptibility
11 1.7 2 5.6 7 7.8 28
(N = 32)
Baseline Analysis
Baseline Phenotypic Analysis of 009 and 043
0
10
20
30
40
50
60
70
80
90
100
PI NRTI NNRTI
% R
esis
tan
ce
56%74%
20%
• 24% of the Isolates from 009 and 043 showed ATV-
Resistance at Baseline
Cross-Resistance of Baseline ATV-Resistant Isolates from 009 and 043
0
20
40
60
80
100
120
NFV IDV LPV RTV SQV
% R
esis
tanc
e 100%
47% 43%
62% 59%
Response Based on Baseline Genotype
Response of Antiretroviral-Experienced Patients from Studies 009 and 043
0
10
20
30
40
50
60
70
80
90
100
I84V L90M A71V N88 M46I
PI Mutation at Baseline
% o
f V
iro
log
ic F
ail
ure
s a
nd
DC
s
ATVOther
Cross-Resistance
Cross-resistance of HIV-1 Clinical Isolates by Phenotype
(Percent Resistant)
ATV-ResistantN = 416
APV-ResistantN = 236
IDV-Resistant
N = 58
LPV-ResistantN = 285
RTV-ResistantN = 465
SQV-ResistantN = 303
NFV-ResistantN = 677
ATV 100% 91% 79% 87% 75% 95% 61%APV 51% 100% 50% 67% 50% 61% 34%IDV 79% 97% 100% nd 82% 82% 53%LPV 69% 93% nd 100% 70% 73% 49%RTV 84% 98% 88% 99% 100% 92% 65%SQV 69% 78% 40% 71% 60% 100% 45%NFV 100% 97% 97% 97% 94% 99.7% 100%
Baseline phenotypic data from all studies
Cross-Resistance of HIV-1 Clinical Isolates by Genotype
(Percent Resistant)
I84VN = 95
G48VN = 32
L90MN = 343
V82N = 285
D30NN = 166
I50VN = 8
I50LN = 20
ATV 93% 94% 66% 64% 38% 12% 95%APV 84% 41% 41% 42% 5% 100% 0%IDV 100% nd 66% 74% 12% nd 0%
LPV 89% 75% 54% 74% 7% 100% 0%RTV 98% 94% 77% 83% 11% 87% 0%SQV 94% 97% 60% 44% 20% 25% 0%NFV 95% 100% 85% 79% 98% 50% 0%
Baseline genotypic and phenotypic data from all studies.
ATV Resistance Against PI-Resistant Clinical Isolates (n = 551)
Number ofIsolates
Resistantto 1 PI
(n = 157)
Number ofIsolates
Resistantto 2 PIs(n = 57)
Number ofIsolates
Resistantto 3 PIs(n = 99)
Number ofIsolates
Resistantto 4 PIs(n = 96)
Number ofIsolates
Resistantto 5 PIs
(n = 142)
19 (12%) 11 (19%) 65 (66%) 81 (84%) 135 (95%)
Number of ATV-resistant isolates (%)
ATV Susceptibility Against PI-Resistant Clinical Isolates (n = 551)
Number ofMarketed PIs
that Isolates areResistant To
Median fold-changein ATV susceptibility
1 1.62 2.13 4.04 6.25 22.0
ATV Resistance Summary• I50L mutation is specific for ATV resistance and is
the predominant mutation developing in antiretroviral therapy-naïve patients
• Viruses with the I50L mutation remain susceptible to other PIs
• Mutations L90M, I84V, N88S/D and A71V/T appear to confer ATV resistance and reduce the clinical response to ATV
• There is a clear trend toward ATV resistance as isolates become resistant to three or more PIs
Atazanavir Efficacy Results
Thomas Hammerstrom, PhD
Division of Antiviral Drug Products
Phase II and III Clinical Trials
• Pivotal Phase III Trial - 34– Endpoint = Percent Sustained < 400 copies/mL
to Week 48, Time Averaged Difference from Baseline (TAD)
– ART Naïve Population– Control is Efavirenz
• Phase II Trials - 7 and 8– Endpoint = Percent < 400, TAD– ART Naïve Population– Control is Nelfinavir
Phase II and III Clinical Trials
• Pivotal Phase III Trial - 43– Endpoint = TAD– ART Experienced Population– Control is Kaletra
Results in Trials with ART Naïve Subjects
Percent Sustained <400 copies/mL to Week 48
Trial Arm %<400 95% Interval ATV - Con
34 EFV 251 / 405 62%
ATV 271 / 405 67% -1.5%, 11.6%
7 NFV 62 / 103 60%
ATV 62 / 103 60% -13.8%, 13.0%
8 NFV 54 / 91 63%
ATV 121 / 181 69% -5.0%, 19.4%
Results in Trial with ART Experienced Subjects
Trial 43, ATV vs Kaletrafor 24 Weeks
Endpoint Arm Estimate 95% Interval
%<400 KAL 98 / 150 = 65%
ATV 70/150 = 47% -30%, -7.9%
TAD KAL -1.65
ATV -1.39 .078, .44
Is ATV Better than Placebo ART Experienced Subjects?Two Meta-analysis Methods:
1. Calculate Difference of ATV and Placebo from Trial 43 and Kaletra Trials
2. Compare Confidence Intervals for ATV + 2 NRTI’s in Trial 43 with Confidence Intervals for 2 NRTI’s alone from other NDA’s
ATV vs Placebo% <400
Source Arm Estimate DIFF SEE
Trial 43 ATV 70/150 = 47%KAL 98 / 150 = 65% -19% 5.73%
Trial 863 KAL 259 / 326 = 79%
NFV 233 / 327 = 71% 8% 3.36%
Trial 511 NFV 66/ 99 = 67%
PLA 7/ 101 = 7% 60% 5.37%
Imputed ATV
PLAC 49% 8.54%
ATV vs Placebo% <400
Source Arm Estimate DIFF SEE
Trial 43 ATV 70/150 = 47%KAL 98 / 150 = 65% -19%
5.73%
Trial 888 KAL 84 / 148 = 57%
S. PI 46 / 140 = 33% 24% 5.69%
Imputed ATV
Selected PI 5% 8.07%
ATV vs Control% <400
Source Control Difference 95% Interval
Trial 43 KAL -19% -30%, -7.9%
Imputed Sel PI 5% -10.8%, 21%
Discounted Sel PI 4.5% -12.3%, 23%
Imputed PIacebo 49% 32%, 66%
Percent BLQ with 95% Limits
0% 20% 40% 60% 80% 100%
Percent BLQ
3 Drug Test Arms 2 Drug Control Arms
3 Drug Control Arms ATV, Trial 43
ATV vs PlaceboTAD, Week 24
Source Arm Estimate DIFF SEE
Trial 43 ATV -1.39KAL -1.65 .26 .093
Trial 863 KAL -1.798
NFV -1.801 .003 .057
Trial 511 NFV -1.77
PLA -1.40 -.37 .083
Imputed ATV
PLAC -.107 .137
ATV vs PlaceboTAD, Week 24
Source Arm Estimate DIFF SEE
Trial 43 ATV -1.39KAL -1.65 .26
.093
Trial 888 KAL -.972
S. PI -.867 -.104 .078
Imputed ATV
Selected PI .156 .121
ATV vs ControlTAD, Week 24
Source Control Difference 95% Interval
Trial 43 KAL .26 .078, .44
Imputed Sel PI .156 -.081, .393
Imputed Placebo -.107 -.376, .162
TAD with 95% Limits
-3.00 -2.50 -2.00 -1.50 -1.00 -0.50 0.00
TAD
3 Drug Test Arms 2 Drug Control Arms
3 Drug Control Arms ATV, Trial 43
Efficacy Conclusions
1. Equal or Better than NFV or EFV on %<400 at week 48 in 3 Trials with Naïve Subjects
2. 95% Lower Limits on %<400 no more than 5% worse than NFV or EFV in 2 out of 3 Trials
Efficacy Conclusions
3. Equal or Better than NFV or EFV on TAD at week 48 in 2 out of 3 Trials with Naïve Subjects
4. 95% Upper Limits on TAD no more than .28 log copies worse than NFV or EFV in all 3 Trials
Efficacy Conclusions
5. Statistically Significantly Worse than Kaletra on both %<400 and TAD at week 24 in 1 Trial with Experienced Subjects
6. Indirect Imputations: Support for Efficacy on Primary Endpoint, Ambiguity on Secondary Endpoint
Efficacy Conclusions
6. Indirectly shown at least 33% better than placebo, no more than 10% worse than selected PI on %<400
7. 95% Confidence Limits on %<400 higher than limits seen on all 2 drug combinations in previous NDA’s
Efficacy Conclusions
8. Indirectly shown no more than .16 log copies worse than Placebo on TAD at week 24
9. 95% Confidence Limits on TAD comparable to limits seen on several 2 drug combinations in previous NDA’s
Safety Issues
Hyperbilirubinemia
HyperbilirubinemiaToxicity Grading Scale
• Total bilirubin toxicity grading scale
Grade 1 1.1 – 1.5 x ULN
Grade 2 1.6 – 2.5 x ULN
Grade 3 2.6 – 5.0 x ULN
Grade 4 > 5.0 x ULN
• Upper limit of normal for total bilirubin 1.0 - 1.5 mg/dL
• Upper limit of normal for direct bilirubin 0.2 - 0.5 mg/dL
Studies 007 & 008HyperbilirubinemiaDose Dependence
0%
10%
20%
30%
40%
50%
60%
70%
200mg 400mg 500mg 600mg
Bilirubin (Grade 3 & 4)
Dose Reduction
0%
25%
50%
75%
100%
Study 007 & 008(N=279)
91% 47%
Study 034(N=404)
86% 33%
Study 043(N=144)
74% 20%
Grade 1-4 Grade 3-4
Percentage of Subjects with HyperbilirubinemiaAtazanavir - 400mg
Incidence of Jaundice and Scleral Icterus Phase 2 and 3 Clinical Studies
Atazanavir - 400 mg
Study 007/41008/44N=279
034
N=404
043
N=144Percentage of Subjects
Jaundice 9 11 10
Scleral Icterus 8 11 6
Total Subjects* 16 21 15
*Patients may have reported one or both events.
Three patients in 034 (1%) and 2 patients in 043 (1%) discontinued for jaundice or scleral icterus without grade 4 hyperbilirubinemia.
Grade 4 Hyperbilirubinemia and Dose Reduction
Study 034N=404
043N=144
Number with Gd 4 Total Bilirubin (%)
Gd 4 Bilirubin 26 (6) 4 (2)Dose Reduction 20 (5) 2 (1)Discontinuation 1 (<1) 0 (0)
Atazanavir - 400 mg
Study 034 Mean Total and Direct Bilirubin
Atazanavir - 400 mg
0
1
2
3
4
5
6
7
<2.5 2.5-5.0 >5.0
Mean (mg/ dl)
Bilirubin (mg/ dl)
Total Bilirubin Direct Bilirubin
Total Bilirubin > 10 mg/dL
Occurred in 10 patients across clinical trials • 4/10: transient, predominantly unconjugated (DB 0.3
mg/dl)
• 1/10: diagnosed w/SHL, DB - 0.6 mg/dl
• 5/10: also with other LFT abnormalities– 4 with viral hepatitis (A, B, C)– One had a total bilirubin > 10 mg/dl prior to randomization
which resolved prior to treatment and then worsened temporarily on study.
LFT Abnormalities - ATV versus NFV Background: ddI/d4T
Study007
Grade 1-4 LFTs
ATVN=101
NFVN=100
Percentage of SubjectsAST/SGPT 64 46
ALT/SGOT 63 47
Total Bili 89 13Alk Phos 16 8
LFT Abnormalities: ATV versus EFV Background: AZT/3TC
Study034
Grade 1-4 LFTs
ATVAZT/3TC
EFVAZT/3TC
N=404 N=401Percentage of Subjects
AST/SGPT 25 31
ALT/SGPT 18 22
Total Bili 86 3
Alk Phos 8 12
Discontinuations Due to Hepatotoxicity/Abnormal LFTs
All Studies• Atazanavir - 15/1596 (1%)
– Ten had chronic hepatitis B or C– One had acute hepatitis B– One had history of hepatic steatosis– Three subjects with no apparent risk factors
• Comparators - 8/892 (1%)– Five had chronic hepatitis B or C– One had acute hepatitis B– One was hep B core Ab positive but surface Ab and antigen
negative– One on RTV/SQV w/ no apparent risk factors
HyperbilirubinemiaConclusions
• Inhibition of UGT 1A1• Predominantly unconjugated • Reversible upon discontinuation of atazanavir• Jaundice/scleral icterus are likely to be common
adverse events in clinical practice resulting in more frequent discontinuations than seen in clinical trials.
• Risk for hepatotoxicity similar to other marketed ARV
Lipid Profiles
Study 034 Lipid Profiles at Week 48
Percent Change from Baseline
-15
-10
-5
0
5
10
15
20
25
30
TOT C LDL HDL TG
ATV
EFV
Pe
r ce
nt C
ha
nge
fro
m B
ase
line
Pe
rce
nt C
ha
nge
fro
m B
ase
line
Study 034 Lipid Profiles at Baseline and Week 48
0
2
4
6
8
10
12
14
16
ATV EFV ATV EFV ATV EFV
Baseline
F/u
Pe
rce
nta
ge
of
Su
bje
cts
Pe
rce
nt a
ge
of
Su
bj e
cts
TC>240TC>240
LDL>160LDL>160
TG>400TG>400
Study 043Lipid Profiles at Week 24
Percent Change from Baseline
-10
0
10
20
30
40
50
60
70
TOTALCHOL
LDL HDL TG
ATV
LPV/r
Pe
rce
nt
Ch
an
ge
fr o
m B
ase
line
Pe
rce
nt
Ch
an
ge
fr o
m B
ase
line
Study 043 Lipid Profiles at Baseline and 24 Weeks
0
5
10
15
20
25
ATV LPV/ r ATV LPV/ r ATV LPV/ r
Baseline
F/u
mg
/dL
mg
/dL
TC>240TC>240
LDL>160LDL>160
TG>400TG>400
TRIALS 7 & 8, CHANGE IN FASTING TGONLY SUBJECTS WITH FASTING BASELINE
-20
-10
0
10
20
30
40
50
60
70
80
0 20 40 60 80 100 120
WEEKS
CH
AN
GE
IN F
AS
TIN
G T
RIG
LY
CE
RID
ES
LipodystrophyTreatment-Naïve Studies
Study 034 007/041ATV EFV ATV
alldoses
NFV
Percentage of SubjectsAny Event 15 12 22 18
Lipodystrophy* 9 7 13 10
Weight gain 3 1 1 1
Weight loss 3 4 13 11
* * Includes events of lipoatrophy, lipohypertrophy, and lipodystrophy.Includes events of lipoatrophy, lipohypertrophy, and lipodystrophy.
CV Events -Myocardial Infarction
• Three MIs in atazanavir-treated patients and three MIs in patients receiving comparators
• One subject receiving RTV/SQV underwent three vessel bypass surgery
Lipid ProfilesConclusions
• Lipid effects of atazanavir appeared to persist through 108 weeks of treatment, although data from phase 2 trials is limited by study design.
• Benefits for treatment-experienced patients less well defined as factors other than current protease inhibitor use appear to contribute at least to hypertriglyceridemia.
• Lipid effects do not appear to be associated with a
reduced incidence of lipodystrophy. • Cardiovascular benefit is unknown at this time.
Evaluation of the QT Interval
In Vitro Evaluation of Potential Cardiac Effects
• Modest inhibition of IKr (HERG) - 15% at 30 µM• Moderate inhibition of Ca channels - IC50 of 10 µM• Weak inhibition of Na channels - IC50 > 30 µM• In Purkinje fiber studies, a dose-dependent increase in
mean action potential duration was observed.
Study 076
• 3-treatment, 3-period crossover study • 72 subjects received multiple, once-daily
doses of atazanavir • Subjects assigned atazanavir 400 mg, 800
mg, and placebo in six different sequences• Washout period of 14 days
QTc Changes by Correction Formula
QTcB at Tmax from baseline to 800 mg dose is 7.9 msec
(95% CI 2.8, 12.9) QTcF at Tmax
from baseline to 800 mg dose is -1.6 msec
(95% CI -4.2, 1.1)
20 40 60 80 100 120Heart Rate (bmp)
0.30
0.35
0.40
0.45
QT
cB (
sec
ond
s)
20 40 60 80 100 120Heart Rate (bmp)
0.30
0.34
0.38
0.42
0.46
QT
cF(s
econ
ds)
Studies 034 and 043Prolonged QTc Intervals
Study 034• Incidence of prolonged QTc intervals similar between
atazanavir and efavirenz regimens (2%).• One subject receiving efavirenz had a QTc interval >
500 msec.
Study 043• Nine subjects (ATV, 2 subjects; LPV/RTV, 7 subjects)
experienced a post-baseline QTc prolongation.
Study 034 and 043 CV Events Potentially Related to Arrhythmia
• Sudden death or torsades de pointes• CV events leading to treatment discontinuation • CV events coded as SAEs • Grade 3 - 4 CV events• All CV events
Events reviewed - No events of sudden death, torsades de pointes, events suspicious for TdP, or an imbalance between treatment arms in events potentially attributable to TdP was observed.
Effect of Atazanavir on the QT IntervalConclusions
• Data from placebo-controlled study 076 limited by lack of positive control (e.g. moxifloxacin)
• Current data indicates that atazanavir has little or no effect on the QT interval; however, the overall risk is unknown
• No signal for increased risk relative to comparators was identified in clinical trials
Evaluation of the PR Interval
Causes of PR Interval Prolongation and AV Block
• Medications - e.g. antihypertensives, digoxin
• Fibrosis of the conduction system
• Ischemic heart disease
• Valvular or congenital heart disease
• Cardiomyopathy
• Myocarditis
First Degree AV BlockClinical Significance
ACC/AHA/NASPE 2002 Guidelines for Implantation of Cardiac Pacemakers and Antiarrythmic Devices
Class II B recommendation:
First degree AV block greater than 300 msec in patients with LV dysfunction and symptoms of congestive heart failure in whom a shorter AV interval results in hemodynamic improvement
Study 076 (Healthy Volunteers)
Plot of Mean PR Versus Time Since Dosing
Study 034 PR Interval
Time Mean PR Interval
Post-dose (min, max)
msec
EFV 2-3 hours 153 (101, 251)
ATV* 2-3 hours 160 (110, 287)
*Maximum PR intervals: 265 - 307
Study 034 First Degree AV Block
Treatment Incidence of First Degree AV Block (%)
Males Females Total
Efavirenz 3 0 2
Atazanavir 4 6 4.5
Study 041 PR Interval
Time Mean PR Interval
Post-dose (min, max)
msec
NFV 2-3 hours 158 (97, 203)
ATV* 2-3 hours 164 (120, 243)
*Maximum PR intervals: 234 - 250
Studies 041 and 044First Degree AV Block
Study Dose N 1st Degree
AV Block (%)
041 ATV 400 148 5
NFV 47 9
044 ATV 400 172 9
ATV 600 127 14
Study 043 PR Interval
Time Mean PR Interval
Post-dose (min, max)
msec
LPV/r 2-3 hours 157 (114, 250)
ATV* 2-3 hours 157 (114, 209)
*Maximum PR Intervals: 194 - 218
Study 043 First Degree AV Block
Treatment Incidence of First Degree AV Block (%)
Males Females Total
Lopinavir/r 6 4 6
Atazanavir 7 3 6
Case Narratives - Other Conduction Abnormalities Potentially Related to
Atazanavir
• On day 1053 of therapy in study 007/041, a 43 year old male intentionally ingested a large number of ATV/3TC/d4T pills
• Received activated charcoal• Severely prolonged PR interval with bifascicular block
was observed on ECG• Patient was monitored for 5 days until ECG
normalized
Case Narratives - Other Conduction Abnormalities Potentially Related to
Atazanavir
• A 50 year old male with HTN was hospitalized on day 11 of ATV/ 3TC/DLV/TDF for angina and SOB
• On verapamil SR for HTN• An ECG showed junctional rhythm with retrograde
atrial activation. ARV medications held• One day following admission an ECG showed
persistence of junctional rhythm• Two days following admission the patient was found
unresponsive with idioventricular rhythm• Autopsy showed 90% LAD without infarct
Effects on PR Interval Conclusions
• Dose dependent prolongation of the PR interval• First degree AV block most common abnormality
observed• Incidence of first degree block appears to be
similar to that observed with selected PIs• Severe prolongation (> 300 msec) or more serious
events appear to be rare
Pediatric ProtocolPACTG 1020-A
• Atazanavir + 2 NRTIs• 48 enrolled; 29 continuing on study• Adverse event profile in these patients
appears similar to adults• Due to wide variability of pK data in all age
cohorts, a dose has not yet been defined for any group
Drug-Drug Interactions
Drug-Drug Interactions
• Potential interaction with ATV– CYP3A inhibitor, inducer, or substrate– drugs that increase pH– drugs that cause PR prolongation– 2C9 (e.g. warfarin) or 1A2 (e.g. theophyline) -
not studied
Drug Interactions - Diltiazem
• Diltiazem – CYP 3A substrate + inhibitor
– PR prolongation
– ATV diltiazem Cmax and AUC ~ 100%
PR interval (msec)200-250 >250
Study day
Count (%) Count (%)6 (atazanavir) 10 (33%) 0 (0%)
11 (atazanavir + diltiazem) 14 (46.7%) 4 (13.3%)23 (diltiazem) 3 (11%) 0 (0%)
Drug Interactions - Oral Contraceptives
• Co-administration of atazanavir and ethinyl estradiol/norethindrone (Ortho-Novum 7/7/7) was evaluated
Cmax AUC
Ethinyl estradiol 1.15 1.48
Norethindrone 1.67 2.10
AtazanavirOverall Conclusions
• Antiviral activity similar to efavirenz or nelfinavir in treatment-naive patients
• Inferior to lopinavir/r in treatment-experienced patients, but multiple analyses indicate activity in this population
• Low pill burden may enhance compliance in selected patients
• Unique resistance pathway in treatment-naïve subjects
AtazanavirOverall Conclusions
• Hyperbilirubinemia appears to be due to inhibition of UGT 1A1 and reversible with treatment discontinuation
• Risk for hepatotoxicity appears to fall within the range of that seen with other ARV medications
AtazanavirOverall Conclusions
• Dose-dependent prolongation of the PR interval• Incidence of first degree AV block appears to be
similar to that observed in lopinavir/ritonavir and nelfinavir treated patients
• Clinically significant events due to prolongation of the PR interval appear to be rare
• Effects of atazanavir on the QT interval appear to be minimal
AtazanavirOverall Conclusions
• Favorable lipid profile as compared to selected protease inhibitors and efavirenz
• Impact on cardiovascular events unknown • Does not appear to “reverse” triglyceride elevations
seen in treatment-experienced patients• Does not appear to result in a decreased incidence
of lipodystrophy
QuestionsQuestions
Question 1Question 1 • Do the efficacy and safety of atazanavir support its
approval for the treatment of HIV infection? As part of your discussion please comment on:
» Treatment effects seen in naїve and experienced patients
» Hyperbilirubinemia observed in clinical trials
» The effect of atazanavir on the PR and QT intervals
Question 2Question 2
• If atazanavir is recommended for approval, does its safety profile warrant additional clinical or laboratory monitoring?
Question 3Question 3
• Does the effect of atazanavir on lipid parameters offer patients a clinically significant advantage over other treatment options?
Question 4Question 4
• Based on the resistance data, what recommendations would you have regarding its use in naïve and experienced patients?
Question 5Question 5
• Please provide recommendations for any Phase 4 studies of atazanavir?