Drug-Drug Interactions in HIV

Stephen Becker, M.D.

San Francisco, California

Drug Interactions in HIV – A Case

Study in Avoid - Approach Behavior
Interactions feared Interactions exploited

1995 1998 2000

1
 Drug Interactions in HIV – A Case
Study in Avoid - Approach Behavior
Interactions feared Interactions exploited

1995 1998 2000

ZDV and d4T

PIs and the era of

CYP 3A4 inhibition

> 40 contraindicated
meds

Drug Interactions in HIV – A Case

Study in Avoid - Approach Behavior
Interactions feared Interactions exploited

1995 1998 2000

Kaletra development program

ZDV and d4T

PIs and the era of NNRTIs and the era of

CYP 3A4 inhibition CYP 3A4 induction

> 40 contraindicated
meds

Grapefruit juice
and SQV

2
 Drug Interactions in HIV – A Case
Study in Avoid - Approach Behavior
Interactions feared Interactions exploited

1995 1998 2000

Kaletra development program

ZDV and d4T Herbal products

PIs and the era of
CYP 3A4 inhibition
> 40 contraindicated
meds
Grapefruit juice
and SQV
TDF
NNRTIs and the era of - ddI
CYP 3A4 induction - ATV
PXR and the molecular
basis for enzyme induction

Major Advances in Understanding of

HIV Drug Interactions
• Ritonavir and CYP 3A4 inhibition
• Measurement of drug concentration in the
intracellular compartment
– NRTI triphosphates
– ? PIs
• Elucidation of host xenobiotic response and
role of PXR in enzyme induction
• Drug transporters

3
 Some Basics

Pharmacokinetics and Pharmacodynamics

in Drug Interactions

Biologic fluid Compartment Pharmacologic

Drug dose
concentration of effect effect

Pharmacokinetics Pharmacodynamics

4
Pharmacokinetics and Pharmacodynamics
in Drug Interactions

Antagonistic
ADME Additive
Synergistic

Pharmacokinetics Pharmacodynamics

Drug Interactions: Potential Sites of

Interaction
CYP450 Efflux
system pumps
Conjugative enzymes

Efflux
pumps
Enterocyte
Efflux
3A4 pumps

Gut Lumen

5
 Drug Interaction Topics
• PI issues
– Dual and dual-boosted combinations
• NNRTI issues
– Efavirenz and statins
• NRTI issues
– Ribavirin and thymidine analogs
– SPD754 and 3TC
– Tenofovir
• Mechanism: Xenobiotic response elements
• Herbal and botanical interactions

PI Issues

6
CYP 3A4 and Drug Interactions

Weak Inhibitors Potent Inhibitors

Saquinavir Amprenavir Ritonavir

Atazanavir
Indinavir
Lopinavir
Nelfinavir

CYP 3A4 and Drug Interactions

Weak Inducers Potent Inducers

Nelfinavir Efavirenz Amprenavir

Lopinavir Nevirapine Ritonavir
Tipranavir

7
 PI and Drug Class Interactions
• Ergotamine • Macrolide antibiotics
derivatives • PDE5 inhibitors
• Oral contraceptives • Azole antifungals
• Methadone • Anti-tb agents
• Calcium channel • Anti-arrhythmics
blockers

Types of Enzyme Inhibition

• Reversible
– Ritonavir
– Other PIs
• Irreversible (mechanism based)
– Ritonavir
– Delavirdine
– Bergamottin

8
 Reversible CYP Enzyme Inhibition

Heme
P450

Drug
Endoplasmic
reticulum

Irreversible CYP Enzyme Inhibition

Heme
P450

X Drug
Endoplasmic
reticulum

9
 English Tea and Florida Grapefruit:
The Case of Bergamottin
• Inhibits gut but not hepatic 3A4
• Irreversible (mechanism based) inhibition
• Recovery in approximately 3 days
• Contained in Earl Gray tea, grapefruit juice,
Seville oranges, bitter orange

PDE5 Inhibitors and HIV PIs

10
RTV and Erectile Dysfunction Agents
Fold Change
Drug Usual dose Modified dose
↑ AUC

Sildenafil 50 mg/day 11 25 mg/48 hrs

Vardenafil 10 mg/day 49 2.5 mg/72 hrs

Tadalafil 10 mg/day 2.2 10 mg/72 hrs

Combining PIs with Synergistic

Activity – Saquinavir and
Atazanavir

11
 Saquinavir PK With and Without
Atazanavir
4000
SQV/RTV 1600/100 mg
Geometric mean [SQV] ng/mL

SQV/RTV/ATV1600/100/300 mg
3000

2000 n = 18

1000

0
0 2 4 6 8 10 12 14 16 18 20 22 24
Time (h)
Boffito et al. 11th CROI, 2004: poster 607

Atazanavir PK Profile When

Administered with SQV/r QD
5000
ATV/SQV/RTV 300/1600/100
Geometric mean [ATV] ng/mL

4000 ATV 400

3000
n = 18

2000

1000

0
0 2 4 6 8 10 12 14 16 18 20 22 24
Time (h)
Boffito et al. 11th CROI, 2004: poster 607, ATV PI

12
 Saquinavir and Atazanavir
• Small study dosed at 1600/100/300 QD
• Higher rates of hyperbilirubinemia and
jaundice/icterus than ATV historic norm
• Lipid friendly
• Requires further study in once and twice daily
regimens, with and without RTV

Amprenavir, Fos-amprenavir (908)

and Lopinavir/ritonavir Interactions

13
 Minister of Silly Walks Assists in
Drug – Drug Interaction Study

ACTG 5143/5147s
• Treatment experienced study, with planned
real time PK substudy done at week 2
• LPV/r 400/100 bid vs. 908/r 700/100 bid vs.
combination
• All patients received TDF plus 1-2 NRTIs
based on resistance studies
• Trial halted on basis of PK findings

Kashuba, ICAAC, 2003, abstract 855A

14
 ACTG 5143: Exposures of APV vs. APV-LPV/r

9000

908 + LPV/rtv (n=15)

8000
Amprenavir Concentration (ng/mL)

908/rtv (n=8)
7000

6000

5000

4000

3000

2000

1000

0
0 2 4 6 8 10 12
Time Post-Dose (hr)

ACTG 5143: Exposures of LPV vs. LPV/-APV

14000
908 + LPV/rtv (n=15)
12000 LPV/rtv (n=8)
Lopinavir Concentration (ng/mL)

10000

8000

6000

4000

2000

0
0 2 4 6 8 10 12
Time Post-Dose (hr)

15
 Fosamprenavir (908) and Lopinavir
• A murkier situation than with APV and LPV/r
• Mechanism not defined
• Neither dosage separation nor additional RTV
appears to solve the interaction
• Seronegative study (>40% drop-out) with
908/LPV/r 1400/533/133 bid (yikes) yielded
adequate APV levels for WT virus, but
inadequate LPV levels
Wire, CROI, 2004, abstract 612; Corbett, CROI, 2004, abstract 613

Fosamprenavir (908) and Lopinavir

• Due to role of PXR induction?

• Clinical issue of great importance for
patients currently successfully managed on
APV/LPV/r regimen
• At a minimum need a ‘switch’ study to
demonstrate means of transition from APV
to 908

Marzolini, CROI, 2004, abstract 135

16
 Drug Interactions Through Enzyme
Induction

Common Enzyme Inducers

• Rifampin
• Phenobarbital
• Phenytoin
• HIV PIs: Amprenavir >> ritonavir
>lopinavir > nelfinavir
• Efavirenz and nevirapine
• Others

17
 Enzyme Induction: The Role of
Orphan Nuclear Receptors

Nuclear Receptor Paradigms

Classic Receptors
• Ligands synthesized
from endogenous
endocrine sources
• Regulated by negative
feedback control

18
 Nuclear Receptor Paradigms

Classic Receptors Orphan Nuclear Receptors

• Ligands synthesized • Ligands are xenobiotics or
from endogenous dietary lipids
endocrine sources • Binding activates
• Regulated by negative feedforward cascade of
feedback control metabolism, transport,
storage and excretion

PXR and Activation of CYP 3A4

and Efflux Pumps

PXR RXR

19
 PXR and Activation of CYP 3A4
and Efflux Pumps

PXR RXR

3A4

Enzyme
induction

PXR and Activation of CYP 3A4

and Efflux Pumps

PXR RXR

P-gp MRP 2

3A4
OAT2 MRP 1
Removal from Removal
CNS, gut, from
Renal Enzyme Cellular
lymphocytes hepatocytes
excretion induction efflux

20
 PXR/SXR: Xenobiotic Response
• Astoundingly flexible (promiscuous) binding
domain
• Ancient system, noted in all studied species
between humans and fish
• Expressed primarily in liver and gut
• Has little apparent variability between individuals
• Involved in “cross-talk” with other nuclear
receptors in regulating feed-forward functions

Enzyme Induction Through

Xenobiotic Response Elements

Transcription Enzyme
Inducers PXR
Production

3A4 Gene

3A4

21
 Enzyme Induction Through
Xenobiotic Response Elements

Transcription Enzyme
Inducers PXR
Production

3A4 Gene
2D6 Gene
MDR1 Gene
OATP Gene
Conjugative Enzyme Genes

Enzyme Induction Through Nuclear

Receptors

PXR

Rifampin CAR 3A4

HNF4α

22
 Activators (Ligands) for PXR/SXR
• Steroids
• Phenobarbital
• Rifampicin
• Taxol
• Nifedipine
• Hyperforin (St. John’s wort)
• Ritonavir
• Amprenavir
Marzolini, CROI, 2004, abstract 135

Activators (Ligands) for PXR/SXR

• Steroids
• Phenobarbital
• Rifampicin
• Taxol
• Nifedipine
• Hyperforin (St. John’s wort)
• Ritonavir
• Amprenavir
Marzolini, CROI, 2004, abstract 135

23
 Agents with both 3A4 induction and
inhibitory properties will likely have
more complex drug – drug interactions,
and require formal PK study to permit
safe and effective use

Tissue Specific CYP 3A4

Expression and Drug Interactions
• Ritonavir inhibition
– Gut and hepatic
• Efavirenz induction
– Hepatic only
• Bergamottin inhibition
– Gut only

24
 Saquinavir and Fosamprenavir

• Studied doses 1000/700/100-200 BD

• Small study
• APV induction of SQV required 200mg of
RTV to sustain adequate SQV levels
• Twice daily dual-boosted PI regimens more
likely in treatment experienced settings

Boffito, CROI, 2004, abstract 608

Saquinavir Plasma Concentration – Time

Profile When Administered with 908
4000 SQV/RTV 1000/100mg (day 1)
SQV/RTV/908 1000/100/700 mg (day 11)
Geometric mean [SQV] (ng/mL)

3000 SQV/RTV/908 1000/200/700mg (day 22)

2000 n = 18

1000

0
0 2 4 6 8 10 12
Time (h)
Boffito et al. 11th CROI, 2004: poster 608

25
 Saquinavir and Fosamprenavir
• Studied doses 1000/700/100-200 BD
• Small study
• APV induction of SQV required 200mg of
RTV to sustain adequate SQV levels
• Twice daily dual-boosted PI regimens more
likely in treatment experienced settings
• Will not be a RTV sparing dual boosted PI
combination

Boffito, CROI, 2004, abstract 608

NNRTI Issues

26
 EFV is a Significant Inducer of Simvastatin
and Atorvastatin Metabolism

• Healthy volunteer receiving both statins and

EFV to steady state
• PK of statins before and after EFV
• Non-steady state effect of statins on EFV
• Pharmacodynamic effect: cholesterol reduction
of statin before and after EFV

Gerber et al. CROI, 2004, abstract 603

Pharmacodynamic Effect of EFV

and Selected Statins
Reduction from baseline in LDL-C (mg%)
Simvastatin
0
Atorvastatin
-15
Pravastatin
-30

-45 Statin alone

-60

Modified from Gerber, CROI, 2004, abstract 603

27
 Pharmacodynamic Effect of EFV
and Selected Statins
Reduction from baseline in LDL-C (mg%)
Simvastatin
0
Atorvastatin
-15
Pravastatin
-30

-45 Statin alone

-60 Statin w/EFV

Modified from Gerber, CROI, 2004, abstract 603

In Vitro and In Vivo Interactions

• d4T and ZDV: in vitro and in vivo evidence
supporting the interaction. Evident
pharmacodynamic consequence
• Ribavirin and thymidine analogs: in vitro
evidence, not substantiated in vivo. No
pharmacodynamic consequence

28
 NRTI Issues

NRTI Intracellular Pharmacokinetics

NRTI
P
g
?
NRTI P
NRTI ENT Entry PP
M Efflux
NRTI R
PP PP PP P
NRTI 4
PP PP
Cellular
trapping

58

29
 Proven and Speculated Interactions
• Thymidine analogs, ZDV and d4T
• Cytidine analogs, 3TC and ddC
• Ribavirin and thymidine analogs

Ribavirin and Intracellular NRTI-TP

Levels: The Definitive Study
• Nested APRICOT substudy, N = 48, patients
receiving peg-INF + RBV or peg-INF + PLA
• Baseline and week 8-12 sampling

Gries, CROI, 2004, abstract 136LB

30
 Ribavirin and Intracellular NRTI-TP
Levels: The Definitive Study
• Nested APRICOT substudy, N = 48, patients
receiving peg-INF + RBV or peg-INF + PLA
• Baseline and week 8-12 sampling
0.5 Mean IC AUC0-12 Ratio Ribavirin

Placebo
0.25

0
BL Wk 12 BL Wk 12 BL Wk 12 BL Wk 12

ZDV-TP/dT-TP d4T-TP/dT-TP

Gries, CROI, 2004, abstract 136LB

SPD754 and 3TC: Why We Study

the Compartment of Effect
• Deoxycytidine analog with additive activity
when paired with 3TC
• Share common intracellular anabolic pathway
• Study of plasma and IC PK of co-administered
SPD754 and 3TC

Bethell, CROI, 2004, abstract 138

31
 SPD754 and 3TC: Plasma and
Intracellular Interactions

8
SPD754 Alone
Mean plasma SPD754

7
6 SPD754 + 3TC
5
(µg/mL)

4
3
2
1
0
0 4 8 12
Hours

Bethell, CROI, 2004Abstract 138

SPD754 and 3TC: Plasma and

Intracellular Interactions
• Plasma PK: no interaction
• Intracellular PK: major interaction

8 2.5
SPD754 Alone
754-TP (pmol/106cells)
Mean plasma SPD754

7
Mean intracellular

2
6 SPD754 + 3TC
5
(µg/mL)

1.5
4
3 1
2
0.5
1
0 0
0 4 8 12 0 4 8 12
Hours Hours

Abstract 138

32
 SPD754 and 3TC: Why We Study
the Compartment of Effect
• Deoxycytidine analog with additive activity
when paired with 3TC
• Share common intracellular anabolic
pathway
• Plasma PK of SPD754 and 3TC unaffected
by co-administration
• 3TC reduces SPD754-TP by 4- to 6-fold
• Example demonstrating Sutton’s Law of PK

Bethell, CROI, 2004, abstract 138

And Then There’s Tenofovir:

Unpredicted Interactions
and Opportunity to Increase Basic
Pharmacologic Understanding

33
 Tenofovir Interactions
• TDF lowers exposures of certain PIs
– Atazanavir
• TDF exposures raised by certain PIs
– Atazanavir
– Lopinavir
• TDF raises levels of ddI exposures
• No plasma interactions with 3TC, FTC, ABC,
ribavirin or adefovir

TDF Interactions, Potential Mechanisms

and Pharmacodynamic Effect
Interaction Possible mechanism(s) PD effect
↑ clearance thru DME or
transporters; ? altered
↓ ATV Anticipated
bioavailability due to ATV
gastric pH requirements
↑ TDF with Altered clearance; ↓ renal
Possible
certain PIs transport (OAT2)
PMPA-MP inhibition of
↑ ddI Possible
PNP

34
TDF Interactions, Potential Mechanisms
and Pharmacodynamic Effect
Interaction Possible mechanism(s) PD effect
↑ clearance thru DME or
transporters; ? altered
↓ ATV Anticipated
bioavailability due to ATV
gastric pH requirements
↑ TDF with Altered clearance; ↓ renal
Possible
certain PIs transport (OAT2)
PMPA-MP inhibition of
↑ ddI Possible
PNP

TDF Interactions, Potential Mechanisms

and Pharmacodynamic Effect
Interaction Possible mechanism(s) PD effect
↑ clearance thru DME or
transporters; ? altered
↓ ATV Anticipated
bioavailability due to ATV
gastric pH requirements
↑ TDF with Altered clearance; ↓ renal
Possible
certain PIs transport (OAT2)
PMPA-MP inhibition of
↑ ddI Possible
PNP

35
 How can we dose TDF and ATV
together?

ATV and TDF Interactions

Unboosted ATV (n=34) Boosted ATV (n=10)
PK
Parameter % ATV 300
ATV 400 ATV 300 % ATV
ATV 400 ATV RTV 100
+ TDF RTV 100 change
change TDF 300
70 696 513
118 (ng/mL) (ng/mL) (ng/mL)
Cmin ↓ 40 ↓ 26
(ng/mL)

29,196 21,866 46,073 34,459

AUC ↓ 25 ↓ 25
(ng h/mL) (ng h/mL) (ng h/mL) (ng h/mL)
5785 4579 4422 3190
Cmax ↓ 21 ↓ 28
(ng/mL) (ng/mL) (ng/mL) (ng/mL)

36
 ATV and TDF Interactions
Unboosted ATV (n=34) Boosted ATV (n=10)
PK
Parameter % ATV 300
ATV 400 ATV 300 % ATV
ATV 400 ATV RTV 100
+ TDF RTV 100 change
change TDF 300
70 696 513
118 (ng/mL) (ng/mL) (ng/mL)
Cmin ↓ 40 ↓ 26
(ng/mL)

29,196 21,866 46,073 34,459

AUC ↓ 25 ↓ 25
(ng h/mL) (ng h/mL) (ng h/mL) (ng h/mL)
5785 4579 4422 3190
Cmax ↓ 21 ↓ 28
(ng/mL) (ng/mL) (ng/mL) (ng/mL)

ATV and TDF Interactions

Unboosted ATV (n=34) Boosted ATV (n=10)
PK
Parameter % ATV 300
ATV 400 ATV 300 % ATV
ATV 400 ATV RTV 100
+ TDF RTV 100 change
change TDF 300
70 696 513
118 (ng/mL) (ng/mL) (ng/mL)
Cmin ↓ 40 ↓ 26
(ng/mL)

29,196 21,866 46,073 34,459

AUC ↓ 25 ↓ 25
(ng h/mL) (ng h/mL) (ng h/mL) (ng h/mL)
5785 4579 4422 3190
Cmax ↓ 21 ↓ 28
(ng/mL) (ng/mL) (ng/mL) (ng/mL)

37
 ATV and TDF Interactions
Unboosted ATV (n=34) Boosted ATV (n=10)
PK
Parameter % ATV 300
ATV 400 ATV 300 % ATV
ATV 400 ATV RTV 100
+ TDF RTV 100 change
change TDF 300
70 696 513
118 (ng/mL) (ng/mL) (ng/mL)
Cmin ↓ 40 ↓ 26
(ng/mL)

29,196 21,866 46,073 34,459

AUC ↓ 25 ↓ 25
(ng h/mL) (ng h/mL) (ng h/mL) (ng h/mL)
5785 4579 4422 3190
Cmax ↓ 21 ↓ 28
(ng/mL) (ng/mL) (ng/mL) (ng/mL)

ATV and TDF Interactions

Unboosted ATV (n=34) Boosted ATV (n=10)
PK
Parameter % ATV 300
ATV 400 ATV 300 % ATV
ATV 400 ATV RTV 100
+ TDF RTV 100 change
change TDF 300
70 696 513
118 (ng/mL) (ng/mL) (ng/mL)
Cmin ↓ 40 ↓ 26
(ng/mL)

29,196 21,866 46,073 34,459

AUC ↓ 25 ↓ 25
(ng h/mL) (ng h/mL) (ng h/mL) (ng h/mL)
5785 4579 4422 3190
Cmax ↓ 21 ↓ 28
(ng/mL) (ng/mL) (ng/mL) (ng/mL)

38
 Solving the Interaction
• Requires understanding of mechanism
• Requires formal PK study
• In the case of ATV, what is the desired
exposure: 400 vs. 300/100
• Caution warranted when a ‘solution’ is
offered by the commercial division within
pharma
• In most instances clinicians have other
available options

Herbal and Botanical Issues

39
 Herbal and Botanical Agents:
Interactions with Prescribed Meds
• Herbal/botanical products used by 14% of
adult U.S. population
• Most frequently used products
– Ginko products
– St. John’s wort
– Ginseng products
– Garlic
– Echinacea

Drug Interactions: Potential Sites of

Interaction
CYP450 Efflux
system pumps
Conjugative enzymes

Efflux
pumps
Enterocyte
Efflux
3A4 pumps

Gut Lumen

40
 Enzyme Induction Through
Xenobiotic Response Elements

Transcription Enzyme
Inducers PXR
Production

3A4 Gene
2D6 Gene
MDR1 Gene
OATP Gene
Conjugative Enzyme Genes

Effect of St. John’s Wort on PK/PD

Drug PK Effect or PD Response
SSRIs ↑ BP, serotonin syndrome
Amitryptline AUC↓ 22%
Cyclosporin A AUC↓ 46-52%; organ rejection
Digoxin AUC↓ 25%
Indinavir AUC↓ 57%
Methadone AUC↓ 19-60%
Simvastatin AUC↓ 50%
Oral contraceptives Loss of effectiveness
Warfarin 50% ↓ INR
Sildenafil Loss of effectiveness

Modified from Huang, CPT 75(1), 2004

41
 Effect of St. John’s Wort on PK/PD

SSRIs: Serotonin syndrome, Methadone: AUC↓ 19-60%

↑ BP
Amitryptline: AUC↓ 22%
Cyclosporin A: AUC↓ 46-
52%; organ rejection
Digoxin: AUC↓ 25%
Indinavir: AUC↓ 57%
Simvastatin: AUC↓ 50%
Oral contraceptives:
Loss of effectiveness
Warfarin: 50% ↓ INR
Sildenafil: Loss of
effectiveness

Modified from Huang, CPT 75(1), 2004

Effect of Herbal Products on P-gp

(reduction in digoxin transport)
• Black cohosh: Abolished transport
• St. John’s wort: Abolished transport
• Ecinacea: Decreased transport 70-80%
• Feverfew: Decreased transport 70-80%
• Valerian: Decreased transport 70-80%

Dresser, ASCPT, 2004

42
 Hoist on Pharmacologic Petard

Summary – Factors Determining

Drug Interactions
• Drug factors
– Relative potency as inhibitor or inducer
– Co-administered agents
• Host factors
– Expression of enzyme and transporter systems
– Function of enzyme and transporter systems
– Organ (renal and hepatic) function
• Disease state factors
– Up- or down-regulation of enzyme and
transporter systems

43
 Conclusions
• We have usefully exploited certain drug
interactions and improved clinical outcomes
• Known drug interactions lacking an
understanding of mechanism and formal
study should be used with appropriate care
and caution
• Interactions should be expected in the post-
approval stages for HIV agents. Interactions
require study in the compartment of effect

Conclusions
• Delineation of host xenobiotic response
systems has provided an understanding of
enzyme induction and will greatly assist the
process of future drug development
• Herbal and botanical products require
regulation. Interactions with drug
metabolizing enzyme systems, transporters and
PXR leads to clinically meaningful and
untoward outcomes

44