THE PHARMACOTHERAPY OF HYPERTENSION

1
Managing the Clinical Challenges of Drug
Interactions in HIV Therapy
2
Learning Objectives

• Describe basic pharmacokinetic and
  pharmacodynamic fundamentals as related to HIV
  therapy
• Discuss clinically relevant drug interactions
  with HIV medicines and the implications for
  patient care
• Identify therapeutic options to potentially
  reduce or avoid the risk of drug interactions
  in the management of patients with HIV

3
Categories of Interactions

• Drug Interactions
• Pharmacokinetic
  Pharmacodynamic
• (effect body has on drug)
  (effect drug has on body)
• Absorption Additive
• Distribution
  
  Synergistic
• Metabolism
  
  Antagonistic
• Excretion

4
Pharmacokinetics (PK)

• Effect the Body has on the Drug
• Absorption omeprazole, ranitidine, ddI
• Distribution phenytoin, warfarin
• Metabolism ritonavir, efavirenz
• Excretion trimethoprim-sulfamethoxazole
• Various disease states may affect PKs

5
CYP450 and Drug Metabolism

• Key points
• Majority of drugs metabolized
• by CYP3A4 and CYP2D6
• CYP3A4 and CYP2D6
• extensively involved with
• PI/NNRTI metabolism
• Enzymes can be induced or
• inhibited

Adapted from Goodman and Gilmans The
Pharmacological Basis of Therapeutics, 9th ed.
6
Select Medications Affected by CYP3A4







7
Pharmacodynamics (PD)
Effect a Drug has on the Body

• Synergistic Effects
• zidovudine (Retrovir?) lamivudine (Epivir?)
• Additive Effects
• didanosine (Videx?) zalcitabine (Hivid?)
• Antagonistic Effects
• zidovudine (Retrovir?) stavudine (Zerit?)

8
HIV Drug-Drug Interactions

• Involving the most commonly prescribed
  medications in the US.
• Lipid-lowering therapy and protease inhibitors
• Acid suppressive agents and protease inhibitors
• Fluticasone and boosted protease inhibitors
• Erectile dysfunction and protease inhibitors
• Involving other ARV and OI treatment
• NNRTIs and protease inhibitors
• Tipranavir and protease inhibitors
• Rifampin/rifabutin with NNRTI or protease
  inhibitors
• Involving drugs of abuse
• HAART and recreational drugs
• Buprenorphine and atazanavir

9
HIV Drug-Drug Interactions

• Involving the most commonly prescribed
  medications in the US.
• Lipid-lowering therapy and protease inhibitors
• Acid suppressive agents and protease inhibitors
• Fluticasone and boosted protease inhibitors
• Erectile dysfunction and protease inhibitors
• Involving other ARV and OI treatment
• NNRTIs and protease inhibitors
• Tipranavir and protease inhibitors
• Rifampin/rifabutin with NNRTI or protease
  inhibitors
• Involving drugs of abuse
• HAART and recreational drugs
• Buprenorphine and atazanavir

10
Top 10 Prescriptions of 2004

• Lipitor atorvastatin
• Zocor simvastatin
• Prevacid lansoprazole
• Nexium esomeprazole
• Procrit epoetin alfa
• Zoloft sertraline
• Epogen epoetin alfa
• Plavix clopidogrel
• Advair Diskus fluticasone
• Zyprexa olanzapine

IMS (Intercontinental Marketing Service) National
Sales Perspectives 2/2005
11
1 Lipid Lowering Agents and PIs

• SQV/RTV1
• Atorvastatin ?347 AUC
• Simvastatin ?3059 AUC
• Pravastatin ?50 AUC
• NFV2
• Atorvastatin ?74 AUC
• Simvastatin ?505 AUC
• LPV/r3
• Atorvastatin ?588 AUC
• Pravastatin ?30 AUC

• fibrates4
• fluvastatin4,5
• pravastatin
• statin-fibrates
• atorvastatin
• lovastatin
• simvastatin

1Fitchenbaum CJ, et al. AIDS. 200216569-577,
2Hsyu PH, et al. Antimicrob Agents Chemother.
2001453445-3450, 3Carr RA, et al. 40th ICAAC.
Toronto, 2000. Abstract 1644, 4Calza L, et al.
AIDS. 200317851-859,
5Doser N, AIDS. 200211982-1983.
12
LPV/r and Rosuvastatin

• Rosuvastatin (ROS) not metabolized by CYP450
• HIV-infected patients on LPV/r (400/100 BID,
  n22) with TC 239 mg/dL treated with ROS for 12
  wks2
• LPV and RTV levels unchanged ROS levels
  increased 1.51.9 fold over historic controls

van der Lee M, et al. 13th CROI, Denver 2006, 588
Data on file, Astra-Zeneca
13
Ezetimibe for Lipid Management

• First prospective study with ezetimibe (Zetia?)
  in HIV (n22)
• Open-label, 24-week study of patients with LDL
  ?130 mg/dL, despite pravastatin
• Ezetimibe 10 mg/day added to regimen
• Beneficial effect at Week 6 seems to be waning by
  Week 24, except for continued ? in HDL-C
• No adverse events noted
• PK substudy (n7) no changes in LPV and NVP
  levels after Tx

Change in lipids from BL at Week 6 and 24
Change from BL ()
Negredo E, et al. 45th ICAAC, Washington DC 2005,
H-336
14
2 Impact of Acidic Environment on PIs

• Weak Bases (pKa lt 6)
• APV (1.9)
• FosAPV (1.4 )
• ATV (4-5 )
• RTV (2.8)
• Strong Bases (pKa gt6 )
• IDV (6.2)
• SQV (7.1)
• NFV (6)
• Non-ionized (pKa)
• LPV (No pKa exists)

• amprenavir
• fosamprenavir
• atazanavir
• ritonavir
• indinavir
• nelfinavir
• saquinavir
• lopinavir

Greater risk for decreased solubility and
absorption with ARAs Less risk for
solubility changes with ARAs
Kashuba AD, et al. Antimicrobial Agents and
Chemotherapy 199943(8)1817-1826 Longer, Mark

Shetty, Bhasker Zamansky, Irina Tyle, Praveen.
Journal of Pharmaceutical Sciences (1995),
84(9), 1090-3. ) AHFS
15
Common Acid Reducing Agents

• Proton Pump Inhibitors (PPIs)
• eg Prilosec? (omeprazole), Prevacid?
  (lansoprazole)
• Histamine-2 (H2) Blockers
• eg Pepcid? (famotidine), Axid? (nizatidine),
  Zantac? (ranitidine), Tagamet? (cimetidine)
• Antacids
• Calcium carbonate and magnesium hydroxide in
  didanosine buffered tablets (Videx?)
• Duration of action varies by drug class
• PPI gt H2 blockers gt antacids up
  to 72h 10 12h a few hours

References Product Monographs
16
Effect of Acid Reducing Agents on PIs

• LPV/r or ATV/RTV omeprazole and ranitidine
  interaction
• PK analysis of LPV/r BID and QD tablets or ATV300
  / RTV100 given with omeprazole or ranitidine
  (n71 healthy subjects)1
• ATV AUC and Ctrough ? 62 61 with OME and ?
  51 and 49 with RAN
• ARAs had no effect on LPV levels
• SQV omeprazole interaction2
• SQV/RTV (1000/100 mg BID) and omeprazole (40 mg
  QD) administered at SQV steady state
• 82106 ? in all SQV exposure measures further
  studies need to elucidate safety

1. Klein C, et al. 13th CROI, Denver 2006, 578,
PE4.3/2 2 Winston A, et al. ibid, PE4.3/16
17
ATV Label Changes 1-25-06

• ATV should NOT be administered with proton-pump
  inhibitors (PPIs)
• ATV dose adjustment required if administered with
  H2-receptor antagonists

Summary of ATV Label Changes Jan/Feb06
Bristol-Myers Squibb
18
(No Transcript)
19
3 Fluticasone and Boosted PIs

• Cushings syndrome reported after treatment with
  RTV-boosted PIs and inhaled fluticasone
• 3 cases in children (2 LPV/r, 1 FPV/RTV)1 and 6
  cases (3 LPV/r, 1 ATV/LPV/r, 1 ATV/RTV, 1
  SQV/RTV) in adults2
• RTV inhibits metabolism of fluticasone through
  CYP3A4
• 3 patients switched to beclomethasone had
  resolution of symptoms
• Beclomethasone is mainly metabolized by tissue
  esterases and this may explain the difference in
  outcome

Fluticasone Beclomethasone Flovent,
Flonase Beconase, Vancenase, Qvar
1. Dollfus C, et al. 10th EACS, Dublin 2005, PE
15.4/1 2. Samaras K, et al. J Clin End Met
20059043948
20
4 Erectile Dysfunction Agents and PIs

• Drug Interaction likely with all PIs (and
  probably Rescriptor)
• Sildenafil (Viagra?) AUC increased 2-11 fold
  depending on the PI involved
• Start with at most 25mg, do not repeat dose for
  at least 48 hours
• May consider increasing subsequent doses in 25mg
  increments for those not responding
• Toxicity would include priapism, severe
  hypotension, visual changes

N Engl J Med. 2001344984-96., DHHS Guidelines
February 4, 2002, www.hivguidelines.org
21
What About Vardenafil and Tadalafil?

• Use vardenafil (Levitra?) with caution at reduced
  doses of no more than 2.5 mg every 72 hours with
  increased monitoring for adverse events
• Use tadalafil (Cialis?) with caution at reduced
  doses of 10 mg every 72 hours with increased
  monitoring for adverse events

www.hivguidelines.org
22
HIV Drug-Drug Interactions

• Involving the most commonly prescribed
  medications in the US.
• Lipid-lowering therapy and protease inhibitors
• Acid suppressive agents and protease inhibitors
• Fluticasone and boosted protease inhibitors
• Erectile dysfunction and protease inhibitors
• Involving other ARV and OI treatment
• NNRTIs and protease inhibitors
• Tipranavir and protease inhibitors
• Rifampin/rifabutin with NNRTI or protease
  inhibitors
• Involving drugs of abuse
• HAART and recreational drugs
• Buprenorphine and atazanavir

23
HIV Drug-Drug Interactions

• Involving the most commonly prescribed
  medications in the US.
• Lipid-lowering therapy and protease inhibitors
• Acid suppressive agents and protease inhibitors
• Fluticasone and boosted protease inhibitors
• Erectile dysfunction and protease inhibitors
• Involving other ARV and OI treatment
• NNRTIs and protease inhibitors
• Tipranavir and protease inhibitors
• Rifampin/rifabutin with NNRTI or protease
  inhibitors
• Involving drugs of abuse
• HAART and recreational drugs
• Buprenorphine and atazanavir

24
5 Combining NNRTIs With PIs

• Efavirenz or nevirapine
• LPV/r Increase to 3 tablets BID (in experienced
  patients)
• LPV/r Standard 2 tablets BID in naïve patients
• ATV Need to boost with ritonavir - 300mg ATV
  plus RTV 100mg QD
• FPV Increase to 1400mg QD RTV 300mg QD or use
  700mg FPV RTV 100mg BID
• IDV Increase to 1000mg Q8H or w/ RTV

Kaletra Product Information 2005, Abbott
Crixivan Product Information 2000, Merck
Agenerase Product Information 2000,
GlaxoSmithKline Reyataz Product Information
2003, Bristol-Myers Squibb Lexiva
Product Information 2003, GlaxoSmithKline.
25
6 Tipranavir Combined With Other PIs

• Subjects with 3 PI mutations at codons 33, 82,
  84 and 90 (n296)
• Started new NRTIsTPV/RTV vs other PI RTV
• Week 2 TPV added
• Transient virologic response to TPV/r other PI
  RTV ( 1.2 log10)
• TPV lowers Cmin, Cmax, and AUC of other boosted
  PIs
• Decrease in median Cmin from wk 2 to 4
• APV 51
• LPV 45
• SQV 84

Walmsley S, et al. XV IAC, Bangkok 2004,
WeOrB1236
26
Tipranavir and Other ARVs

• Prior studies show 4060 ? in LPV with TPV
  coadministration
• Patients on stable LPV/r (400/100 mg) switched
  to2
• TPV 500 with LPV/r 400/300 mg BID (Group A n7)
• TPV 500 with LPV/r 533/233 mg BID (Group B n6)
• LPV levels enhanced but variable (TDM recommended)

• TPV/RTV (500/200 BID) (n19) with ENF (n20)1
• TPV T½ ? from 4.1 to 9.6 h
• T½ of RTV ? from 2.7 to 4.3 h
• Mechanism of interaction and clinical relevance
  are unknown

1. Gonzalez de Requena D, et al. 13th CROI,
Denver 2006, 579 2. Harris M, et al. ibid, 584
27
7 Rifampin Effects on PIs and NNRTIs
Finch, et al. Arch Intern Med. 2002162985-92
Reyataz 2003 Product Information, Bristol-Myers
Squibb Lexiva Product Information 2003,
GlaxoSmithKline.
28
Nevirapine and Rifampin (RFP)
C12 NVP between groups at Weeks 8 and 12

• n140 d4T, 3TC, NVP with or without anti-TB
  therapy with rifampin
• Coadministration of NVP and RFP result in ? NVP
  18
• With standard dose of NVP in NVP-RFP group, mean
  C12 NVP still greater than the recommended IC50
• Few viral failures in this study, but did not
  correlate with NVP levels
• No differences in adverse events of LFTs between
  groups
• Conclusion
• This combination needs to be used with caution
  (with TDM if possible)

NVP level (mg/L, mean SD)
p
NVP n56
NVP-RFP n62
6.57 3.15
5.10 3.13
Week 8
6.55 3.10
5.69 3.90
Week 12
0.048
6.56 3.11
5.40 3.53
TOTAL
Patients with C12 NVP lt3.4 mg/L
35
p0.020
p0.001
NVP-RFP
30
NVP
25
20
Patients ()
15
10
5
0
Manosuthi K, et al. 45th ICAAC, Washington DC
2005, H-414
Week 8
Week 12
29
PK of 2 Adjusted Dose Regimens
Lopinavir/ritonavir in Combination With Rifampin
in Healthy Volunteers
Day 1- 10
lopinavir/ritonavir 400/100 mg BID
Add Rifampin QD
Day 11- 15
Dose escalate lopinavir/ritonavir
Dose escalate RTV
Add additional 1 cap RTV (100 mg
BID) 400/200mg BID
Increase lopinavir/ritonavir to 533/133 mg BID
Day 16
Day 17
Increase lopinavir/ritonavir to 667/167 mg BID
Add additional 2 caps RTV (200 mg BID) 400/300
mg BID
Day 18-24
Increase lopinavir/ritonavir to 800/200 mg BID
Add additional 3 caps RTV (300 mg BID) 400/400
mg BID
LaPorte CJL, et al. 42nd ICAAC, San Diego,
September 2002, A-1821
30
Lopinavir/ritonavir and Rifampin
16
dose escalation
rifampin
lopinavir/r
12
8
Lopinavir Concentration (µg/mL)
4
0
1
3
7
10
13
16
20
22
24
18
Study day
Arm w/ escalation to

• 32 healthy subjects enrolled
• 12 discontinued due to AEs
• Lab abnormalities
• 9 subjects had Grade 2 or 3 AST/ALT elevations (3
  in the lopinavir/r vs 6 in the RTV dose
  escalation arms - occurred after addition of
  rifampin)
• Grade 2 hyperbilirubinemia 1 subject
  discontinued
• Grade 3 cholesterol and triglycerides - 1
  subject discontinued
• Most common AEs (gt50) overall
• Headache fatigue urine discoloration GI
  (nausea diarrhea abdominal pain/cramps)

LPV/r 800/200 mg BID
Arm w/ escalation to
LPV/r 400/400 mg BID
LaPorte CJL, et al. 42nd ICAAC, San Diego,
September 2002, A-1821
31
Rifabutin (RFB) Use With PI/NNRTIs
MMWR 200049185-9 MMWR 20045337Product
Information Reyataz 2003, Bristol-Myers Squibb
Lexiva 2003 Product
Information, GlaxoSmithKline Kaletra Product
Information 2003, Abbott.
32
HIV Drug-Drug Interactions

• Involving the most commonly prescribed
  medications in the US.
• Lipid-lowering therapy and protease inhibitors
• Acid suppressive agents and protease inhibitors
• Fluticasone and boosted protease inhibitors
• Erectile dysfunction and protease inhibitors
• Involving other ARV and OI treatment
• NNRTIs and protease inhibitors
• Tipranavir and protease inhibitors
• Rifampin/rifabutin with NNRTI or protease
  inhibitors
• Involving drugs of abuse
• HAART and recreational drugs
• Buprenorphine and atazanavir

33
HIV Drug-Drug Interactions

• Involving the most commonly prescribed
  medications in the US.
• Lipid-lowering therapy and protease inhibitors
• Acid suppressive agents and protease inhibitors
• Fluticasone and boosted protease inhibitors
• Erectile dysfunction and protease inhibitors
• Involving other ARV and OI treatment
• NNRTIs and protease inhibitors
• Tipranavir and protease inhibitors
• Rifampin/rifabutin with NNRTI or protease
  inhibitors
• Involving drugs of abuse
• HAART and recreational drugs
• Buprenorphine and atazanavir

34
8 Interactions Between Heroin and ARVs

• Heroin (diacetylmorphine) is deacetylated by
  esterases to form active metabolite
  6-acetylmorphine, which is further deacetylated
  to morphine
• Heroins conversion occurs rapidly
• ARVs would not be expected to affect this
  metabolism of heroin to morphine
• Morphine is then glucuronidated to
  morphine-3-glucuronide and morphine-6-glucuronide
  (M6G)
• M6G is also a potent opioid agonist
• Ritonavir may increase glucoronidation and
  metabolism of morphine inducing withdrawal

35
Interactions Between Club Drugs and ARV

• Cocaine
• Mainly metabolized by enzymes other than P450
• lt10 metabolized to norcocaine (active
  metabolite) via CYP3A4
• Interaction could exist between cocaine and
  inhibitors of P450
• PIs, delavirdine, macrolides and ketoconazole
• Overall, interaction may not be clinically
  significant
• Amphetamines
• 15 is eliminated renally (as urine becomes more
  acidic renal excretion increases)
• Metabolized by CYP2D6 isoform
• Ritonavir, and delavirdine may increase drug
  levels by 2-3 fold
• Increased likelihood of overdose

36
Interactions Between Club Drugs and ARV

• GHB
• Major route of elimination is expired breath as
  carbon dioxide
• P450 systems may play a large role in the
  elimination of drug
• Potential interaction between GHB and PIs,
  delavirdine or other potent enzymes inhibitor
• Narrow recreational/overdose index makes this
  drug potentially dangerous when combined with
  other drugs
• THC
• Metabolized by several isoforms including
  3A3/4,2C9 and 2C6
• May have increase or decrease in drug levels by
  PI
• Overall, no clinically significant interaction
  with HIV meds
• Ketamine
• Verapamil increases drug concentration
• PI may increase drug concentration via inhibition
  of 3A4 isoform
• Although wide margin of safety- increased levels
  may lead led to respiratory depression

37
Drug,Street Name Metabolism Effects Cocaine
(Coke, blow) Non-specific esterase Resp
depression 10 CYP3A4 Seizures,
arrythmias Ecstasy (X, MDMA) CYP2D6
Tachycardia, HTN, dry mouth dehydration GH
B (Liquid X) CYP2D6 Seizures, bradycardia,
resp depression, hypotension, coma Heroin
(Smack, China, CYP3A4 CNS depression,
drowsiness, brown junk, White) resp
depression, N/V Alcohol CYP2E1, 3A Confusion,
disorientation, loss of balance, resp
depression Amphetamines (Crystal) CYP2D6 Paranoi
a, anxiety, depression, hallucinations,
tachycardia Amyl nitrate (poppers) hydrolytic
denitration Inhaled acts as vasodilator hypo
tension, tachycardia, HA Benzodiazepines Some via
CYP3A4 CNS depression, resp depression triaz,
midaz, clonaz Ketamine (Special K) Possibly
CYP2D1, 3A4 Paranoia, hallucinations,
anxiety mania LSD (Acid) Liver
hydroxylation Paranoia, hallucinations Marijuana
(pot, THC) CYP3A4, 2C9, 2C6 Tachycardia, dry
mouth, loss of inhibitions, hallucinations
38
9 Atazanavir/RTV and Buprenorphine
Bruce RD, Altice FL. AIDS 2006, 20783793.
39
Summary Drugs to Avoid With PIs

• Simvastatin
• Lovastatin
• Astemizole
• Terfenadine
• Cisapride
• Pimozide
• Bepridil

• St. Johns Wort
• Rifampin (with exceptions)
• Rifapentine
• Midazolam
• Triazolam
• Ergot alkaloids

• Additionally avoid with ritonavir amiodarone,
  flecainide, propafenone, quinidine
• Proton pump inhibitors should not be used with
  atazanavir

40
Recommended Regimens for HIVTreatment-naïve
Patients DHHS 2006
Preferred Regimens
Lopinavir/ritonavir (3TC or FTC) ZDV
Efavirenz (3TC or FTC) (ZDV or TDF)
Alternative Regimens
PI-based Atazanavir (3TC or FTC) (ZDV or d4T
or ABC or ddI) or (TDF RTV 100
mg/d) Fosamprenavir (3TC or FTC) (ZDV or d4T
or ABC or TDF or ddI) Fosamprenavir/RTV (3TC
or FTC) (ZDV or d4T or ABC or TDF or
ddI) Indinavir/RTV (3TC or FTC) (ZDV or d4T
or ABC or TDF or ddI) Lopinavir/ritonavir (3TC
or FTC) (d4T or ABC or TDF or ddI) Nelfinavir
(3TC or FTC) (ZDV or d4T or ABC or TDF or
ddI) Saquinavir/RTV (3TC or FTC) (ZDV or
d4T or ABC or TDF or ddI)
NNRTI-based Efavirenz (3TC or FTC) (ABC or
ddI or d4T) Nevirapine (3TC or FTC) (ZDV or
d4T or ddI or ABC or TDF)
Triple NRTI Abacavir 3TC ZDV
Not recommended for use in 1st trimester
pregnancy or women with high pregnancy potential.
Only when a preferred or alternative NNRTI- or
PI-based regimen cannot or should not be used as
initial therapy. Low-dose RTV (100400 mg/day).
High incidence (11) of symptomatic hepatic
events was observed in women with pre-NVP CD4 T
cell counts gt250 cells/mm3 and men with CD4 T
cell counts gt400 cells/mm3 (6.3). NVP should not
be initiated in these patients unless the benefit
clearly outweighs the risk. Soft gel, hard gel
capsules or tablets
Available at http//aidsinfo.nih.gov/guidelines
41
October 2005 DHHS GuidelinesTreatment Goals for
Virologic Failure
Available at http//aidsinfo.nih.gov/Default.aspx
. Revision October 6, 2005.
42
October 2005 DHHS GuidelinesManagement
Strategies for Virologic Failure
Available at http//aidsinfo.nih.gov/Default.aspx
. Revision October 6, 2005.
43
Select Resources

• Provider resources
• www.hivguidelines.org
• www.aidsinfo.nih.gov
• www.hiv-druginteractions.org
• www.hopkins-aids.edu
• Patient resources
• www.aidsmeds.com
• www.aidsinfonyc.org

44
Conclusions

• HAART related drug interactions often
  undocumented or conflicting
• PI and NNRTI-based regimens most likely to result
  in drug interactions
• Self-education and online databases can help to
  identify interactions
• Clinical pharmacy services can provide guidance
  in absence of data