Title: THE PHARMACOTHERAPY OF HYPERTENSION
1Managing the Clinical Challenges of Drug
Interactions in HIV Therapy
2Learning 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
3Categories of Interactions
- Drug Interactions
-
-
- Pharmacokinetic
Pharmacodynamic - (effect body has on drug)
(effect drug has on body) -
-
- Absorption Additive
- Distribution
Synergistic - Metabolism
Antagonistic - Excretion
4Pharmacokinetics (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
5CYP450 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.
6Select Medications Affected by CYP3A4
7Pharmacodynamics (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?)
8HIV 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
9HIV 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
10Top 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
111 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.
12LPV/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
13Ezetimibe 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
142 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
15Common 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
16Effect 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
17ATV 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)
193 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
204 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
21What 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
22HIV 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
23HIV 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
245 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.
256 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
26Tipranavir 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
277 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.
28Nevirapine 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
29PK 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
30Lopinavir/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
31Rifabutin (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.
32HIV 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
33HIV 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
348 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
35Interactions 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
36Interactions 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
37Drug,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
389 Atazanavir/RTV and Buprenorphine
Bruce RD, Altice FL. AIDS 2006, 20783793.
39Summary 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
40Recommended 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
41October 2005 DHHS GuidelinesTreatment Goals for
Virologic Failure
Available at http//aidsinfo.nih.gov/Default.aspx
. Revision October 6, 2005.
42October 2005 DHHS GuidelinesManagement
Strategies for Virologic Failure
Available at http//aidsinfo.nih.gov/Default.aspx
. Revision October 6, 2005.
43Select 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
44Conclusions
- 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