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Drug interactions with
antiretrovirals & warfarin
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Introduction
Patients with HIV infection who have access to care are now
living longer and, as a result, are requiring treatment for
other chronic conditions associated with aging such as
diabetes, hypertension and cardiac disease
Warfarin has a longstanding history of well documented
drugdrug interactions with medications used for other
conditions (e.g., amiodarone, uconazole, trimethoprim-sulfamethoxazole); therefore, interactions between warfarin
and antiretrovirals are anticipated to occur.
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Introduction
Despite the potential for interaction, virtually no formal
pharmacokinetic studies exist for examining the use of warfarin with
various antiretrovirals
2- to 10-foldincrease in the occurrence of venous thromboembolism
(VTE) in patients with HIV
Data were collected through literature searches conducted in August
of 2009 using multiple databases including Medline (1950 2009),
EMBASE (1980 2009), International Pharmaceutical Abstracts
(1970 2009)and the Cochrane Data base of Systematic
Reviews.
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CYP P450 drug metabolism
Over 70% of the medications marketed today are
metabolized in the body through the CYP450 enzyme
system
There are 18 functional families within the CYP450
system with different physiological functions
Most drug metabolism mediated through the CYP450
system is accounted for by15 individual enzymeswithin families 1, 2 and 3
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Altogether, > 90%of oxidative drug metabolism is
orchestrated through
CYP3A4 the most abundant
CYP2C9 is the second most abundant
CYP2C19
CYP2B6
CYP1A2
CYP2E1 and
CYP2D6
CYP P450 drug metabolism
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Factors that contribute to the development of clinically signicant
interactions between drugs include
the afnity of each agent for the CYP enzyme,
the availability of alternate metabolic pathways,
the inherent ability of the inhibitor or inducer to alter the metabolic activity of
the enzyme system (e.g., inhibition constant; Ki),
as well as the therapeutic index of the substrate
Substrates that are only metabolized through a singleCY
P enzymeare at greater risk for drugdrug interactions because of the absence
of an alternate metabolic pathway.
CYP P450 drug metabolism
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Warfarin
Vitamin K epoxide reductase, inhibiting the reduction of
vitamin K
Has a narrow therapeutic window
Racemic mixture of two active enantiomers (R-warfarin, S-
warfarin)
S-isomer is approximatelyve times more potent than the
R-isomer(70% of the activity)
Both compounds are hepatically metabolized via the CYP450
enzyme system
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R-warfarin uses a mixture ofCYP450
isoenzymes including CYP1A1, CYP1A2and
CYP3A4
S-warfarin is almost exclusively metabolized
through the CYP2C9pathway, making it more
susceptible to clinically signicant druginteractions due to the absence of an alternate
metabolic route
Warfarin
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Warfarin pharmacogenomics
Single nucleotide polymorphisms (SNPs) exist in the gene
that codes for CYP2C9
Approximately50SNPs have been described for the CYP2C9
gene.
A potential complicating factor for predicting warfarin drug
interactions is the genetic polymorphism displayed by
CYP2C9
The two alleles most commonly associated with altered
warfarin metabolism are 2C9*2 and 2C9*3.
Both of these alleles decrease the metabolic activity of
CYP2C9
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Warfarin pharmacogenomics
When comparing to homozygous wild-type
CYP2C9*1, homozygous 2C9*2decreased
metabolic activity to ~12%,while homozygous2C9*3decreased activity to 5%.
Multiple studies have demonstrated that patients
with either allele generally require lower doses ofwarfarin both at initiation of therapy as well as
during maintenance therapy.
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Warfarin pharmacogenomics
Overall, while >30 variant alleles have been identied and
described, genetic polymorphismin 2C9 accounts for only12%of
dose alterations with warfarin .
Patients with decreased CYP2C9 activity secondary to either the
2C9*2 or 2C9*3 allele on stable warfarin therapy may theoretically
be at lower risk for signicant changes in serum concentration with
co administration ofCYP2C9 inhibitors because of the lower
metabolic efciency ofCYP2C9 in these patients.
Conversely, strong CYP2C9 inducers may cause disproportionate
reductions in warfarin serum concentration in patients who are poor
CYP2C9 metabolizers compared with patients with homozygous
wild-type CYP2C9*1.
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Antiretrovirals and warfarin
Although situations exist when interactions result in altered
antiretroviral serum concentrations, this scenario is less common
than when antiretrovirals serve as the offending agent in altering the
absorption and metabolism of other medications.
Of the six classes of antiretrovirals, none of the currently approved
nucleoside reverse transcriptase inhibitors, integrase inhibitors or
fusion inhibitors displays any relevant CYP450 effects.
The approved chemokine coreceptor 5 (CCR5) receptor antagonist
maraviroc is a substrate ofCYP3A4 and is prone to interactions
with other drugs metabolized through this pathway, but it has
shown no signicant ability to inhibit or induceCYP3A4 or any other
CYP enzymes
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Non-nucleoside reverse-
transcriptase inhibitors Nevirapine is generally considered to be a metabolic inducer,
displaying induction effects on both CYP3A4 and CYP2C9
isoenzymes .
Efavirenz and etravirine have mixed proles, exerting both inhibition
and induction effects on CYP enzymes
Studies have shown that efavirenz inhibits CYP2C9/19 and
CYP2B6, while exhibiting either induction or inhibition ofCYP3A4
depending on the substrate
Etravirine is a newer, second generation NNRTI with less clinical
experience, but data from the manufacturer demonstrate that
etravirine is a potent inhibitor ofCYP2C9/19 and inducer ofCYP3A4
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Protease inhibitors
Ritonaviris no longer used at clinically therapeutic doses (400 600 mg) but
rather is utilized as a low dose (100 200 mg) boosting agent in combination with
other PIs to enhance their pharmacokinetic properties byinhibiting CYP3A4-
mediated metabolism.
Darunavir, lopinavirand tipranavirrequire ritonavir co administration to
achieve their full antiretroviral effect .
Although atazanavir, fosamprenavir, indinavir, nelnavir and saquinavir can be
administered without ritonavir boosting, modern treatment guidelines endorse
boosting these agents, with the exception of nelnavir, which should not be
coadministered with ritonavir
With regard to CYP2C9, induction of warfarin metabolism has been reported to
occur with darunavir (administered with ritonavir), lopinavir/ritonavir, nelnavir
and ritonavir when used as a sole PI
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Protease inhibitors
Both darunavir (with ritonavir) and lopinavir/ritonavir displayed apparent
induction ofCYP2C9 resulting in decreased serum concentrations of S-warfarin
while tipranavir (with ritonavir) displayed no net effect on CYP2C9 .
The manufacturers of atazanavir, fosamprenavir and indinavir all state limited
interaction potential with CYP2C9 substrates due to the fact that none of these
medications appear to affect CYP2C9 metabolism.
This potential for interaction, however, is altered when these agents are boosted
with ritonavir, which generally displays CYP2C9 induction
Saquinavir alone probably inhibitsCY
P2C
9 to some extent.
Dose increases ranging from 40 to 140%were necessary to restabilize INRs in a
therapeutic range.
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Conclusion & Expert opinion
Empiric reduction in warfarin dose should be
considered for patients receiving warfarin and efavirenz,
etravirine or saquinavir, with subsequent dosing
adjustments based on laboratory monitoring.
Patients receiving nevirapine, lopinavir/ritonavir,
nelnavir or ritonavir boosted darunavir, atazanavir,
fosamprenavir or indinavir may require signicantly
higher warfarin doses to achieve a therapeutic INR.
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Reference
Drug interactions with antiretrovirals and warfarin;
Expert Opin. Drug Saf. (2010) 9(2):215-223
Pharmacogenetics of Warfarin; The Annual
Review of Medicine,2010
CLINICAL AND TOXICOLOGICAL RELEVANCE OF
CYP2C9: Drug-Drug Interactions and
Pharmacogenetics, Annu. Rev. Pharmacol.
Toxicol.
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