drug interactions with

8/8/2019 Drug Interactions With

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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



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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.



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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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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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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.

drug interactions with

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