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Severe Interaction Between Ritonavir and Acenocoumarol

Article  in  Annals of Pharmacotherapy · May 2002

DOI: 10.1345/aph.19361 · Source: PubMed

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Josep M Llibre Joan Romeu

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Severe Interaction Between Ritonavir and Acenocoumarol

Josep M Llibre, Joan Romeu, Estibaliz López, and Guillem Sirera

OBJECTIVE: To report a clinically severe interaction between ritonavir (RTV) and acenocoumarol resulting in a decrease in the
anticoagulant effect severe enough to eventually preclude RTV administration.
CASE SUMMARY: An asymptomatic, HIV-infected, 46-year-old man with mitraortic prosthetic valves receiving acenocoumarol therapy
started stavudine, lamivudine, and RTV 600 mg twice daily. His international normalized ratio (INR) decreased dramatically (the
opposite of what should be expected). Although the acenocoumarol dose was progressively increased to 3 times the original dose,
it was impossible to achieve the previous INR and RTV was withdrawn.
DISCUSSION: RTV is an inducer of the hepatic isoenzymes CYP1A2, CYP1A4, and CYP2C9/19 and leads to extensive metabolism
of acenocoumarol that cannot be balanced by dose increases. This effect is the opposite of what was expected to occur,
considering that RTV is also a strong inhibitor of most hepatic isoenzymes.
CONCLUSIONS: RTV severely decreases the anticoagulant effect of acenocoumarol. It must be added to the list of drugs that affect
the action of oral anticoagulants, and it probably should be avoided in patients receiving acenocoumarol.
KEY WORDS: acenocoumarol, HIV infection, protease inhibitors, ritonavir.

Ann Pharmacother 2002;36:621-3.

he wide range of drug interactions associated with pro-
T tease inhibitors, especially ritonavir (RTV), are related
to their potency in inhibiting the CYP3A4 hepatic isoen-
zyme.1 Until now it has been very unusual to initiate high-
ly active antiretroviral therapy (HAART) in patients re-
ceiving oral anticoagulants. It was thought that RTV could
increase warfarin concentrations by inhibiting its hepatic
metabolism, although information is scarce.2 According to
the manufacturer’s prescribing information,3 RTV could
theoretically increase the AUC of warfarin up to 1.5–3
times, and the preclinical and postmarketing studies did
not preclude the use of RTV with oral anticoagulants.
We report a clinically severe interaction of RTV and
acenocoumarol resulting in a decrease in the anticoagulant
effect severe enough to eventually preclude the administra-
tion of RTV.
dose were required. Previous drug interactions that altered the INR re-
sponse to acenocoumarol had never been observed in this patient.
The patient presented with viral rebound (from 717 to 1780 HIV
RNA copies/mL); the drug regimen was changed to stavudine, lamivu-
dine, and RTV 600 mg twice daily. His first INR measurement since the
introduction of the new regimen (8 d later) showed a dramatic drop, the
opposite of what should have been expected. Repeated INR tests were
done every 5 days, and the acenocoumarol dose was progressively in-
creased until it was threefold the original dose (Figure 1); it was impossi-
ble to achieve the previous desired INR even with that dose. Although
RTV could have been increased to even higher doses, it was considered
too dangerous and RTV was withdrawn. The INR increased to the previ-
ous baseline pattern in only 4 days, and the acenocoumarol dosage was
returned to 3 mg/d. The patient was switched to nelfinavir 10 days later,
with the remaining 2 nucleosides unchanged. Although an interaction
with acenocoumarol also appeared with nelfinavir and the acenocoumarol
dose was progressively increased, an INR of 2.5 could eventually be ob-
tained with an acenocoumarol increase of 210%. This interaction re-
mained stable for 9 months, while the patient was undergoing nelfinavir
therapy.

Case Report Discussion

An asymptomatic, HIV-infected, 46-year-old man with mechanical
mitraortic prosthetic valves had been receiving acenocoumarol for 5
years. His goal anticoagulation level was an international normalized ra-
tio (INR) of 2.5–3.5, and his baseline acenocoumarol dosage was 24
mg/wk (range 20–26) with excellent INR control. He had been treated
with 2 nucleoside analogs (zidovudine and didanosine) for 17 months,
achieving viral suppression (<200 HIV RNA copies/mL). His INR re-
mained stable during this period, and no changes in the acenocoumarol
Author information provided at the end of the text.
Protease inhibitors also inhibit the liver’s cytochrome
P450 enzymes, causing increases in exposure of a wide
range of drugs that are metabolized by these enzymes.1
RTV has the most potent inhibitory effect in the cytochrome
P450 enzymes, and therefore has the most potential for
significant drug interactions.4 Its affinity for the different
isomeric forms of the enzymes is CYP3A > CYP2D6 >
CYP2C9 > CYP2C19.5,6 The main interactions occur when
concurrent medication is extensively metabolized via the

www.theannals.com The Annals of Pharmacotherapy ■ 2002 April, Volume 36 ■ 621

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JM Llibre et al.
isoenzyme CYP3A4; it is strongly recommended that these
drugs be avoided. The magnitude of drug interactions is
difficult to predict, particularly for drugs that are metabo-
lized by multiple enzymes or have low intrinsic clearance
by CYP3A.7
RTV was thought to result in a 1.5- to 3-fold increase of
warfarin’s AUC via inhibition of the isoenzymes CYP3A4
and CYP2C9/19.1 It is currently recommended to closely
monitor the INR when RTV is started, in order to reduce
the dose of warfarin if required.1,2,6 However, RTV has
many additional mechanisms of drug interactions. It also
induces the isoenzymes CYP1A2, CYP1A4, glucurono-
syltransferase, and CYP2C9/19, decreasing concentrations
of substances metabolized by these enzymes.4-7
Acenocoumarol, the oral anticoagulant most extensively
used in Europe, is a racemic mixture with identical amounts
of every optical compound, metabolized via the isoen-
zymes CYP2C9 (S-enantiomer) and CYP1A2 (R-enan-
tiomer, the most potent one). These enzymes present ge-
netic polymorphism that produces up to 10-fold differ-
ences in the ability of individuals to metabolize drugs.8
The excellent INR control our patient experienced with
daily doses of acenocoumarol 3.4 mg (usual therapeutic
range 1–8 mg/d) during the previous years rule out the
possibility that our patient was an extensive metabolizer.
Our patient had no other factors known to induce the cy-
tochrome P450 system (e.g., alcohol intake, opportunistic
hepatic infections, treatment-related hepatotoxicity).5 Nei-
ther lamivudine nor stavudine are known to affect cy-
Figure 1. Interaction between acenocoumarol and ritonavir and nelfinavir.
Acenocoumarol dose is expressed as mg/week. ■ = INR; ◆ = acenocoumarol
dose. INR = international normalized ratio (prothrombin time).
622 ■ The Annals of Pharmacotherapy ■ 2002 April, Volume 36
tochrome P450 function.1,4,5 Besides that, our patient had
been undergoing double nucleoside therapy, and no inter-
actions with acenocoumarol were noted. It seems clear that
RTV’s induction of CYP2C9 and CYP1A2 activity led to
an extensive metabolization of acenocoumarol that could
not be balanced by dose increases. RTV was withdrawn
when the patient was receiving a daily acenocoumarol
dose of 10.3 mg (300% increase), achieving an INR of
only 1.14. Although theoretically an INR of 2.5–3.5 could
eventually have been obtained with further acenocoumarol
dose increases, the extremely high daily acenocoumarol
dose would expose the patient to a very increased risk of
bleeding if RTV were incidentally stopped (e.g., due to ad-
verse events or irregular compliance).
It appears that RTV caused a severe drug– drug interac-
tion with acenocoumarol. According to the Naranjo proba-
bility scale,9 this interaction was probable. Our observation
is consistent with other preliminary reports involving the
coadministration of RTV and warfarin. Since 1997, a de-
crease in the anticoagulant activity of acenocoumarol after
RTV’s onset was reported in 2 patients,10,11 persisting after
a two- to threefold increase in the acenocoumarol dose, al-
though digestive intolerance forced RTV to be withdrawn.
Another case12 of a slighter decrease in warfarin’s activity
after a protease inhibitor (indinavir) introduction could be
easily compensated with an increase of only 5–6.75 mg in
the warfarin dose. Due to skin rashes, indinavir was changed
to RTV and a 175% dose increase of warfarin was required
during the following 3 months. In fact, while our patient
was receiving nelfinavir, the acenocoumarol interaction
could be balanced by an acenocoumarol dose increase,
suggesting the existence of the same interaction, but at a
lower level, such as that reported with indinavir.
In another patient taking warfarin,13 the addition of RTV
also resulted in an INR decrease. Interestingly, this patient
started concurrent long-term clarithromycin prophylaxis, and
the INR could easily be maintained within the therapeutic
range by only doubling the warfarin dose. It could be that
the strong inhibitory effect of clarithromycin on the cy-
tochrome P450 system (opposed to RTV’s induction) bal-
anced the effect of RTV. Furthermore, the interaction with
warfarin seems to be less severe than with acenocoumarol.
Finally, a slight interaction has also been reported with
saquinavir.14 It is likely that the low concentrations achieved
with the hard gel formulation of saquinavir, as well as its
low interaction with the cytochrome P450 enzyme system,
fully explains the low degree of the interaction in this case.
The fact that administration of protease inhibitors to pa-
tients receiving oral anticoagulation has been uncommon
until now probably explains why this severe interaction has
not previously been detected. However, as the threats of
AIDS and death have lessened and a massive decrease in
morbidity for patients receiving HAART has occurred, this
scenario may well become more and more common. RTV
is currently used mainly at lower dosages (100–200 mg/d)
only to “boost” the plasma concentrations of other protease
inhibitors.15 However, the pharmacologic interactions that
RTV can induce at these doses with all the compounds
www.theannals.com

known to present interactions with the drug at full doses
(such as acenocoumarol) have not been formally studied.
Nonnucleoside reverse transcriptase inhibitors (nevira-
pine, efavirenz) may also affect the cytochrome P450 sys-
tem function, but they do so to a lesser extent. Abacavir, a
new nucleoside reverse transcriptase inhibitor, does not af-
fect the function of this enzyme. So, in HIV-infected pa-
tients receiving oral anticoagulants who are candidates for
HAART, the combination should probably be abacavir-
based, or as an alternative, nonnucleoside reverse tran-
scriptase inhibitor–based.
Summary
RTV, an HIV protease inhibitor, is a strong inhibitor of
most hepatic isoenzymes. However, it also acts as an inducer
of the isoenzymes CYP1A2, CYP1A4, and CYP2C9/19.
Acenocoumarol is metabolized mainly via the isoenzymes
CYP2C9 and CYP1A2. In this case, the inductor effect of
RTV on these enzymes predominated when both drugs
were coadministered, and the extensive metabolization of
acenocoumarol could not be balanced by dose increases
and eventually precluded the administration of RTV. RTV
must be added to the prodigious and expanding list of
drugs that affect the action of oral anticoagulants and prob-
ably should be avoided in patients receiving acenocoumarol.
Josep M Llibre MD, Senior Registrar, Internal Medicine Depart-
ment, Hospital Sant Jaume, Barcelona, Spain
Joan Romeu MD, Staff, HIV Unit, Hospital Universitari Germans
Trias i Pujol, Barcelona
Estibaliz López MD, Staff, HIV Unit, Hospital Universitari Germans
Trias i Pujol
Guillem Sirera MD, Staff, HIV Unit, Hospital Universitari Germans
Trias i Pujol
Reprints: Josep M Llibre MD, Internal Medicine Department, Hos-
pital Sant Jaume, 08370 Calella, Barcelona, Spain, FAX 349
37661573, E-mail jmllibre@bcgest.scs.es
References
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Case Reports
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EXTRACTO
OBJETIVO: Comunicar una interacción clínicamente severa entre ritonavir
y acenocumarol que provocó un aumento del efecto anticoagulante tan
importante que implicó la retirada de ritonavir.
RESUMEN DEL CASO: Un varón de 46 años de edad con infección por HIV y
prótesis valvulares mitral y aórtica en tratamiento con acenocumarol inició
tratamiento con d4T + 3TC + ritonavir (600 mg/12 h). Su INR se redujo
drasticamente (efecto contrario de lo esperado). A pesar de ir aumentando
la dosis de acenocumarol hasta triplicarla fue imposible conseguir su INR
previo por lo que debió suspenderse el tratamiento con ritonavir.
DISCUSIÓN: Ritonavir es un inductor de los isoenzimas hepáticos
CYP1A2, CYP1A4 y CYP2C9/19 y provoca una metabolización de
acenocumarol tan extensa que no puede compensarse mediante
incrementos de dosis. Este efecto es justo el opuesto a lo esperado
considerando que ritonavir es asimismo un potente inhibidor de la
mayoría de isoenzimas hepáticos.
CONCLUSIONES: Ritonavir disminuye el efecto anticoagulante de
acenocumarol de manera muy marcada. Debe añadirse a la lista de
fármacos que interaccionan con los anticoagulantes orales y,
probablemente, debería contraindicarse en pacientes en tratamiento con
acenocumarol.
Josep M Llibre
RÉSUMÉ
OBJECTIF: Signaler une interaction cliniquement grave entre le ritonavir
(RTV) et l’acénocoumarol laquelle a résulté en une diminution si
importante de l’effet anticoagulant que l’utilisation éventuelle du RTV a
été exclue.
PRÉSENTATION SOMMAIRE DU CAS: On a débuté une thérapie à base de d4T
+ 3TC + ritonavir (600 mg bid) chez un homme âgé de 46 ans infecté par
le VIH asymptomatique et traité avec de l’acénocoumarol pour des
prothèses valvulaires mitrale et aortique. Son RNI a chuté de façon
dramatique (tout juste le contraire de ce à quoi on s’attendait). Bien que la
dose d’acénocoumarol ait été augmenté progressivement jusqu’à 3 fois, il
a été impossible d’atteindre le précédent RNI et le ritonavir a été retiré.
DISCUSSION: Le RTV est un inducteur des isoenzymes hépatiques
CYP1A2, CYP1A4, et CYP2C9/19 ce qui entraîne un métabolisme
important de l’acénocoumarol qui ne peut être compensé par des
augmentations de doses. Cet effet est tout juste le contraire de ce à quoi
on s’attendait étant donné que le RTV est aussi un inhibiteur puissant de
la plupart des isoenzymes hépatiques.
CONCLUSIONS: Le RTV diminue de façon importante l’effet anticoagulant
de l’acénocoumarol. Il doit être ajouté à la liste des médicaments qui
affectent l’action des anticoagulants oraux, et il devrait probablement
être évité chez les patients recevant de l’acénocoumarol.
Marie Larouche
■ 2002 April, Volume 36 ■ 623