Drug-drug interactions with raltegravir
David M. Burger
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Department of Clinical Pharmacy and Nijmegen Institute for Infection, Inflammation and Immunology (N4i), Radboud University Nijmegen Medical Centre
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Nijmegen
,
the Netherlands
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David M. Burger, PharmD, PhD Departmsnt of Clinical Pharmacy 864 Radboud University Nijmegen Medical Centre Geert Grooteplein 10
6525 GA Nijmegen
The Netherlands Tel.:
Objective: To review all currently published drug-drug interaction studies with the HIV-integrase inhibitor raltegravir. Methods: A PubMed search was conducted for all published reports up to August 1, 2009 as well as a review of updated European and US Prescriber's Information (EMEA & FDA) and abstracts from recent international scientific meetings. Results: A total of 14 drug-drug interaction studies were found. Due to the relatively broad therapeutic range of raltegravir almost all co-administered agents can safely be combined with raltegravir, with the exception of rifampin in which a doubling of the raltegravir dose to 800mg BD is currently recommended. Conclusions: Raltegravir is not without drug-drug interactions but due to the lack of an effect on CYP450 or UGT by raltegravir and the broad therapeutic range of raltegravir itself, this agent can safely combined with almost all tested agents.
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INTRODUCTION
Drug-drug interactions remain a major concern in the
treatment of HIV-infected patients. This is caused by
the treatment and prophylaxis of opportunistic
infections, the treatment of malignancies, the high
prevalence of use of psycho-active agents in the
HIV-infected patient population, the treatment of adverse
effects caused by this polypharmacy, etc.. As a result, it
is more likely that a drug-drug interaction is present in
a particular patient than that it is absent, and any HIV
clinician should always be suspecting a drug-drug
interaction when prescribing medications to an
HIV-infected patient.
With the recent introduction of newer antiretroviral
agents such as the HIV-integrase inhibitor raltegravir,
there is an urgent need for an updated and complete
overview of potential drug-drug interactions with this
agent, especially when raltegravir is used in patients
being treated with multiple recently-developed
antiretroviral agents, or as a substitute of other drugs in
otherwise virologically stable patients (switch scenario).
PHARMACOKINETICS OF RALTEGRAVIE
The pharmacokinetics of raltegravir after single and
multiple doses have been mainly characterized in
healthy subjects [1]. The drug is rapidly absorbed with
a median tmax in the fasted state of approximately 1
hour. Raltegravir plasma concentration decrease in a
biphasic manner with a rapid initial phase (t 1/2 of
approx. 1 hour) and a slower terminal phase (t 1/2 of
approx. 7-12 hour). During twice-daily dosing, this
terminal elimination half-life is difficult to assess, but it is
more apparent after single dosing or multiple QD
dosing. Steady-state conditions are already reached after 2
days with only minimal accumulation over time.
Raltegravir AUC increases almost proportionally in a single
dose range of 10 1,600mg.
Food has a remarkable effect on raltegravir
pharmacokinetics. When compared to intake on an empty
stomach, the AUC of raltegravir was decreased by
46%, increased by 13% and almost doubled after
intake with a low-fat, a moderate fat, or a high-fat meal,
respectively [2]; in all cases, intersubject variability was
increased by concomitant food intake. Because in
phase III studies raltegravir was allowed to be taken
with or without food, and there is a broad therapeutic
range of raltegravir exposure (see below), it is
recommended that raltegravir can be taken without regard to
food.
Raltegravir is not metabolized by cytochrome P450
enzymes but rather by glucuronidation. The enzyme
responsible for the formation of phenolic hydroxyl
glucuronide metabolite of raltegravir appears to be the
UDP-glucuronosyltransferase (UGT) 1A1 subtype,
with minimal contributions of UGT1A3 and
UGT1A9 [3]. Approximately 7-14% of a raltegravir
dose is excreted unchanged in the urine. Moderate
hepatic insufficiency (Child-Pugh scores 7-8) or severe
renal insufficiency (creatinin clearance 13.0 28.8
mL/min/1.73 m2) did not have a clinically important
effect on raltegravir pharmacokinetics [4]. There are
known genetic polymorphisms in UGT1A1, more
precisely the UGT1A1 *28/*28 genotype, which is
associated with Gilberts syndrome. UGT1A1 activity is
approximately 30% of that in normal healthy volunteers,
and, as expected, leads to average 41% higher plasma
concentrations of raltegravir [5]. This increase is not
considered clinically significant.
Raltegravir is bound to plasma proteins for
approximately 83% at therapeutic concentrations. Animal data
demonstrate passage through the placental barrier, but
not through the blood-brain barrier. Human data on
penetration into sanctuary sites is pending.
PHARMACOKINETIC PHARMACODYNAMIC
RELATIONSHIPS FOR RALTEGRAVIR
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