Drug-drug interactions with raltegravir

European Journal of Medical Research, Nov 2009

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 800 mg 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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Drug-drug interactions with raltegravir

David M. Burger 0 1 0 Department of Clinical Pharmacy and Nijmegen Institute for Infection, Inflammation and Immunology (N4i), Radboud University Nijmegen Medical Centre , Nijmegen , the Netherlands 1 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. - 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 In order to be able to make (...truncated)


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David M Burger. Drug-drug interactions with raltegravir, European Journal of Medical Research, 2009, pp. 17-21, 14, DOI: 10.1186/2047-783X-14-S3-17