Important note: Information in this article was accurate in January 2007. The state of the art may have changed since the publication date.
Expanded Access Drug Profile: Raltegravir (RAL, MK-0518)
Hopkins HIV Report 2007 Jan; 19(1):8,10
Amanda R. Colquitt, Pharm.D. and Paul A. Pham, Pharm.D.
Johns Hopkins
Manufacturer: Merck Pharmaceuticals
Class: Integrase inhibitor
Studied Indications: Treatment-naïve patients or patients with multi-drug resistant HIV-1 infection.
Studied Dose: 100, 200, 400, and 600 mg twice daily
Pharmacology/Drug-drug Interactions: RAL does not require boosting with ritonavir (RTV) to optimize therapeutic concentrations. It is not a potent inhibitor or inducer of CYP3A4; therefore, drug interactions with CYP3A4 substrates are unlikely. It is primarily metabolized by glucuronidation via the enzyme, UDPglucuronosyltransferase (UGT) 1A1; therefore, inhibitors (atazanavir) and inducers (rifampin, phenobarbital, and phenytoin) of glucuronosyl transferase may increase or decrease RAL concentrations, respectively.
Clinical Studies Results: Treatment-naïve patients: Results of a two-part, Phase II, 48-week, double-blind, randomized trial of treatment-naïve patients were reported at 24-weeks: The dose finding portion of the study demonstrated antiviral activity of RAL as monotherapy at 100, 200, 400, or 600 mg bid for 10 days. Approximately 50%-57% of patients achieved HIV RNA levels <400 c/mL [Morales-Ramirez JO, et al. 10th European AIDS Conference, 2005, Abstract LBPS1/6]. The second part of the study compared RAL or EFV in combination with TDF and lamivudine (3TC) in 198 patients [Markowitz M, et al. Int Conf AIDS. 2006 Aug 13-18;16: Abstract THLB0214]. Baseline characteristics of the 160 ART-naïve patients randomized to RAL plus TDF and 3TC were: viral load 4.6-4.8 log10 c/mL and CD4 271-314 cells/mm3. Undetectable viral load was achieved in 85% to 100% of patients across all arms. The efficacy was similar in EFV and the RAL arms across all dosages. However, those in the RAL groups achieved virologic suppression to <50 c/mL more rapidly than those in the EFV. After 24 weeks of treatment, the mean increase in CD4 count from baseline ranged from 139 to 175 cells/mm3 in the RAL groups compared to 112 cells/mm3 in the EFV group.
Treatment-experienced patients: In a randomized, double-blind, placebo-controlled trial of patients with multi-drug resistant HIV, doses of RAL of 200, 400, or 600 mg bid were evaluated [Grinsztejn B, et al. Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 159LB]. All patients were genotypically or phenotypically resistant to at least1 drug in each of three classes (NNRTI, NRTI, PI). Baseline characteristics of the 124 patients randomized to RAL plus optimal background regimen (OBR) vs OBR alone were: viral load 4.7 log10 c/mL, CD4 226 244 cells/mm3, and 9-11 years of prior ART. The OBR contained a median of 4 antiretrovirals with 45 (36%) receiving enfuvirtide. An undetectable (<50 c/mL) viral load was achieved in 56-72% and 20% of RAL and control patients, respectively.
Adverse Drug Reactions: RAL was generally well tolerated in clinical trials. In one study, pruritis was noted in 2-7%, grade 3/4 transaminase elevation in 2%, and hepatomegaly, tenderness and fever in one patient [Grinsztejn B, et al. Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 159LB]. In a study comparing RAL with EFV, flatulence was more common in RAL treated patients (6% vs 0%); as expected, headache, dizziness, insomnia, and abnormal dreams were more common in the EFV group [Markowitz M, et al. Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. ThLB0214].
Expanded Access Program [Merck Pharmaceuticals HIV Investigational Studies website www.benchmrk.com. Accessed October 16, 2006.]: EARMRK, Merck Pharmaceuticals’ expanded access program (EAP), offers RAL, now in Phase III development, to HIV-infected patients with limited or no treatment options. Patients will receive RAL 400 mg bid in addition to optimized background therapy (OBT).
Inclusion criteria:
Exclusion criteria:
Prior use of RAL in a clinical trial
The need for any medications prohibited by the protocol (including phenobarbital, phenytoin, and rifampin)
Acute hepatitis due to any cause or clinically significant chronic liver disease
Presence of a condition which investigators deem will interfere with adherence and safety
Pregnant or breast-feeding Additional information regarding the RAL EAP is available at www.benchmrk.com. This study is registered on www.clinicaltrials.gov under identifier NCT00369941.
2007-01-10
HHR-2007-01-06
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