Pharmacy & Therapeutics- August 2008 - (Page 446) DRUG FORECAST when it is taken under fasting conditions, etravirine should always be administered with food. The absorption of etravirine is not affected by the coadministration of oral ranitidine (Zantac, GlaxoSmithKline) or omeprazole (e.g., Prilosec, AstraZeneca) in healthy patients. It is 99% bound to plasma proteins, primarily albumin and alpha1-acid glycoprotein. Distribution through other plasma compartments, such as the cerebrospinal fluid and genital tract secretions, have not been evaluated in clinical trials. Etravirine is metabolized primarily hepatically through cytochrome CYP 450 3A4, CYP 2C9, and CYP 2C19 enzymes. In clinical trials, clearance for etravirine was reduced in HIV-1 patients with hepatitis B or C; however, no dosage adjustment is necessary. Elimination occurs mainly via the feces (93.7%), with small amounts of the drug excreted in the urine (1.2%). The mean elimination half-life of etravirine is 41 (±20) hours after steady state. Although several clinical trials involving etravirine are ongoing, the agent’s pharmacokinetic parameters have not been established in children or treatment-naive adults. No significant differences in pharmacokinetics in terms of race, sex, or age have been demonstrated in patients 18 to 77 years of age.6 The presence of three or more NNRTI mutations sharply diminishes the response to etravirine regimens. These mutations are Val90Ile, Ala98Gly, Leu100Ile, L ys101Glu, L ys101Pro, Val106Ile, Val179Asp, Val179Phe, T yr181Cys, Tyr181Ile, Tyr181Val, Gly190Ala, and Gly190Ser. The presence of the most common mutations (K103N and Y181C) did not affect the treatment response in patients receiving etravirine in the DUET studies.4–6 The DUET-1 Trial Clinical data were collected between November 10, 2005, and July 18, 2006. DUET-1 included 615 participants from Argentina, Brazil, Chile, France, Mexico, Panama, Puerto Rico, Thailand, and the U.S. who were randomly assigned, in a 1:1 ratio, to receive TMC125 (etravirine) (n = 304) or placebo (n = 308). Participants received either 200 mg of etravirine or placebo as a twice-daily drug regimen. The investigator selected a background regimen that included an NRTI and optional enfuvirtide. All patients were to receive darunavir 600 mg with ritonavir 100 mg twice daily as a background antiretroviral regimen. The NRTI agent was selected and administered according to virus genotype resistance at screening. A total of 70 participants (42 in the etravirine group, 56 in the placebo group) discontinued treatment because of virological failure, defined as a viral load reduction of less than 0.5 log 10 copies/mL from baseline at the eighth week or less than 1.0 log10 copies/mL at week 12. Analyses were by intention to treat. The primary endpoint—obtaining a confirmed viral load of less than 50 copies/mL at week 24—was reached by 170 etravirine patients (56%) and by 119 placebo par ticipants (39%). Overall, achievement of a secondary endpoint— obtaining a confirmed viral load of less than 400 copies/mL, a change in viral load from baseline, a change in CD4 cell count from baseline, and safety and tolerability—was greater with etravirine than with placebo. Regardless of the amount of additional active agents received, 224 patients taking etravirine (74%) and 158 patients taking placebo (51%) achieved a viral load of less than 400 copies/mL at week 24. Twenty-one etravirine patients (47%) and four placebo patients (9%) achieved a viral load of less than 50 copies/mL without any additional active agents in the background regimens. The etravirine group reported a mean change in viral load of –2.41 log10 copies/mL from baseline (standard deviation [SD], 1.28), whereas the placebo group reported only –1.70 log10 copies/mL (SD, 1.49). According to the data, the etravirine patients attained a greater increase in CD4 count at an average of 89 (93.65) CLINICAL TRIALS In November 2006, Tibotec Pharmaceuticals launched clinical trials to study the potential use of etravirine in treatment-experienced HIV-1 patients. Based on the findings, etravirine was approved in 2008. DUET-1 and DUET-2 were randomized, double-blind, placebo-controlled phase 3 trials that were conducted to compare the therapeutic outcomes of etravirine plus a background regimen against placebo in combination with a background regimen. The investigators also sought to distinguish which patients had reused or who did not use enfuvirtide (Fuzeon, Roche). Participants included HIV-1–infected patients who were at least 18 years of age with a viral load of more than 5,000 copies/mL, who were receiving stable antiretroviral therapy for at least eight weeks, and who had a minimum of one confirmed NNRTI resistance–associated mutation. DUET-1 and DUET-2 were indistinguishable from one another, but they were performed in treatment-experienced HIV-1 patients with documented evidence of NNRTI and PI resistance in different regions.4,5 DRUG RESISTANCE Etravirine’s activity against resistant strains is strongly affected by the number of NNRTI mutations present as well as by the specific mutations. It is critical to discontinue the first-generation NNRTI that has demonstrated resistance in order to avoid any further resistance that would diminish the efficacy of etravirine. Table 1 Baseline Characteristics: DUET and DUET Pooled -1 -2 Analysis Etravirine + BR (n = 599) Median viral load (log10 copies/mL) Median CD4+ (cells/mm3) Previous NNRTI use ≥1 (%) Median NNRTI RAMs (range) Previous enfuvirtide use (%) 4.8 99 91.8 2 (0–5) 39.6 Placebo + BR (n = 604) 4.8 109 92.1 2 (0–4) 41.9 BR = background regimen; NNRTI = non-nucleoside reverse transcriptase inhibitor; RAMs = resistance-associated mutations. From etravirine (Intelence), package insert, January 2008.6 446 P&T® • August 2008 • Vol. 33 No. 8
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