Pharmacokinetic (PK) Interaction of AG1549, a Novel Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI), with Protease Inhibitors (PI)

M. JACOBS*¹, G. LEOUNG¹, B. DEZUBE², C. HENDRIX³, T. DAHL⁴, T. WONG⁴, T. FUJIWARA⁵, M. AMANTEA⁶, P. HAWLEY⁶, and L.PARADISO⁶. ¹HIVCare at St. Francis Mem. Hosp., San Francisco, CA; ²Beth Israel Deaconess Med. Ctr., Boston, MA; ³Johns Hopkins Univ. Sch. of Med., Baltimore MD; ⁴Lexigen Pharmaceuticals Corp., Lexington, MA; ⁵Shionogi & Co., Osaka, Japan and ⁶Agouron Pharmaceuticals, Inc., San Diego, CA

AG1549, an investigational NNRTI formerly known as S-1153, licensed by Agouron Pharmaceuticals, Inc. from Shionogi & Co., Ltd., has a novel resistance profile, exhibiting potent antiviral activity against HIV variants with RT substitutions, including K103N, which confer broad cross-resistance among the approved NNRTIs.  Since in vitro studies with human liver microsomes demonstrate that CYP3A is the major isoform for its metabolism, other drugs that share this pathway may alter the kinetics of AG1549.  In this study, 29 HIV infected patients on stable therapy with nelfinavir and AZT (or d4T) and 3TC had AG1549 added for 28 days at doses varying from 175 to 1800 mg BID.  In addition, 11 patients on indinavir rather than nelfinavir were treated with AG1549 at 175mg BID.
AG1549 was well tolerated at all doses with no serious adverse events reported.  The most common treatment emergent drug-related adverse events were diarrhea and nausea.  PK results indicate that AG1549 displays first-order elimination over the studied dosage range.  The observed minimum and maximum AG1549 plasma concentrations ranged from 0.128 to 3.24 and 1.79 to 9.13 mg/mL, respectively.
In comparison to other trials where AG1549 was used without a PI, it appears nelfinavir increases the concentration of AG1549 by approximately two-fold. AG1549 administered twice daily in the presence of nelfinavir is well tolerated and achieves target antiviral concentrations.

Key Words: NNRTI, pharmacokinetics, Protease Inhibitors

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