Background: There is a strategic need for new treatments options in HIV infection enabling clinicians to obtain long term virological / immunological regression and patients to benefit from user-friendly safe drugs.
Objective: To the structural, pharmacokinetic and virological characteristics of GW 908.
Methods: Overview of structural development steps, pharmacokinetic and virological data.
Results: Because the intrinsic bioavailability of amprenavir (APV) is high a solubilizing strategy was chosen to optimize membrane penetration of this drug. The synthesis of highly polar and/or charged compounds expected to render APV freely soluble in the intestinal tract
was undertaken, At the gut wall the polar appendix is removed and APV delivered to the lipohilic media ready to be absorbed across the gut membrane. In vivo evaluation of about 75 compounds led to a phosphate compound, GW908, as the candidate. Cell-permeation experiments in a caco-2 system and PK studies in dogs indicated that the compound is cleaved before/during absorption into circulation consistent with the solubilization model. The intrinsic solubility of GW908 allowed for a compact and convenient tablet formulation. The animal toxicology profile is similar to APV Treatment-naïve (N=85) adults were assessed in a double-blind, randomized cross-over phase II study comparing 1395 mg or (3 tabs) vs. 1860 mg (4 tabs) vs. 1200 mg APV BID
combined with abacavir+lamivudine. The 1395 mg dosage regimen yielded Cmax,ss=0.82 µg/mL(range:0.68-0.98), AUCss=1.00 µg.h/mL(0.87-1.15), Ctss=1.10 µg/mL(0.86-1.40), overall equivalent plasma exposure compared to APV. GW 908 resulted in a 2Log decrease in plasma HIV RNA and 100 CD4+/mm3 increase. Prodrug in plasma is negligible. Adverse events were infrequent, included headache and sleep disorders. Laboratory safety was unremarkable.
Conclusion: GW908, the calcium phosphate ester of APV, is a water-soluble drug offering a compact dosing formulation. Phase I and II of GW908 in healthy volunteers and HIV infected patients showed equivalent exposure to APV (steady state AUC). Treatment with GW908 results in a
clinically significant decrease in HIV RNA and increase in CD4 count. Thus, GW908 is a significant advance in the simplification of PI therapy allowing for incorporation of a potent and safe agent within HAART regimens. Studies with GW908 are currently evaluating pharmacoenhancement with ritonavir, OD dosing, comparison vs. nelfinavir in treatment-naïve and vs. lopinavir in pre-treated patients as well as prospective evaluation of lipodystrophy/metabolic parameters.
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