17th International HIV Drug Resistance Workshop 10-14 June 2008, Sitges, Spain

HEXADECYLOXYPROPYL TENOFOVIR (CMX157) HAS ENHANCED POTENCY IN VITRO AGAINST NRTI-RESISTANT HIV RELATIVE TO TENOFOVIR AND A FAVOURABLE PRECLINICAL PROFILE

Antivir Ther. 2008; 13(Suppl. 3):A6 (abstract no. 4)

ER Lanier, B Lampert, L Trost, G Painter and M Almond
Chimerix Inc., Research Triangle Park, NC, USA

BACKGROUND: Tenofovir disoproxil fumarate (tenofvir-DF) is one of the most widely used nucleoside/tide reverse transcriptase inhibitors (NRTIs). However, it loses activity against specific HIV mutants, including those with K65R, multiple thymidine analogue mutations (TAMs) or multi-NRTI resistant (MNR) mutations and has been associated with nephrotoxicity. Unlike tenofovir-DF and most prodrugs, hexadecyloxypropyl tenofovir (CMX157) is not efficiently cleaved to free tenofovir in the plasma in vivo. This should increase the levels of active tenofovir-diphosphate in target cells for HIV, thereby lowering the apparent IC₅₀, and reduce the rate of secretion into the kidney.

METHODS: CMX157 IC₅₀s were determined for a panel of 30 NRTI isolates with major NRTI mutations, including K65R with or without M184V, multiple TAM combinations with or without M184V, K70E in various combinations and MNR complexes including T69SXX and Q151M (PhenoSense™). A separate panel of 14 NRTI-resistant clinical isolates and wild-type isolates from subtypes A–G, O and HIV-2 were examined in plasma blood mononuclear cells (PBMCs). Additional studies determined activity in monocytic cells, the effect of human serum on activity, cytotoxicity in dividing and non-dividing cells, tenofovir-diphosphate levels in PBMCs and toxicity/toxicokinetics in rats.

RESULTS: IC₅₀s for CMX157 ranged from 0.66 nM for L74V/M184V to 57 nM for T69SSG/M184V/L210W/ T215Y in the PhenoSense™ assay (corresponding IC₅₀s for tenofovir were 227 nM and 16,959 nM, respectively). CMX157 IC₅₀s for M41L/L210W/T215Y averaged 6.3 nM without M184V and 2.2 nM with M184V (2,240 and 770 nM for tenofovir, respectively). Similar data were obtained in PBMCs. CMX157 IC₅₀s against major HIV subtypes ranged from 0.2 nM (B) to 7.2 nM (O). No toxicity was observed in rats administered CMX157 up to 100 mg/kg/d for 7 days; the CMX157 C_max was 1,200 nM on day 7 and the AUC_0-inf was 8,050 ng*h/ml. Tenofovir-diphosphate levels were 33fold higher in PHA/IL-2 stimulated human PBMCs after 24 h exposure to 1,000 nM CMX157 versus tenofovir in vitro (1.65 and 0.05 pM/10⁶ cells, respectively).

CONCLUSIONS: CMX157 is substantially more potent than tenofovir in vitro, possibly due to higher active anabolite levels in target cells. Toxicology and toxicokinetic data reveal high systemic exposure with no indication of nephrotoxicity. CMX157 is being developed for treatment of HIV.

2008-06-10
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