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

PRECLINICAL PROFILE OF R7180, A PRODRUG OF THE NOVEL NNRTI RO-5028, WITH HIGH ANTIVIRAL POTENCY AGAINST WILD-TYPE AND NNRTI-RESISTANT VIRUSES

Antivir Ther. 2008; 13(Suppl. 3):A29 (abstract no. 27)

K Klumpp, J Dunn, G Su, Y Li, A Zhou, D Stefanidis, S Chanda, M Martin, S Harris, T Mirzadegan, A Paul, H Javanbakht, JQ Hang, A Briggs, JB Xu, M Irwin, M Fielden, S Swallow, N Cammack, Z Sweeney and G Heilek
Roche Palo Alto LLC, Palo Alto, CA, USA

BACKGROUND: A new series of non-nucleoside reverse transcriptase inhibitors (NNRTIs) was optimized with regards to antiviral potency against wild-type and NNRTI-resistant viruses. In addition, a delivery strategy was devised to allow increased oral bioavailability, increasing inhibitory quotient and effectiveness of virus replication suppression.

METHODS: Optimization and characterization of NNRTIs were based on structural and biochemical assessments of their binding to HIV-RT, inhibition of HIV-RT activity and inhibition of HIV replication in single- and multiple-cycle replication assays in cell culture. Pharmacokinetics were determined in rats, dogs and cynomolgus monkeys and preclinical safety assessments were conducted in rats and dogs. Plasma exposures of the prodrugs, parents and major metabolites were determined by LC-MS/MS.

RESULTS: RO-5028 represents a new series of NNRTIs with unique HIV-RT binding interactions. RO-5028 is a potent inhibitor of wild-type HIV-1 in cell culture (mean IC₅₀=1.3 nM). The binding affinity to human serum proteins is lower than that of efavirenz. Antiviral potency of RO-5028 in the presence of human serum was reduced 3.9-fold, a smaller effect as compared with efavirenz, etravirine or rilpivirine. RO-5028 potently inhibits replication of HIV-1 variants with common NNRTI resistance mutations (for example, K103N/Y181C, L100I/K103N and G190A/S). In a panel of 50 viruses derived from NNRTI-pretreated patients, RO-5028 inhibited 90% of viruses with human serum binding adjusted IC₅₀ values lower than 100 nM. R7180, a prodrug of RO-5028, increased oral bioavailability and dose proportionality of RO-5028, allowing the potential achievement of high inhibitory quotients in humans. In toxicity studies of up to 4 weeks duration in dogs, R7180 was not associated with any significant pathological or clinical findings at dose levels up to 40 mg/kg, while reaching plasma concentrations up to 24 µM (>4,700-fold above human serum adjusted antiviral IC₅₀). No overt signs of toxicity were noted in rats, although plasma concentrations in rats were limited by auto-induction to ~4.4 µM.

CONCLUSIONS: R7180 represents a series of prodrugs for novel NNRTIs with high antiviral potency against wild-type and NNRTI-resistant HIV-1. R7180 is efficiently converted to the active parent RO-5028, achieving high oral bioavailability and well-tolerated in toxicity studies where high plasma exposures were achieved, therefore supporting further development of R7180 for the treatment of HIV infection.

2008-06-10
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