DPC 961 and DPC 963 are new non-nucleoside reverse transcriptase inhibitors (NNRTIs) under investigation by Bristol-Myers Squibb. They have been selected for development due to their ability to inhibit NNRTI resistant viruses in the test tube, specifically those with the common NNRTI mutation K103N.

However, the drugs do not appear to be very effective against virus with multiple NNRTI associated mutations. Resistance to DPC 961 and DPC 963 has emerged at a slower rate than to efavirenz in test-tube experiments. In addition, in vitro resistance testing suggests that HIV which is resistant to efavirenz or nevirapine may still be susceptible to DPC 961 (Jeffrey 2000).

A pharmacokinetic study in healthy volunteers found a C_min 18 times higher than the estimated in vitro IC₉₀ for virus with the K103N mutation primarily associated with efavirenz resistance, and six times higher than the IC₉₀ for virus with the K103N and Y181C mutations associated with NNRTI cross-resistance (Joshi). Viruses with further mutations were less susceptible to DPC 961.

Development of DPC 961 was suspended after several trial participants reported the emergence of suicidal thoughts after commencing the drug. The future of DPC 963 is uncertain.

References

Corbett JW et al. Discovery of HIV-1 NNRTI development candidates DPC961 and DPC963. Fourth Congress on Drug Therapy in HIV Infection, Glasgow, abstract P21, 1998.

Erickson-Viitanen S et al. DMP 961, DMP 963: 2nd generation non-nucleoside reverse transcriptase inhibitors active against the RT K103N mutant. Sixth Conference on Retroviruses and OIs, Chicago, 1999, abstract 13.

Jeffrey S et al. New second generation NNRTIs: improved resistance and cross-resistance profiles. XIII International AIDS Conference, Durban, abstract TuPpA1145, 2000.

Joshi A, et al. Pharmacokinetics of a second generation NNRTI, DPC 961, after multiple oral doses in healthy volunteers. Seventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract102, 2000.

Rayner M et al. Second generation NNRTIs require multiple mutations for selection of highly resistant HIV in vitro. XIII International AIDS Conference, Durban, abstract TuOrA347, 2000.