GW420867X is a non-nucleoside reverse transcriptase inhibitor that was licensed from Hoechst Marion Roussell in 1997. The drug is related to quinotaline, or HBY 076, a drug that was discontinued by Bayer.

Development of GW420867X was stopped by manufacturer Glaxo-Wellcome (now GlaxoSmithKline) in February 2000 due to interactions with other anti-HIV drugs.

GW420867X was dropped because experts felt that its profile as a powerful cytochrome p450 3A4 inducer would make it very difficult to partner with other anti-HIV drugs. Most anti-HIV drugs are metabolised via p450 3A4. Drugs such as GW420867X, that induce p450 3A4 metabolism, speed up the clearance of other drugs processed that way. In effect, GW420867X would have cleared other anti-HIV drugs from the body very quickly. In order to counteract this process, doses of other drugs would have to be increased, possibly resulting in unacceptable increases in pill burdens and drug-related adverse events.

Dosage and effectiveness

GW420867X was suitable for once daily dosing, with a very high trough concentration (115 times the IC₅₀ at 200mg a day). Taken with or without food, even high fat meals do not affect absorption.

A four-week dosing study of GW420867X found an average viral load reduction of 1.5 log after a week of monotherapy treatment. Dosage did not significantly affect viral load reduction, but the higher doses were associated with a trend towards more side-effects. Most common adverse events were headache, nausea, flatulence and dizziness (Arasteh). GW420867X showed activity against HIV which is resistant to other NNRTIs.

Key research

Arasteh reported a placebo-controlled, dosing study of GW420867X (placebo, or 50, 100 or 200 mg per day, after an initial double dose) in 60 HIV-infected individuals. After a week of monotherapy, AZT/3TC were added for 3 weeks. Baseline viral loads were between 4.4-4.9 log and CD4 counts were over 300. At day 8, the average viral load reduction for people receiving GW420867X was 1.5 log, with no significant difference between the dosing arms. At day 28 70-85% of participants on GW420867X plus AZT.3TC had viral loads below 400. There was a trend to more side-effects in the higher dosing groups. common side-effects reported were headache (42%), nausea 925%), flatulence (15%), and dizziness (10%).

Prince reported a safety and dosing study of GW420867X which found that a single dose (between 300mg-1200mg) has a half life of 50 hours. Reported side-effects included headache, drowsiness, dizziness and malaise/fatigue.

References

Arasteh K et al. Preliminary tolerability, pharmacokinetics (PK), and initial effect on plasma HIV-1 RNA following administration of GW420867X once-daily (50mg, 100 mg and 200 mg) for 28 days to patients infected with HIV-1. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, abstract 504, 1999.

Balzarini J et al. Long-term exposure of HIV-1-infected cell cultures to combinations of the novel quinoxaline NNRTI GW420867X with lamivudine, abacavir and a variety of NNRTIs. Antiviral Therapy 4(supplement 1):10, 1999.

Cass LM et al. The bioavailability of the novel nonnucleoside reverse transcriptase inhibitor GW420867X is unaffected by food in healthy male volunteers. Journal of Clinical Pharmacology 41(5):528-535, 2001.

Kleim JP et al. NNRTI GW420867X: comparative evaluation of the in vitro resistance profile. Sixth Conference on Retroviruses and Opportunistic Infections, Chicago, abstract 600, 1999.

Moore KHP et al. Pharmacokinetics and safety of escalating single and repeat oral doses of GW420867X, a novel non-nucleoside reverse transcriptase inhibitor. European Journal of Clinical Pharmacology 56(11):805-811, 2001.

Prince W et al. GW420867X, a new non-nucleoside reverse transcriptase inhibitor (NNRTI) - initial phase I evaluation. Twelfth International Conference on Antiviral Research, Jerusalem, abstract P49, 1999.

Thomas SA et al. CSF entry of the novel non-nucleoside reverse transcriptase inhibitor, GW420867X. Neuroreport 11(17):3811-3815, 2000.