Calanolide A is a new non-nucleoside reverse transcriptase inhibitor (NNRTI) derived from a plant found in the Malaysian rain forest. A related compound, calanolide B, also has anti-HIV activity. Both drugs are being developed by Sarawak Pharmaceuticals.

A preliminary dosing study among HIV-infected individuals showed a significant antiviral effect compared with placebo.

The drug is active in the test tube against HIV with the two most common NNRTI-related mutations, K103N and Y181C, and selects for a mutation which does not cause cross-resistance with any other NNRTIs currently under investigation. A substitution at codon Y188H of reverse transcriptase has been associated with 30-fold resistance to calanolide A in vitro (Quan 1999). The drug is metabolised by cytochrome P450 CYP3A, and its developers have suggested that drug levels may be enhanced if co-administered with ritonavir (Norvir).

Dose ranging and safety studies in HIV-negative volunteers suggest that it causes dizziness, nausea, headache and an oily taste in the mouth.

Key research

Creagh treated 47 HIV-negative volunteers with +calanolide A. Reported adverse events included dizziness, taste perversion, headache, eructation and nausea. Half-life of the drug was 20 hours for 800mg and time to maximum plasma concentration was between 24-5.2 hours.

Sherer enrolled 43 HIV-infected subjects in a randomised, double-blind, placebo-controlled, dose-ranging study of calanolide. Twice daily doses of 200 mg, 400 mg and 600 mg of placebo were taken for 14 days. Viral load reduction in the 600 mg arm at day 14 was -0.81 log which was greater than placebo (p<0.027).

References

Creagh T et al. Safety and pharmacokinetics of single doses of (+)-calanolide a, a novel, naturally occurring nonnucleoside reverse transcriptase inhibitor, in healthy, human immunodeficiency virus-negative human subjects. Antimicrobial Agents and Chemotherapy (United States) 45(5): 1379-86, 2001.

Quan Y et al. Sensitivity and resistance to (+)-calanolide A of wild-type and mutated forms of HIV-1 reverse transcriptase. Antiviral Therapy 4(4):203-9, 1999.

Sherer R et al. A phase 1B study of (+)-calanolide A in HIV-1-infected, antiretroviral-therapy-naive patients. Seventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 508, 2000.

Xu ZQ et al. Plant-derived and semi-synthetic calanolide compounds with in vitro activity against both human immunodeficiency virus type 1 and human cytomegalovirus. Antivir Chem Chemotherapy 11(1):23-9, 2000.