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A Phase IB Study of (+)-Calanolide A in HIV-1-Infected, Antiretroviral Therapy Naive Patients R. SHERER*1, B. DUTTA2, R. ANDERSON3, J. LAUDETTE-ABOULHAB4, A. KAMARULZAMAN5, R. D’AMICO6, N. PATON4, M. S. ABDULLAH7, R. POLLARD8, T. COOLEY9, M. FLAVIN2, and Z.-Q. XU2.
1CORE Ctr., Cook County Hosp., Chicago, IL; 2Sarawak MediChem Pharmaceuticals, Lemont, IL; 3Anderson Clin. Res., Pittsburgh, PA; 4CDC, Tan Tock Seng Hosp., Singapore; 5Univ. Hosp., Kuala Lumpur, Malaysia; 6Beth Israel Med. Ctr., New York, NY; 7Univ. of Malaya, Kuala Lumpur, Malaysia; 8Univ. of Texas Med. Branch at Galveston; and 9Boston Univ. Med. Ctr., MA Background: (+)-Calanolide A is a potent non-nucleoside reverse transcriptase inhibitor (NNRTI) and it exhibits in vitro synergistic to additive effects when combined with different NRTIs, Pis, and other NNRTIs.
Objectives: To assess the pharmacokinetics (PK) and preliminary antiviral effect of (+)-calanolide A in HIV-1-infected adults.
Methods: In two Phas IB randomized, double-blind, placebo-controlled, dose-range studies, (+)-calanolide A was administered orally to HIV-infected subjects for 14 days at dosages of 200 mg bid (cohort 1), 400 mg bid (cohort 2), or 600 mg bid (cohort 3). A total of 43 subjects were randomized and dosed in these studies. At every visit during blinded and follow-up period (14 days), clinical and laboratory assessments including efficacy parameters (viral load & CD4 count) were done for each subject.
Results: The antiviral effect of (+)-calanolide A appeared to be dose-dependent and did not maximize until Day 14 or Day 16. In the 600 mg bid cohort at day 14, the mean viral load reduction from baseline was -.81 log10 and had a significantly greater antiviral activity (p=0.027<0.05) when compared with the placebo group. Genotypic results did not indicate the emergence of mutations during 14-day treatment period.
Conclusions: Further clinical studies to evaluate the long-term antiviral effects of (+)-calanolide A in combination with other antiretroviral agents are warranted.
Key Words: (+)-Calanolide A, HIV/AIDS, NNRTI
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