RUCKLE J, CREAGU T, TOLBERT D, GILTNER J, DUTTA B, THOMAS C, WRIGHT T, XU Z; Interscience Conference on Antimicrobial Agents and Chemotherapy.
Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 1999 Sep 26-29; 39: 14 (abstract no. 324).
Northwest Kinetics, LLC, Tacoma, WA
BACKGROUND: (+)-Calanolide A, a natural product originally isolated from several tropical plants of the genus Calophyllum in Malaysia, is a novel NNRTI. It has exhibited enhanced activity against the Y181C mutation of HIV-1 and is active against isolates with dual Y181C and K103N mutations. In the in vitro cultural assay, (+)-calanolide A selected the T139I mutation. This mutation was previously unknown and is susceptible to almost all other antiretrovirals including NNRTIs.METHODS: Safety and pharmacokinetics of single and multiple escalating doses of (+)-calanolide A have been evaluated in a total of 94 healthy HIV-negative subjects. Four cohorts received single doses of 200 to 800 mg; five cohorts received multiple doses of 200 mg qd, and 200 mg to 800 mg bid, respectively, for 5 days. Safety evaluations included CBC/diff., blood chemistry, PT, PTT, urinalysis, ECG, vital signs, and physical exams.RESULTS: All adverse events were mild and transient. The most common adverse events were dizziness, oily taste, headache, nausea, and eructation. No drug-related rash was observed and no dose-related patterns in adverse events were apparent. Pharmacokinetic analyses indicated good bioavailability and a relatively long half-life (~20 hours). Food had little effect on total drug absorption. A possible gender-associated difference was suggested in the single dose study, but appeared to be insignificant at steady state in the multiple dose cohorts. Both AUC and Cmax increased with increasing dose. However, nonlinearity of dosing was observed in the multiple dose cohorts.CONCLUSION: (+)-Calanolide A is generally well tolerated in single and multiple doses up to 800 mg bid and its toxicity profile is different from other approved NNRTIs. It appears that therapeutic levels of (+)-calanolide A can be achieved, based on the in vitro EC[90] values against HIV-1.
Publication Types:
Keywords:
- Area Under Curve
- Calophyllum
- HIV Infections
- HIV-1
- In Vitro
- Malaysia
- Safety
- Single Person
- pharmacokinetics
- psychology
Other ID:
UI: 102244606
From Meeting Abstracts