Safety and pharmacokinetic profile of multiple escalating doses of (+)-calanolide A, a naturally occurring nonnucleoside reverse transcriptase inhibitor, in healthy HIV-negative volunteers.
BACKGROUND
(+)-Calanolide A is a naturally occurring nonnucleoside reverse transciptase inhibitor (NNRTI) that exhibits enhanced activity against HIV-1 isolates with the Y181C mutation and retains activity against HIV-1 isolates with dual Y181C and K103N mutations. Previous studies have demonstrated that (+)-calanolide A has a favorable safety profile in both animal and human subjects.


METHODS
In this study, the safety and pharmacokinetics of multiple escalating doses of (+)-calanolide A were evaluated in a total of 47 healthy, HIV-seronegative individuals.


RESULTS
All adverse events seen in the study were mild to moderate in intensity and were transient. The most common adverse events seen were headache, dizziness, nausea, and taste perversion (oily aftertaste). Laboratory abnormalities were determined to be clinically insignificant or unrelated to (+)-calanolide A administration. No dose-related pattern in adverse event or laboratory abnormality incidence was apparent. In all cohorts examined, administration of (+)-calanolide A produced highly variable plasma levels and absorption profiles. No accumulation of parent compound was seen over the 5-day treatment course, with the day 5 area under the curve (AUC) being approximately one half of that seen on the first day of dosing. Steady-state trough plasma levels were determined in the two highest dose cohorts (600 mg and 800 mg bid for 5 days). Mean elimination half-life in the two highest dosing cohorts combined was 15.5 hours in men and 35.2 hours in women.


CONCLUSIONS
These pharmacokinetic properties, together with the benign safety profile, and unique in vitro resistance pattern warrant the continued development of this potential new antiviral agent.
Eiznhamer
David A
DA
MediChem Life Sciences, Inc., Woodridge, Illinois, USA.
Creagh
Terri
T
Ruckle
Jon L
JL
Tolbert
Dwain T
DT
Giltner
Jeremy
J
Dutta
Bipul
B
Flavin
Michael T
MT
Jenta
Tuah
T
Xu
Ze-Qi
ZQ
D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D015331:Cohort Studies; D003374:Coumarins / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1; D006801:Humans; D008297:Male; D039681:Pyranocoumarins; D012016:Reference Values; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
D019380:Anti-HIV Agents; D003374:Coumarins; D039681:Pyranocoumarins; D018894:Reverse Transcriptase Inhibitors; C075959:calanolide A