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Phase 1, Single Ascending Oral Dose Study of the Safety, Tolerability, and Pharmacokinetics of MPC-9055 a Novel HIV-1 Maturation Inhibitor in HIV Negative Healthy Subjects
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Reported by Jules Levin
CROI 2009 Feb 8-12 Montreal
Andrew Beelen, James Otto, Matthew Fidler, Elizabeth Sanguinetti, Patricia Smiley, Alfred Balch, Matthew Medlocka, Mary Jackson, Edward Swabb
Myriad Pharmaceuticals Inc., Salt Lake City, UT, USA & a PPD, Inc., Austin, TX, USA
AUTHOR CONCLUSIONS
MPC-9055 had a favorable safety profile following single, oral dose administration in healthy volunteers
Most adverse events were mild with the most common being nausea, diarrhea, and lightheadedness
Food increased MPC-9055 exposure nearly 2-fold
Plasma concentrations increased in a less than dose proportional manner
ABSTRACT
BACKGROUND:
MPC-9055 is a potent, orally bioavailable, small molecule inhibitor of human immunodeficiency virus-1 maturation. MPC-9055 targets a unique cleavage event in the HIV life cycle by inhibiting processing of the viral capsid protein p25 to p24. Inhibition of this final step in Gag processing leads to the noninfectious virion and thereby prevents subsequent rounds of HIV infection.
METHODS:
This was a first-in-human, single oral dose, double blind, placebo controlled, sequential escalating design study to evaluate the safety, tolerability and pharmacokinetic parameters of MPC-9055 under fasted and fed conditions. The fasted dose levels were 1, 2, 4, 8, 16, 32 and 48 mg/kg. The fed dose levels were 8 mg/kg (high fat) and 16 mg/kg (low fat). *An additional cohort of eight subjects was enrolled to assess the relative bioavailability of an oral tablet formulation. Safety measurements included physical exams, ECGs, vital signs, laboratory parameters, and adverse event monitoring. Pharmacokinetic parameters were summarized and dose-proportionality was assessed using a log-log model.
RESULTS:
Safety: A total of 63* subjects received active drug and 20 received placebo. No serious adverse events or clinically significant laboratory trends or ECG changes were observed. Overall, 30%* of subjects who received active treatment experienced at least one treatment emergent adverse event (AE)
compared to 15% who received placebo. The most common AEs in the active treatment groups were nausea, diarrhea, and lightheadedness*. All AEs were of mild intensity with the exception of 1 AE of moderate intensity diarrhea.
Pharmacokinetic: In the fasted cohorts, mean half-life ranged from 23-42 hours, Tmax ranged from 2-4 hours and Cmax and AUC values increased with increasing dose in a sub-linear fashion. AUC increased approximately 2-fold following either a low-fat or high-fat meal relative to the fasted state. Cmax was also increased in both fed states and Tmax and apparent half-life were not significantly changed.
CONCLUSIONS:
MPC-9055 had a favorable safety and pharmacokinetic profile following single dose administration to healthy volunteers. A multiple dose study in HIV infected individuals is planned.
*New data added to poster after abstract submission
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