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Pharmacokinetics/Pharmacodynamics of PA-457 in a 10-day Multiple Dose Monotherapy Trial in HIV-infected Patients
Patrick Smith*1, A Forrest1, G Beatty2, J Jacobson3, J Lalezari4, J Eron5, R Pollard6, M Saag7, J Doto8, and D Martin8
1Univ at Buffalo Sch of Pharm, NY, US; 2Univ of California, San Francisco, US; 3Beth Israel Med Ctr, New York, NY, US; 4Quest Clin, San Francisco, CA, US; 5Univ of North Carolina at Chapel Hill, US; 6Univ of California, Davis, US; 7Univ of Alabama at Birmingham, US; and 8Panacos Pharma, Gaithersburg, MD, US
Background: PA-457 is the first in a new class of
anti-HIV compounds that inhibit viral maturation by blocking cleavage of
CA-SP1. Our purpose was to characterize the pharmacokinetics/pharmacodynamics of
PA-457 when administered as monotherapy to HIV-infected subjects in a phase II trial.
Methods: A total of 32 HIV-infected adults received 10
days of placebo or oral PA-457 once daily at 25, 50, 100, or 200 mg. A loading
dose (double the maintenance dose) was administered on day 1 in all but the 200-mg
cohort. Plasma viral load and drug concentrations were determined frequently for
21 days. Drug concentrations were assayed by a validated LC/MS/MS method; pharmacokinetic
parameters were determined by standard noncompartmental
methods. Linear and nonlinear regression was used to evaluate the relationship
between antiviral effect and PA-457 drug exposure.
Results: PA-457 was generally well tolerated. Consistent
with previous studies, PA-457 exhibited linear pharmacokinetics, with a long
mean (CV%) half-life of 62.7 (19%) hours. The mean (CV%) oral clearance was 0.21 (28) L/h. Compared to baseline
values, the median (range) Log10 reduction in viral load on day 11 was
0.046 (–0.505, 0.149), –0.174 (–0.589, 0.048), –0.483 (–0.874, 0.295), and –1.05 (–1.62,
–0.071) for the 25-, 50-, 100-, and 200-mg doses, respectively. Both AUC and
trough concentrations were highly associated with antiviral response (p <0.01 for each), with greater
activity observed with increasing drug exposure. Based on the study design, AUC
and trough concentrations were highly correlated (r2 = 0.99), and could not be differentiated as
predictors of response. The maximum antiviral effect (Emax)
for PA-457 was not observable at the highest dose level.
Conclusions:
PA-457 demonstrated significant antiviral
activity at the higher dose levels, with greater activity observed with
increasing drug exposure. Additional antiviral activity is likely with doses
higher than those used in this trial, as Emax
was not reached at 200 mg. Similar to other available ART,
pharmacokinetics/pharmacodynamics appears to be an
important determinant of PA-457 activity. Additional studies to evaluate the
potential role of PA-457 in the treatment of HIV-infection are warranted.
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