13th Conference on Retroviruses and Opportunistic Infections Denver, Colorado - February 5-8, 2006

Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 52

Patrick Smith¹, A Forrest¹, G Beatty², J Jacobson³, J Lalezari⁴, J Eron⁵, R Pollard⁶, M Saag⁷, J Doto⁸, and D Martin^8
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 (E_max) 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 E_max 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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2006-02-05
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