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Pharmacokinetic (PK) and pharmacodynamic (PD) relationship of S/GSK1349572, a next generation integrase inhibitor (INI), in HIV-1 infected patients
I. Song1, S. Chen1, Y. Lou1, J. Borland1, T. Fujiwara2, S. Piscitelli1, S. Min1
1GlaxoSmithKline, Research Triangle Park, United States, 2Shionogi & Co., Ltd., Osaka, Japan
Background: S/GSK1349572 is a novel HIV integrase strand transfer inhibitor that demonstrated PK supporting once daily dosing and good tolerability in healthy subjects. A dose ranging, placebo controlled 10-day monotherapy study showed unprecedented antiviral activity of S/GSK1349572 in HIV-1 infected subjects.
Methods: 35 subjects were randomized to doses of 2mg, 10mg, 50mg, or placebo once daily for 10 days. Serial HIV-1 RNA and PK samples were collected during the study. S/GSK1349572 concentrations were analyzed using a validated LC/MS/MS assay. PK parameters were calculated by non-compartmental methods. Relationship between PK (AUCτ, Cmax, and Cτ) and PD measures (changes in HIV-1 RNA) was assessed using various Emax and linear models. Model selection was based on Akaike Information Criteria value and F-test.
Results: Day10 PK parameters, geometric mean (CV%), and mean change of HIV-1 RNA from baseline to Day 11 are presented.
| | AUCτ
ug*h/mL | Cmax
ug/mL | Cτ
ug/mL | IQ | ΔLog10 HIV-1 RNA | | 2mg QD (n=9) | 2.56 (29%) | 0.22 (25%) | 0.04 (50%) | 0.6 | -1.51 | | 10mg QD (n=7) | 10.1 (20%) | 0.80 (23%) | 0.19 (25%) | 3 | -2.03* | | 50mg QD (n=10) | 43.4 (20%) | 3.34 (16%) | 0.83 (26%) | 13 | -2.46 |
IQ=Cτ/protein-adjusted EC90 [0.064 ug/mL]; *n=9.
S/GSK1349572 demonstrated low variability and time-invariant PK; steady state was achieved by 7 days of dosing, consistent with the kown half-life (~14hours). Greater antiviral activity was associated with higher S/GSK1349572 plasma exposure. Cτ was the PK parameter that best predicted antiviral activity. The relationship between Cτ and reduction in log10 plasma HIV-1 RNA from baseline to Day 11 was best described by a simple Emax model with Emax = -2.6log10 and EC50 = 0.036 ug/mL (p< 0.0001).
Conclusions: S/GSK1349572 demonstrated low PK variability and a clear, predictable, and well characterized exposure-activity relationship, with antiviral efficacy primarily driven by Cτ. These attributes distinguish S/GSK1349572 from raltegravir.
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