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Pharmacokinetic (PK) and Pharmacodynamic (PD) Relationship of S/GSK1349572, a Next Generation Integrase Inhibitor (INI), in HIV-1 Infected Patients
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Reported by Jules Levin
5th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, South Africa, July 19-22, 2009
Sherene Min, Ivy Song, Julie Borland, Shuguang Chen,
Yu Lou, Tamio Fujiwara, Stephen Piscitelli1, Sherene Min1
1GlaxoSmithKline, RTP, NC, USA; 2Shionogi & Co., Ltd., Osaka, Japan
Author Conclusions
S/GSK1349572 demonstrated low PK variability and a clear, predictable, and well characterized exposure-response relationship.
Antiviral activity for INIs is exposure driven.
S/GSK1349572 achieved greater antiviral activity than RAL and ELV after 10-day<
monotherapy.
The PK parameter that best predicts S/GSK1349572 efficacy is Cτ; therefore achieving a high IQ will lead to successful clinical outcomes.
AUTHOR DISCUSSION
The pooled data from S/GSK1349572 and ELV in 10-day monotherapy shows a PK-PD relationship for the integrase inhibitors as a group, in that higher exposure drives higher antiviral activity.
IQ (calculated by Cτ/PA-IC90) is a good predictor of antiviral activity (in short-term monotherapy) for S/GSK1349572.
S/GSK1349572 50mg QD demonstrated unprecedented antiviral activity, attributable to superior IQ achieved.
RAL failed to show PK-PD relationship in 10-day monotherapy due to the narrow dose range studied and unpredictable PK.
In contrast, the Phase 2a study of S/GSK1349572 studied a wide dose range, allowing in-depth understanding of the PK-PD relationship.
The clear PK-PD relationship observed for S/GSK1349572 empowers integrated drug-disease modeling and dose selection in currently on-going Phase 2B clinical trials across different patient populations and the confidence in chronic dosing of S/GSK1349572 in HIV-infected patients.
ABSTRACT
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.
S/GSK1349572 demonstrated low variability and time-invariant PK; steady state was achieved by 7 days of dosing, consistent with the known 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 µg/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.
Introduction
The long-standing Shionogi-GSK Joint Venture has made considerable progress in developing next-generation integrase inhibitors.
S/GSK1349572 is the only once-daily, unboosted integrase inhibitor currently in development with unprecedented antiviral activity and a superior resistance profile.1,2,3
To date, the PK-PD relationship for INI has not been well characterized. There has been a lack of PK-PD relationship demonstrated for raltegravir (RAL); this can largely be attributed to high RAL PK variability.4,5
Elvitegravir (ELV), another INI currently in Phase III clinical development has demonstrated exposure-dependent antiviral activity.6
S/GSK1349572 demonstrated low PK variability which provides a good foundation for understanding the PK-PD relationship of this drug, and can also be applied to better understanding the class.7
A dose ranging, placebo-controlled 10-day monotherapy study of S/GSK1349572 in HIV-1 infected subjects showed a mean 2.5 log decrease from baseline in plasma HIV RNA with the 50mg dose, and a clear dose-response relationship.1
The design and dose selection of this study provided data to better understand the PK-PD relationship of this compound and provide inference across all INIs.
METHODS
35 subjects were randomized to doses of 2mg, 10mg, 50mg, or placebo once daily (QD) 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.
S/GSK1349572 PK parameters were calculated by non-compartmental methods. Relationship between PK 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.
PK measures: AUCτ, Cmax, and C τ on Day 10
- PD measures: reduction in log10 plasma HIV-1 RNA on Day 11 from baseline (pre-dose on Day1), reduction in log10 plasma HIV-1 RNA from baseline to the on treatment nadir.
- Log-linear models: PD = a + b*log10(PK)
- Sigmoid Emax models:
where PK measure is either original or log-transformed; Emax was either estimated or fixed to 2.6, 2.7, or 2.8 to help model converge. γ was either estimated or fixed to 1.
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