Presentation Abstract

Session: 161-Clinical Pharmacology of Antiviral and Anti-Tuberculosis Agents
Tuesday, Sep 11, 2012, 11:15 AM - 1:15 PM
Presentation Title: A-1249 - Lack of Pharmacokinetic (PK) Interaction between Rilpivirine and the Integrase Inhibitors Dolutegravir and S/GSK1265744
Location: Halls A-C
Presentation Number: A-1249
Pres. Time: Tuesday, Sep 11, 2012, 11:15 AM - 1:15 PM
Category: A1
Keywords: Dolutegravir; S/GSK1265744; Rilpivirine
Author(s): S. L. Ford, Pharm.D. - Clin. Pharmacokineticist1, E. Gould, BS - Prin. Clin. Res. Sci. 1, S. Chen, PhD - Mgr. Stats. 1, D. Margolis, MD - Dir. Clin. Dev. 1, W. Spreen, PharmD - Med. Dev. Leader 1, H. Crauwels, PhD - Assoc. Dir. Clin. Pharm. 2, S. Piscitelli, PharmD - Dir. Clin. Dev. 1;
1GlaxoSmithKline, RTP, NC, 2Janssen R&D, Beerse, Belgium.
Financial Disclosures:  S. L. Ford,
GlaxoSmithKline Role(s): Employee.
E. Gould,
GlaxoSmithKline Role(s): Employee.
S. Chen,
GlaxoSmithKline Role(s): Employee.
D. Margolis,
GlaxoSmithKline Role(s): Employee.
W. Spreen,
GlaxoSmithKline Role(s): Employee.
H. Crauwels,
Janssen Infectious Diseases BVBA Role(s): Employee.
S. Piscitelli,
GlaxoSmithKline Role(s): Employee.
Abstract: Background: Dolutegravir (DTG) and S/GSK1265744 are HIV integrase inhibitors (INI) in clinical development. Rilpivirine (RPV, TMC278) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) approved for treatment-naïve HIV infection. Long-acting depot injections of S/GSK1265744 and RPV are also being developed. The combination of an INI and an NNRTI may be an attractive option as part of a 2- or 3-drug regimen for HIV infection. This study evaluated the potential PK interaction between RPV with DTG or with S/GSK1265744. Methods: This Phase I, open-label, two-cohort, single sequence crossover study evaluated the effects of oral co-administration of RPV with DTG or S/GSK1265744. Healthy subjects received either DTG 50mg q24h x 5days or S/GSK1265744 30mg q24h x 12days in Period 1 followed by a washout, RPV 25mg q24h x 11-12 days in Period 2, and RPV 25mg q24h + DTG 50mg q24h x 5days or S/GSK1265744 30mg q24h x 12days in Period 3. Doses were administered following a moderate fat meal. Serial PK sampling was performed on the last day of each Period. Plasma concentrations were determined by LC/MS/MS. PK parameters were estimated by non-compartmental methods. Geometric least squares mean ratios (GMR) and 90% confidence intervals (CIs) of PK parameters were determined for treatment comparisons. Results: The combinations of RPV + DTG and RPV + S/GSK1265744 were generally well-tolerated; no Grade 3-4 AEs were observed, and 1 subject discontinued for personal reasons prior to RPV + S/GSK1265744. Treatment comparisons are shown in Table 1. No significant changes in the PK parameters of any drug were observed. Conclusions: Lack of PK interactions between RPV and DTG or S/GSK1265744 supports co-administration of these agents orally or by long-acting depot injection.
Table 1. GMR (90% CI) for DTG, S/GSK1265744 and RPV Treatment Comparisons
PK ParameterAnalyte
DolutegravirS/GSK1265744Rilpivirine
DTG+RPV vs DTG alone
(n=16)
S/GSK1265744 + RPV vs S/GSK1265744 alone
(n=11)
DTG+RPV vs RPV alone
(n=16)
S/GSK1265744 + RPV vs RPV alone
(n=11)
AUC(0-τ)1.12
[1.05, 1.19]
1.12
[1.05, 1.19]
1.06
[0.976, 1.16]
0.987
[0.890, 1.09]
Cmax1.13
[1.06, 1.21]
1.05
[0.963, 1.15]
1.10
[0.992, 1.22]
0.963
[0.849, 1.09]
1.22
[1.15, 1.30]
1.14
[1.04, 1.24]
1.21
[1.07, 1.38]
0.919
[0.789, 1.07]




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