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Evaluation of Antacid and Multivitamin (MVI) Effects on S/GSK1349572 Pharmacokinetics (PK) in Healthy Subjects
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Reported by Jules Levin
ICAAC Sept 11-15 2009
San Francisco
I. SONG1, A. PATEL, S. MIN1, Y. LOU1, S. CHEN1, P. PATEL1, T. WAJIMA2, S. PISCITELLI1
1GlaxoSmithKline, RTP, NC, USA; 2Shionogi & Co., Ltd., Osaka, Japan
ABSTRACT
Background: S/GSK1349572 is an unboosted once daily integrase inhibitor (INI) with a novel resistance profile that is currently in Phase 2 clinical trials. Previous studies have shown antacids may reduce INI exposure by binding to metal cations. The objectives of this study were to evaluate the effect of metal-cation-containing products (antacid and MVI) on the PK of S/GSK1349572 and to determine a dose separation strategy if necessary.
Methods: This was an open-label, randomized, 4-period cross-over study in
healthy subjects. S/GSK1349572 was administered as a single 50mg dose
either alone, with One A Day Maximum multivitamin, concomitantly with Maalox Maximum Strength 20mL, or 2 hours prior to Maalox Maximum Strength 20mL. There was a washout period of at least 7 days between treatments. Safety evaluations were performed throughout the study and serial PK samples were collected at each treatment. Noncompartmental PK analysis was performed and geometric least squares mean ratios (GLS-MR) and 90% confidence intervals (CI) were generated by the mixed effect model for within-subject treatment comparison.
Results: Sixteen subjects completed all periods and follow-up. Treatments were generally well tolerated with few adverse events and no SAEs reported. No clinically significant lab, vital sign or ECG abnormalities were noted. Treatment comparisons vs S/GSK1349572 given alone are presented.
Conclusions: The modest reductions in S/GSK1349572 exposure with MVI and antacid separated by 2 hours are not considered clinically significant. S/GSK1349572 may be taken concomitantly with multivitamins and should be taken 2 hours before or 6 hours after antacid intake.
This was an open label, randomized, 4-period crossover study.
A total of 16 healthy subjects (male or female between 18 and 65 years of
age) were planned to be enrolled.
Subjects were to participate a screening evaluation and 4 dosing sessions
(sessions were separated by at least 7 days), and a follow-up visit
conducted within 7-14 days after the last dose of study drug.
All doses were administered in the fasting state.
The protocol was reviewed by an independent ethics committee and all
subjects gave written informed consent.
One A Day Maximum, a multi-vitamin supplement, contains the most metal cations (including iron, magnesium, zinc, and copper) compared to other widely used multi-vitamin supplements, and therefore was selected in this study.
Maalox Advanced Maximum Strength contains the most metal cations (including magnesium and aluminum) compared to other widely used antacids, and therefore was selected in this study.
Safety assessments were conduct throughout the study.
Serial PK samples were collected in each treatment period and analyzed to
determine plasma concentration of S/GSK1349572 by validated LC/MS/MS
method.
Non-compartmental PK analysis was performed based on plasma concentration-time data of S/GSK1349572 . Analysis of variance (ANOVA)
was performed using mixed effect model to assess the effect of antacid and MVI on S/GSK1349572 PK. Geometric least squares mean ratios (GMR) and 90% confidence intervals (CI) for each PK parameter were generated.
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