Drug interaction profile for GSK2248761, a next generation non-nucleoside reverse transcriptase inhibitor.

Abstract

AIM:

To evaluate potential drug interactions with antiretroviral therapies or supportive therapies for use in conjunction with the once daily, next generation non-nucleoside reverse transcriptase inhibitor GSK2248761 in patients with HIV-1 infection.

METHODS:

A series of phase I drug interaction studies was conducted.

RESULTS:

GSK2248761 was shown to be a weak CYP3A4 and CYP2D6 inhibitor in a clinical study with a probe cocktail. Mean plasma concentration-time profiles for atazanavir, tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), darunavir (DRV, administered with ritonavir [RTV]), and drospirenone/ethinylestradiol were similar following co-administration of GSK2248761. Plasma raltegravir AUC(0,τ) and C(max) increased by 18% with no change in Cτ when raltegravir was co-administered with GSK2248761. Lopinavir (LPV) plasma AUC(0,τ), C(max) and Cτ decreased by 23%, 14% and 40%, respectively, following administration of lopinavir/ritonavir with GSK2248761. Atorvastatin, rosuvastatin and simvastatin AUC(0,∞) and C(max) increased following co-administration with GSK2248761, with the largest changes observed for simvastatin (3.7-fold and 4.3-fold). Changes in maximum and extent of GSK2248761 exposure were marginal after co-administration with atazanavir, TDF/FTC and raltegravir compared with GSK2248761 administered alone. Co-administration of GSK2248761 with DRV/RTV and LPV/RTV increased plasma GSK2248761 exposures by 1.25- to ≤2-fold compared with GSK2248761 administered alone, and increases in GSK2248761 exposure were higher following single dose co-administration of DRV/RTV or LPV/RTV compared with multiple doses. There were few drug-related AEs, and no treatment-related trends in blood chemistry, haematology, urinalysis, vital signs or ECG findings.

CONCLUSIONS:

These studies indicate that GSK2248761 was safe and well tolerated in healthy adults treated in these studies at the doses and duration of therapy evaluated.

• Authors: Steve Piscitelli, Joseph Kim, Elizabeth Gould, Yu Lou, Scott White, Mark de Serres, Mark Johnson, Xiao-Jian Zhou, Keith Pietropaolo, Douglas Mayers
• Journal: British journal of clinical pharmacology (Br J Clin Pharmacol) Vol. 74 Issue 2 Pg. 336-45 (Aug 2012) ISSN: 1365-2125 [Electronic] England
• PMID: 22288567 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 ViiV Healthcare. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Chemical References

• Androstenes
• Anti-HIV Agents
• Contraceptives, Oral
• Cytochrome P-450 CYP2D6 Inhibitors
• Cytochrome P-450 CYP3A Inhibitors
• Drug Combinations
• Fluorobenzenes
• Heptanoic Acids
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• IDX 899
• Indoles
• Oligopeptides
• Organophosphonates
• Phosphinic Acids
• Pyridines
• Pyrimidines
• Pyrroles
• Pyrrolidinones
• Reverse Transcriptase Inhibitors
• Sulfonamides
• drospirenone and ethinyl estradiol combination
• lopinavir-ritonavir drug combination
• Deoxycytidine
• Lopinavir
• Ethinyl Estradiol
• Raltegravir Potassium
• Atazanavir Sulfate
• Rosuvastatin Calcium
• Tenofovir
• Atorvastatin
• Simvastatin
• Cytochrome P-450 CYP2D6
• Cytochrome P-450 CYP3A
• CYP3A4 protein, human
• Emtricitabine
• Adenine
• Ritonavir
• Darunavir

Topics

• Adenine (administration & dosage, analogs & derivatives, pharmacokinetics)
• Androstenes (administration & dosage, pharmacokinetics)
• Anti-HIV Agents (administration & dosage, pharmacokinetics)
• Atazanavir Sulfate
• Atorvastatin
• Contraceptives, Oral (administration & dosage, pharmacokinetics)
• Cross-Over Studies
• Cytochrome P-450 CYP2D6 (metabolism)
• Cytochrome P-450 CYP2D6 Inhibitors
• Cytochrome P-450 CYP3A (metabolism)
• Cytochrome P-450 CYP3A Inhibitors
• Darunavir
• Deoxycytidine (administration & dosage, analogs & derivatives, pharmacokinetics)
• Double-Blind Method
• Drug Combinations
• Drug Interactions
• Emtricitabine
• Ethinyl Estradiol (administration & dosage, pharmacokinetics)
• Female
• Fluorobenzenes (administration & dosage, pharmacokinetics)
• Heptanoic Acids (administration & dosage, pharmacokinetics)
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (administration & dosage, pharmacokinetics)
• Indoles (administration & dosage, pharmacokinetics)
• Least-Squares Analysis
• Linear Models
• Lopinavir (administration & dosage, pharmacokinetics)
• Male
• Oligopeptides (administration & dosage, pharmacokinetics)
• Organophosphonates (administration & dosage, pharmacokinetics)
• Patient Safety
• Phosphinic Acids (administration & dosage, pharmacokinetics)
• Pyridines (administration & dosage, pharmacokinetics)
• Pyrimidines (administration & dosage, pharmacokinetics)
• Pyrroles (administration & dosage, pharmacokinetics)
• Pyrrolidinones (administration & dosage, pharmacokinetics)
• Raltegravir Potassium
• Reverse Transcriptase Inhibitors (administration & dosage, pharmacokinetics)
• Risk Assessment
• Ritonavir (administration & dosage, pharmacokinetics)
• Rosuvastatin Calcium
• Simvastatin (administration & dosage, pharmacokinetics)
• Sulfonamides (administration & dosage, pharmacokinetics)
• Tenofovir