title: Drug interaction profile for GSK2248761, a next generation non-nucleoside reverse transcriptase inhibitor.
abstract: OBJECTIVE
  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.affiliation: Infectious Diseases MDC, GlaxoSmithKline, Research Triangle Park, NC 27709, USA. stephen.c.piscitelli@gsk.com
authors.forename: Steve
authors.initials: S
authors.lastname: Piscitelli
authors.forename: Joseph
authors.initials: J
authors.lastname: Kim
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Gould
authors.forename: Yu
authors.initials: Y
authors.lastname: Lou
authors.forename: Scott
authors.initials: S
authors.lastname: White
authors.forename: Mark
authors.initials: M
authors.lastname: de Serres
authors.forename: Mark
authors.initials: M
authors.lastname: Johnson
authors.forename: Xiao-Jian
authors.initials: XJ
authors.lastname: Zhou
authors.forename: Keith
authors.initials: K
authors.lastname: Pietropaolo
authors.forename: Douglas
authors.initials: D
authors.lastname: Mayers
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D000736:Androstenes / Q000008:administration & dosage / Q000493:pharmacokinetics; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000069446:Atazanavir Sulfate; D000069059:Atorvastatin; D003276:Contraceptives, Oral / Q000008:administration & dosage / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D000069454:Darunavir; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D004311:Double-Blind Method; D004338:Drug Combinations; D004347:Drug Interactions; D000068679:Emtricitabine; D004997:Ethinyl Estradiol / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D005464:Fluorobenzenes / Q000008:administration & dosage / Q000493:pharmacokinetics; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D007211:Indoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016018:Least-Squares Analysis; D016014:Linear Models; D061466:Lopinavir / Q000008:administration & dosage / Q000493:pharmacokinetics; D008297:Male; D009842:Oligopeptides / Q000008:administration & dosage / Q000493:pharmacokinetics; D063065:Organophosphonates / Q000008:administration & dosage / Q000493:pharmacokinetics; D061214:Patient Safety; D010721:Phosphinic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics; D011758:Pyrroles / Q000008:administration & dosage / Q000493:pharmacokinetics; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000493:pharmacokinetics; D000068898:Raltegravir Potassium; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018570:Risk Assessment; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics; D000068718:Rosuvastatin Calcium; D019821:Simvastatin / Q000008:administration & dosage / Q000493:pharmacokinetics; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics; D000068698:Tenofovir
chemical_list: D000736:Androstenes; D019380:Anti-HIV Agents; D003276:Contraceptives, Oral; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D004338:Drug Combinations; D005464:Fluorobenzenes; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C534138:IDX 899; D007211:Indoles; D009842:Oligopeptides; D063065:Organophosphonates; D010721:Phosphinic Acids; D011725:Pyridines; D011743:Pyrimidines; D011758:Pyrroles; D011760:Pyrrolidinones; D018894:Reverse Transcriptase Inhibitors; D013449:Sulfonamides; C534342:drospirenone and ethinyl estradiol combination; C558899:lopinavir-ritonavir drug combination; D003841:Deoxycytidine; D061466:Lopinavir; D004997:Ethinyl Estradiol; D000068898:Raltegravir Potassium; D000069446:Atazanavir Sulfate; D000068718:Rosuvastatin Calcium; D000068698:Tenofovir; D000069059:Atorvastatin; D019821:Simvastatin; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000068679:Emtricitabine; D000225:Adenine; D019438:Ritonavir; D000069454:Darunavir