title: Pharmacokinetic determinants of virological response to raltegravir in the in vitro pharmacodynamic hollow-fiber infection model system.
abstract: Daily administration (q24h) of raltegravir has been shown to be as efficacious as twice-daily administration (q12h) in the hollow-fiber infection model (HFIM) system. However, q24h regimens were not noninferior to q12h dosing in a clinical trial. We hypothesized that between-patient variability in raltegravir pharmacokinetics (PK) was responsible for the discordance in conclusions between the in vitro and in vivo studies. Hollow-fiber cartridges were inoculated with HIV-infected H9 cells and uninfected CEM-SS cells. Four cartridges received the total daily exposure (800 mg) q24h and four received half the daily exposure (400 mg) q12h. PK profiles with half-lives of 8, 4, 3, and 2 h were simulated for each dosing interval. Cell-to-cell viral spread was assessed by flow cytometry. Viral inhibition was similar between q24h and q12h dosing at the 8- and 4-h half-lives. The q24h dosing was not as efficacious as the q12h dosing when faster half-lives were simulated; a lack of viral suppression was observed at days 3 and 4 for the 2- and 3-h half-lives, respectively. The discrepancy in conclusions between the in vitro HFIM system studies and clinical trials is likely due to the large interindividual variation in raltegravir PK.
authors: Institute for Therapeutic Innovation, Department of Medicine, University of Florida, Orlando, Florida, USA Ashley.Brown@medicine.ufl.edu.
authors: Ashley N
authors: AN
authors: Brown
authors: Institute for Therapeutic Innovation, Department of Medicine, University of Florida, Orlando, Florida, USA.
authors: Jonathan R
authors: JR
authors: Adams
authors: Institute for Therapeutic Innovation, Department of Medicine, University of Florida, Orlando, Florida, USA.
authors: Dodge L
authors: DL
authors: Baluya
authors: Institute for Therapeutic Innovation, Department of Medicine, University of Florida, Orlando, Florida, USA.
authors: George L
authors: GL
authors: Drusano
mesh_terms: D019380:Anti-HIV Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D002460:Cell Line; D019583:Dose Fractionation, Radiation; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005434:Flow Cytometry; D057809:HEK293 Cells; D015658:HIV Infections / Q000188:drug therapy*; D019428:HIV Integrase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008954:Models, Biological; D010349:Patient Compliance; D000068898:Raltegravir Potassium / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology; D013601:T-Lymphocytes / Q000821:virology
chemical_list: D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D000068898:Raltegravir Potassium