title: Population pharmacokinetics of dolutegravir in HIV-infected treatment-naive patients.
abstract: OBJECTIVE
  Dolutegravir is the newest integrase inhibitor approved for HIV treatment and has demonstrated potent antiviral activity in patient populations with a broad range of treatment experience. This analysis aimed to characterize the population pharmacokinetics of dolutegravir in treatment-naive patients and to evaluate the influence of patient covariates.
  
  
  METHODS
  A population pharmacokinetic model was developed using a non-linear mixed effect modelling approach based on data from 563 HIV-infected, treatment-naive adult patients in three phase 2/3 trials who received dolutegravir (ranging from 10-50 mg once daily) alone or in combination with abacavir/lamivudine or tenofovir/emtricitabine.
  
  
  RESULTS
  The pharmacokinetics of dolutegravir were adequately described by a linear one compartment model with first order absorption, absorption lag time and first order elimination. Population estimates for apparent clearance, apparent volume of distribution, absorption rate constant and absorption lag time were 0.901 l h(-1) , 17.4 l, 2.24 h(-1) , and 0.263 h, respectively. Weight, smoking status, age and total bilirubin were predictors of clearance, weight was a predictor of volume of distribution and gender was a predictor of bioavailability. However, the magnitude of the effects of these covariates on steady-state dolutegravir plasma exposure was relatively small (<32%) and was not considered clinically significant. Race/ethnicity, HBV/HCV co-infection, CDC classification, albumin, creatinine clearance, alanine aminotransferase or aspartate aminotransferase did not influence the pharmacokinetics of dolutegravir in this analysis.
  
  
  CONCLUSIONS
  A population model that adequately characterizes dolutegravir pharmacokinetics has been developed. No dolutegravir dose adjustment by patient covariates is necessary in HIV-infected treatment-naive patients.
authors.affiliation: Clinical Pharmacology, GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhang
authors.affiliation: ICON, Marlow, UK.
authors.forename: Siobhán
authors.initials: S
authors.lastname: Hayes
authors.affiliation: ICON, Marlow, UK.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Sadler
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Ilisse
authors.initials: I
authors.lastname: Minto
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Brandt
authors.affiliation: Clinical Pharmacology, GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Piscitelli
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Sherene
authors.initials: S
authors.lastname: Min
authors.affiliation: Clinical Pharmacology, GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Ivy H
authors.initials: IH
authors.lastname: Song
mesh_terms: D000328:Adult; D019540:Area Under Curve; D003198:Computer Simulation; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy*; D019428:HIV Integrase Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D064368:Healthy Volunteers; D006575:Heterocyclic Compounds, 3-Ring / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D008954:Models, Biological; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D016032:Randomized Controlled Trials as Topic; D000099226:Dolutegravir
chemical_list: D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000099226:Dolutegravir
keywords: dolutegravir; integrase inhibitor; population pharmacokinetics; treatment-naive
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