title: Evaluation of the effect of UGT1A1 polymorphisms on dolutegravir pharmacokinetics.
abstract: OBJECTIVE
  To evaluate potential pharmacogenetic effects of UGT1A1 polymorphisms on the pharmacokinetics (PK) of dolutegravir (Tivicay®; ViiV Healthcare, NC, USA), an HIV-1 integrase inhibitor.
  
  
  METHODS
  Analysis of pooled data from nine Phase I and II clinical studies was undertaken for 89 subjects receiving repeat dolutegravir 50 mg once daily (tablet formulation) who were genotyped for known UGT1A1 functional variants.
  
  
  RESULTS
  Geometric mean ratio (92% CI) for subjects carrying low (*28/*28 and *28/*37) and reduced activity (*1/*6, *1/*28, *1/*37, *28/*36 and *36/*37) polymorphisms compared with subjects with normal activity (*1/*1 and *1/*36) showed decreased oral clearance (CL/F; 0.765 [92% CI: 0.659-0.889]), increased area under the concentration-time curve (AUC(0-τ); 1.307 [1.125-1.518]) and C(max) (1.221 [1.063-1.402]), respectively.
  
  
  CONCLUSIONS
  Increased dolutegravir exposure in carriers of UGT1A1 reduced function polymorphisms is not clinically significant based on accumulated safety data so dose adjustment in these individuals is not required.
authors: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors: Shuguang
authors: S
authors: Chen
authors: Pamela
authors: P
authors: St Jean
authors: Julie
authors: J
authors: Borland
authors: Ivy
authors: I
authors: Song
authors: Astrid J
authors: AJ
authors: Yeo
authors: Stephen
authors: S
authors: Piscitelli
authors: Justin P
authors: JP
authors: Rubio
mesh_terms: D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics; D019427:HIV Integrase; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006801:Humans; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000099148:UGT1A1 Enzyme; D000099226:Dolutegravir
chemical_list: D014453:Glucuronosyltransferase; D019427:HIV Integrase; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000099148:UGT1A1 Enzyme; D000099226:Dolutegravir; C514801:p31 integrase protein, Human immunodeficiency virus 1