Evaluation of the effect of UGT1A1 polymorphisms on dolutegravir pharmacokinetics

• Published in: Pharmacogenomics Vol. 15; no. 1; p. 9
• Main Authors: Chen, Shuguang, St Jean, Pamela, Borland, Julie, Song, Ivy, Yeo, Astrid J, Piscitelli, Stephen, Rubio, Justin P
• Format: Journal Article
• Language: English
• Published: England 01-01-2014
• Subjects: Genotype; Glucuronosyltransferase - genetics; Heterocyclic Compounds, 3-Ring - administration & dosage; Heterocyclic Compounds, 3-Ring - pharmacokinetics; HIV Infections - drug therapy; HIV Infections - genetics; HIV Integrase; HIV-1 - drug effects; HIV-1 - enzymology; Humans
• ISSN: 1744-8042
• DOI: 10.2217/pgs.13.190

To evaluate potential pharmacogenetic effects of UGT1A1 polymorphisms on the pharmacokinetics (PK) of dolutegravir (Tivicay®; ViiV Healthcare, NC, USA), an HIV-1 integrase inhibitor.
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.
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.
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.