Evaluation of the effect of UGT1A1 polymorphisms on dolutegravir pharmacokinetics. (January 2014)

• Record Type: Journal Article
• Authors: Chen, Shuguang; St Jean, Pamela; Borland, Julie; Song, Ivy; Yeo, Astrid J; Piscitelli, Stephen; Rubio, Justin P
• Is Part Of: Pharmacogenomics. Volume 15:Number 1(2014)
• Page Start: 9
• Page End: 16
• Publication Date: 2014-01
• Subjects: dolutegravir -- HIV-1 -- integrase inhibitor -- pharmacogenetic -- pharmacokinetic -- UGT1A1; Pharmacogenomics -- Periodicals; 615.1
• DOI: 10.2217/pgs.13.190
• Languages: English
• ISSNs: 1462-2416

Abstract

Aim: To evaluate potential pharmacogenetic effects of UGT1A1 polymorphisms on the pharmacokinetics (PK) of dolutegravir (Tivicay ® ; ViiV Healthcare, NC, USA), an HIV-1 integrase inhibitor.Patients & 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 (AUC0-τ ; 1.307 [1.125–1.518]) and Cmax (1.221 [1.063–1.402]), respectively.Conclusion: 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.