Evaluation of the effect of UGT1A1 polymorphisms on dolutegravir pharmacokinetics

Author:

Chen Shuguang1,St Jean Pamela1,Borland Julie1,Song Ivy1,Yeo Astrid J2,Piscitelli Stephen1,Rubio Justin P3

Affiliation:

1. GlaxoSmithKline, Research Triangle Park, NC, USA

2. GlaxoSmithKline, Stevenage, Hertfordshire, UK

3. GlaxoSmithKline, Stevenage, Hertfordshire, UK.

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.

Publisher

Future Medicine Ltd

Subject

Pharmacology,Genetics,Molecular Medicine

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