Evaluation of the Effect of UGT1A1 Polymorphisms on Dolutegravir Pharmacokinetics

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 (AUC_0-τ; 1.307 [1.125–1.518]) and C_max (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.

KEYWORDS::

• dolutegravir
• HIV-1
• integrase inhibitor
• pharmacogenetic
• pharmacokinetic
• UGT1A1

Acknowledgements

The authors wish to acknowledge the following individuals: our GlaxoSmithKline colleagues, M Mosteller and L Drewett for their support of this work.

Financial & competing interests disclosure

Funding for these studies was provided by ViiV Healthcare. All listed authors meet the criteria for authorship set forth by the International Committee for Medical Journal Editors. S Chen, P St Jean, J Borland, I Song, AJ Yeo, S Piscitelli and JP Rubio are employees of GlaxoSmithKline and own stock in GlaxoSmithKline. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

The authors also wish to acknowledge the following individuals for writing assistance during the development of this manuscript: J Rossi and P Farmer (MedThink SciCom). Funding for this writing assistance was provided by ViiV Healthcare.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

Funding for these studies was provided by ViiV Healthcare. All listed authors meet the criteria for authorship set forth by the International Committee for Medical Journal Editors. S Chen, P St Jean, J Borland, I Song, AJ Yeo, S Piscitelli and JP Rubio are employees of GlaxoSmithKline and own stock in GlaxoSmithKline. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.