The Association Between Genetic Polymorphisms of UGT1A1, ABCG2, and NR1I2 and Dolutegravir Pharmacokinetic Parameters in Thai People Living with HIV

<b>Background/Objectives</b>: Dolutegravir (DTG) is recommended as first-line treatment for Thai people living with HIV (PLWH). Real-world studies show high plasma concentration variability, which may increase neuropsychiatric adverse effects. This variability can be influenced by both genetic and nongenetic factors, but data for the Thai population are insufficient. We investigated factors associated with DTG pharmacokinetics in Thai PLWH. <b>Methods</b>: A cross-sectional analysis was conducted in Thai PLWH receiving a 50 mg DTG-based regimen. Intensive blood sampling was performed to determine DTG pharmacokinetic parameters using a non-compartmental analysis. Genotyping for <i>UGT1A1</i>, <i>ABCG2</i>, and <i>NR1I2</i> was performed. Univariable and multivariable linear regression analyses were used to identify factors associated with DTG pharmacokinetics. <b>Results</b>: A total of 104 Thai PLWH were included. Multivariable analysis demonstrated that both the <i>UGT1A1</i> poor metabolizer phenotype and body weight were independently associated with DTG exposure. After adjusting for body weight, the <i>UGT1A1</i> poor metabolizer phenotype was associated with increases of 5.18% in AUC_0-24 and 20.59% in C_trough. No significant association was found between the <i>ABCG2</i> 421 C>A polymorphism and DTG pharmacokinetic parameters. <b>Conclusions</b>: Body weight and the <i>UGT1A1</i> poor metabolizer phenotype significantly impacted DTG exposure in Thai PLWH. Those with the <i>UGT1A1</i> poor metabolizer, particularly with lower body weight, had significantly increased DTG exposures. These findings highlight that dose optimization may be worth exploring in selected individuals in this population.