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More on Dolutegravir at ICAAC 2013: Pharmacokinetics

Dolutegravir (DTG), an integrase strand transfer inhibitor, is he newest addition to the antiretroviral therapeutic armamentarium. In additional to new clinical trials (see the report “New Studies of Dolutegravir at ICAAC 2013”), new data on the pharmacokinetics (PK) of DTG were also presented. DTG is hepatically metabolized, primarily by UGT1A1 to DTG-glucuronide, and to a lesser extent by CYP3A. DTG-glucuronide is renally excreted. Single dose DTG PK studies were conducted in patients with creatinine clearance <30 mL/min and in healthy volunteers [1]. Exposure (AUC) to DTG was 40% lower and DTG-glucuronide 4.3-fold higher in renally-impaired subjects, but these changes were deemed not clinically significant. The authors concluded no DTG dose modification is needed in renal failure. This conclusion was supported by a pharmacodynamic analysis presented in another abstract [2] which showed these lower plasma levels of DTG were still associated with optimal responses in integrase inhibitor-naive patients. The authors cautioned that the reductions in DTG exposure seen in renal failure may be clinically significant in patients with integrase resistance mutations who require high dose DTG. It should also be noted that the safety of chronic exposure to the much higher levels of DTG-glucuronide seen in renal insufficiency was not established by the study.

DTG is being developed in co-formulation with abacavir (ABC) and lamivudine (3TC) to be used as a once daily single tablet regimen (STR) for treatment-naive patients. A PK study conducted in 66 healthy volunteers [3] demonstrated an investigational fixed-dose combination of DTG 50 mg/ABC 600 mg/3TC 300 mg produced similar component plasma levels to the approved formation of DTG alone and the fixed-dose combination of ABC/3TC, fulfilling the standard criteria for bioequivalence. Administration of a high fat meal increased DTG AUC 48%, but administration with food was not judged to be necessary for the optimal activity of DTG or the STR.

1. Weller S, Borland J, Chen S, et al. Pharmacokinetics (PK) and Safety of Dolutegravir (DTG) in Subjects with Severe Renal Impairment and Healthy Controls. 53rd ICAAC, Denver CO, Sept 10-13, 2013, Abstract-A1571.
2. Song I, Chen S, Piscitelli S, Min S. Pharmacokinetics (PK) and PI-Pharmacodynamic (PD) Relationship of Dolutegravir (DTG) in Integrase Inhibitor (INI)-Naive Subjects. 53rd ICAAC, Denver CO, Sept 10-13, 2013, Abstract A-1573.
3. Weller S, Chen S, Borland, et al. Bioequivalence of a Dolutegravir, Abacavir and Lamivudine Fixed-Dose Combination Tablet and the Effect of Food. 53rd ICAAC, Denver CO, Sept 10-13, 2013, Abstract A-1572.

Source: Reporting from Denver for the PRN News: David H Shepp, MD