Metabolism, Excretion, and Mass Balance of the HIV-1 Integrase Inhibitor Dolutegravir in Humans

Abstract

The pharmacokinetics, metabolism, and excretion of dolutegravir, an unboosted, once-daily human immunodeficiency virus type 1 integrase inhibitor, were studied in healthy male subjects following single oral administration of [ 14 C]dolutegravir at a dose of 20 mg (80 Ci). Dolutegravir was well tolerated, and absorption of dolutegravir from the suspension formulation was rapid (median time to peak concentration, 0.5 h), declining in a biphasic fashion. Dolutegravir and the radioactivity had similar terminal plasma half-lives (t 1/2 ) (15.6 versus 15.7 h), indicating metabolism was formation rate limited with no long-lived metabolites. Only minimal association with blood cellular components was noted with systemic radioactivity. Recovery was essentially complete (mean, 95.6%), with 64.0% and 31.6% of the dose recovered in feces and urine, respectively. Unchanged dolutegravir was the predominant circulating radioactive component in plasma and was consistent with minimal presystemic clearance. Dolutegravir was extensively metabolized. An inactive ether glucuronide, formed primarily via UGT1A1, was the principal biotransformation product at 18.9% of the dose excreted in urine and the principal metabolite in plasma. Two minor biotransformation pathways were oxidation by CYP3A4 (7.9% of the dose) and an oxidative defluorination and glutathione substitution (1.8% of the dose). No disproportionate human metabolites were observed.

Effect of Fosamprenavir-Ritonavir on the Pharmacokinetics of Dolutegravir in Healthy Subjects

“…These results were expected, given the induction potential of both APV and RTV on UGT1A1 and CYP3A4, the metabolic pathway of DTG (7,8). The effect of FPV-RTV observed in this study is consistent with the findings for another INI, RAL, which is also primarily metabolized by UGT1A1 and whose plasma exposure was reduced by FPV-RTV to a degree similar to that for DTG (11).…”

“…Dolutegravir is metabolized primarily via uridine 5=-diphosphoglucuronosyltransferase-1A1 (UGT1A1), although cytochrome P450 3A4 (CYP3A4) has a minor role (10% to 15%) in the process, and it is a substrate of the transport protein P-glycoprotein (7,8). Therefore, drugs that induce or inhibit these metabolic pathways may affect the plasma exposure of DTG.…”

“…Drugdrug interaction studies between ritonavir (RTV)-boosted protease inhibitors (i.e., tipranavir [TPV], darunavir, lopinavir, and atazanavir) and DTG have been conducted previously to evaluate changes in the plasma exposure to DTG. These studies have reported modest changes in DTG PK, and dosage adjustments are not required when administered with most commonly used RTVboosted protease inhibitors, except for TPV-RTV (4-6).Dolutegravir is metabolized primarily via uridine 5=-diphosphoglucuronosyltransferase-1A1 (UGT1A1), although cytochrome P450 3A4 (CYP3A4) has a minor role (10% to 15%) in the process, and it is a substrate of the transport protein P-glycoprotein (7,8). Therefore, drugs that induce or inhibit these metabolic pathways may affect the plasma exposure of DTG.…”

Effect of Prednisone on the Pharmacokinetics of the Integrase Inhibitor Dolutegravir

“…This is especially true for drugs for which CYP3A4 is only a minor route of elimination, as is the case for DTG, which is metabolized primarily through UGT1A1 (25). However, a thorough approach was taken to evaluate a potential drug interaction with a commonly used supportive treatment.…”

Use of Integrase Inhibitors in HIV-Infected Children and Adolescents

“…Dolutegravir is metabolized predominately by glucuronidation via UGT1A1, with minor contribution by CYP3A4, and has a limited range of drug interactions [80]. It neither induces nor inhibits CYP isoenzymes or UGT isoenzymes at relevant clinical doses or concentrations [81,82].…”