Siobhn Hayes and Brian Sadler performed the analysis and prepared the manuscript. predictor of bioavailability. However, the magnitude of the effects of these covariates on steady-state dolutegravir plasma exposure was relatively small ( Harpagoside 32%) and was not considered clinically significant. Race/ethnicity, HBV/HCV co-infection, CDC classification, albumin, creatinine clearance, alanine aminotransferase or aspartate aminotransferase did not influence the pharmacokinetics of dolutegravir in this analysis. Conclusions Harpagoside A Harpagoside populace model that properly characterizes dolutegravir pharmacokinetics has been developed. No dolutegravir dose adjustment by patient covariates is necessary in HIV-infected treatment-naive patients. experiments suggest that DTG retains activity against viral strains harboring major integrase resistance mutations selected for by both raltegravir (RAL) and elvitegravir (EVG) [5], two previously approved integrase inhibitors. These findings have been confirmed in clinical studies demonstrating DTG’s activity in subjects with resistance to RAL [6]. The pharmacokinetics (PK) of DTG Harpagoside have been evaluated in both healthy and HIV-1 infected adult subjects. The primary objectives of evaluating DTG PK in healthy subjects were to understand the disposition of DTG after oral administration and to assess the effect of formulations, food, drugCdrug interactions and enzyme polymorphisms on DTG PK. Effects of intrinsic factors, including age, gender, body size, Rabbit Polyclonal to GRIN2B and race/ethnicity and extrinsic factors, including smoking, hepatitis B computer virus/hepatitis C computer virus (HBV/HCV) co-infection and disease status, were primarily evaluated in HIV-infected subjects using sparse PK samples collected in phase 2/3 trials and a populace PK modelling approach. Based on studies and phase 1 studies, DTG is usually highly bound (98.9%) to human plasma proteins, is eliminated primarily through hepatic metabolism with minimal renal excretion ( 1% of dose administered orally), is metabolized primarily through uridine diphosphate glucuronosyltransferase (UGT) 1A1 with some contribution from cytochrome P450 (CYP) 3A4, and is a substrate of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) [1,2]. DTG has exhibited low to moderate between subject and within subject PK variability. In phase 1 studies in healthy subjects, between-subject variability (%BSV) for area under the plasma concentrationCtime curve (AUC) and maximum plasma concentration (= 45): Week 2 at pre-dose, 2, 3, 4, 8 and 24 h post-dose; Week 12 and 24 at pre-dose and 2C4 h post-dose96 weeksLimited PK (= 96): Weeks 2, 12, and 24 at pre-dose and 2C4 h post-doseSPRING-2 (Phase 3)HIV-infected treatment-naive patients40350 mg DTG once daily with either ABC/3TC (600 mg/300 mg) or TDF/FTC (300 mg/200 mg) fixed-dose combination (FDC)Week 4: pre-dose and 1C3 h or 4C12 h post-dose;96 weeksWeek 24: pre-dose; Week 48: pre-dose and 1C3 h or 4C12 h post-dose Open in a separate windows ABC, abacavir; DTG, dolutegravir; FTC, emtricitabine; PK, pharmacokinetics; 3TC, lamivudine; TDF, tenofovir disoproxil fumarate. Study ING111521 was a phase 2a, multicentre, randomized, parallel, double-blind, dose-ranging, placebo-controlled study to compare antiviral effect, security, tolerability and PK of DTG monotherapy = 15 per DTG dose arm). Sparse PK samples at weeks 2, 12 and 24 were collected in most subjects receiving DTG. In Planting season-2, sparse PK samples at weeks 4, 24 and 48 were collected in most subjects receiving DTG. Bioanalytical methods Plasma samples were analyzed for DTG using a validated analytical method [9]. DTG was extracted from human plasma by protein precipitation using acetonitrile made up of [15 N 2H7]-DTG as an internal standard. Extracts were analyzed by liquid chromatographyCtandem mass spectroscopy using a TurboIonSpray? (AB Sciex, Framingham, MA, USA) interface with positive ion multiple reaction monitoring. The lower limit of the assay was 5 ng mlC1 or 20 ng mlC1 depending on the study, with a within- and between- run precision of.