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SINGLE AND MULTIPLE DOSE DOLUTEGRAVIR PHARMACOKINETICS IN THE GENITAL TRACT AND COLORECTUM OF HIV NEGATIVE MEN AND WOMEN
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Reported by Jules Levin
CROI 2013
CROI: Distribution and Antiviral Activity in Cerebrospinal Fluid (CSF) of the Integrase Inhibitor, Dolutegravir (DTG): ING116070 Week 16 Results - (03/06/13)
CROI: Dolutegravir Treatment Response and Safety by Key Subgroups in Treatment Naive HIV Infected Individuals - (03/16/13)
CROI: Dolutegravir (DTG) Versus Raltegravir (RAL) in ART-Experienced, Integrase-Naive Subjects: 24-Week Interim Results From SAILING (ING111762) - (03/06/13)
BENJAMIN N GREENER1, JESSICA L ADAMS1, KRISTINE B PATTERSON2, HEATHER MA PRINCE2, CRAIG SYKES1, MAYA WAI1, JULIE B DUMOND1, NICHOLAS J SHAHEEN2, MYRON S COHEN2, ANGELA DM KASHUBA1,2 SCHOOLS OF PHARMACY1, AND MEDICINE2, UNC-CHAPEL HILL
ABSTRACT
Background: Antiretrovirals (ARV) that achieve adequate concentrations in anatomical sites of transmission such as the GT and colorectum are of great interest for HIV prevention. Two studies were performed to describe the PK of DTG, an HIV integrase inhibitor, in the female and male GT and male colorectum.
Methods: These phase 1, open label, PK studies enrolled 8 healthy women and 12 healthy men who took DTG 50mg daily for up to 8days. 11 blood plasma (BP) samples were collected over 24h following a single dose (PK1) and after multiple doses (PK2). In women, cervicovaginal fluid (CVF) was paired with BP and cervical (CT) and vaginal tissue (VT) biopsies were performed at 1 of 4 time points at each PK. The men collected 3 seminal fluid (SF) and rectal mucosal fluid (RF) samples per PK day and colorectal tissue (RT) biopsies were performed at 1 of 6 time points at each PK. Sparsely sampled matrices generated composite PK profiles. DTG concentrations were analyzed in all matrices by validated LC-MS/MS methods. Noncompartmental PK analysis was conducted using Phoenix WinNonlin v6.3. Spearman Rank Correlations were determined using SAS v9.3. Data are reported as median (IQR). AUC0-24h are reported as μg*h/mL (fluid) or μg*h/g (tissue). The studies are complete and all reported data are final.
Results: CVF AUCs for PK1 and PK2 were 2.60 (1.28-8.10) and 3.16 (2.81-5.22) representing 7.0 (5.0-18)% and 6.0 (4.0-11)% of BP exposures. CT AUC was 2.75 for PK1 and 5.30 for PK2. VT AUC was 2.73 for PK1 and 4.74 for PK2, each representing 7-10% of BP. CT and VT concentrations were correlated to each other (rho=0.70, p=0.003), and to CVF (rho=0.46, p=0.009). PK1 and PK2 SF AUC was 2.02 and 3.23(2.44-4.38), representing 6.6% and 6.8(5.5-9.7)% of BP exposure. RT AUCs for PK1 and PK2 were 5.28 and 7.60 representing 17% of BP. RF AUCs were 1.8-4.7% of RT and concentrations between RF and RT did not correlate (rho = 0.43, p=0.17).
Conclusions: DTG BP PK were consistent with previously published values. CVF and SF exposures were low compared to BP. Although protein binding was not measured, we have previously noted that it is lower in these secretions than BP. At PK2, 94% of female GT tissues, and 100% or RT concentrations were > the PA-IC90 (64 ng/mL). RF was not a strong surrogate for RT, but CVF may be a surrogate for CT and VT exposures.
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