Skip Navigation LinksHome > September 1, 2013 - Volume 64 - Issue 1 > Dolutegravir Pharmacokinetics in the Genital Tract and Color...
JAIDS Journal of Acquired Immune Deficiency Syndromes:
doi: 10.1097/QAI.0b013e31829ed7a4
Clinical Science

Dolutegravir Pharmacokinetics in the Genital Tract and Colorectum of HIV-Negative Men After Single and Multiple Dosing

Greener, Benjamin N. PharmD, MS*; Patterson, Kristine B. MD; Prince, Heather M. A. PA-C; Sykes, Craig S. MS*; Adams, Jessica L. PharmD*; Dumond, Julie B. PharmD, MS*; Shaheen, Nicholas J. MD; Madanick, Ryan D. MD; Dellon, Evan S. MD; Cohen, Myron S. MD; Kashuba, Angela D. M. BScPhm, PharmD, DABCP*,†

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Abstract

Objectives: To describe first-dose and steady state pharmacokinetics (PKs) of dolutegravir (DTG) in blood plasma (BP), seminal fluid (SF), colorectal tissue (RT), and rectal mucosal fluid (RF) of healthy HIV-negative men.

Design: A phase 1, open-label, PK study that enrolled 12 healthy men taking 50 mg DTG daily for 8 days.

Methods: Eleven paired BP samples and 3 SF and RF samples were collected over 24 hours after first (PK1) and multiple (PK2) dosing. RT biopsies were collected at 1 of 6 time points at PK1 and PK2 to generate composite PK profiles. DTG concentrations were analyzed by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS). Noncompartmental PK analysis was conducted with Phoenix WinNonlin v6.3, and Spearman rank correlations were determined using SAS v9.3.

Results: BP area under the concentration–time curves (AUCs) were similar to previous reports, and concentrations at 24 hours (C24 h) were 6- to 34-fold greater than the protein-adjusted concentration required for 90% viral inhibition (PA-IC90) of 64 ng/mL. SF exposures were <7% of BP and below the PA-IC90. RT exposures were 17% of BP and ∼2-fold greater than the PA-IC90. RF AUCs were ∼2%–5% of RT and did not correlate with RT (rho = 0.43, P = 0.17). Accumulation of DTG with multiple dosing was observed in BP, SF, and RT.

Conclusions: DTG BP PKs were consistent with previously published values. SF concentrations were <7% BP, with SF C24 h below the PA-IC90. However, SF protein binding was not measured. Although the AUC of DTG in RT was <20% BP, RT C24 h remained ∼2-fold higher than the PA-IC90. RF was not a strong surrogate for RT concentrations.

© 2013 by Lippincott Williams & Wilkins

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