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.
*University of North Carolina at Chapel Hill Eshelman School of Pharmacy; and
†University of North Carolina at Chapel Hill School of Medicine, The University of North Carolina, Chapel Hill, NC.
Correspondence to: Angela D. M. Kashuba, BScPhm, PharmD, DABCP, 3318 Kerr Hall CB#7569, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7569 (e-mail: email@example.com).
Presented at the 20th Conference on Retroviruses and Opportunistic Infections, Mar 3–6, 2013, Atlanta, GA.
B.N.G.—subject recruitment and study visit conduct, pharmacokinetic and statistical data analysis, and primary author of manuscript. K.B.P.—study visit conduct, clinical study safety officer, critical review of manuscript. H.M.A.P.—subject recruitment and study visit conduct, critical review of manuscript. C.S.S.—analytical data analysis, critical review of manuscript. J.L.A.—study visit conduct, pharmacokinetic and statistical data analysis, critical review of manuscript. J.B.D.—pharmacokinetic and statistical data analysis, critical review of manuscript. E.S.D.—study visit conduct, critical review of manuscript. R.D.M.—study visit conduct, critical review of manuscript. N.J.S.—study visit conduct, critical review of manuscript. M.S.C.—study design, critical review of manuscript. A.D.M.K.—study design, analytical and pharmacokinetic data analysis, funding, critical review of manuscript.
A.D.K.'s spouse is employed by GlaxoSmithKline. The remaining authors have no conflicts of interest to disclose.
Supported by Shionogi-Viiv Healthcare. The project was supported by the National Center for Research Resources; the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant Award Number UL1TR000083; and University of North Carolina at Chapel Hill Center for AIDS Research (5P30AI050410-13; C.S.S., J.B.D., A.D.M.K.), NC TraCS CTSA Grant (UL1TR000083), K23AI077355 (K.B.P.), K23AI093156 (J.B.D.), U01AI095031 (A.D.M.K.), and R37DK49381 (M.S.C.).
Received March 03, 2013
Accepted June 01, 2013