Dolutegravir pharmacokinetics in the genital tract and colorectum of HIV-negative men after single and multiple dosing.

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). Non-compartmental 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 (C-24 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 similar to 2-fold greater than the PA-IC90. RF AUCs were similar to 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 C-24 h below the PA-IC90. However, SF protein binding was not measured. Although the AUC of DTG in RT was < 20% BP, RT C-24 h remained similar to 2-fold higher than the PA-IC90. RF was not a strong surrogate for RT concentrations.