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


METHODS
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, Chapel Hill, NC, USA.
Benjamin N
BN
Greener
Kristine B
KB
Patterson
Heather M A
HM
Prince
Craig S
CS
Sykes
Jessica L
JL
Adams
Julie B
JB
Dumond
Nicholas J
NJ
Shaheen
Ryan D
RD
Madanick
Evan S
ES
Dellon
Myron S
MS
Cohen
Angela D M
AD
Kashuba
D000328:Adult; D003106:Colon / Q000187:drug effects* / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D019428:HIV Integrase Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D012007:Rectum / Q000187:drug effects* / Q000276:immunology; D012661:Semen / Q000187:drug effects* / Q000276:immunology; D016896:Treatment Outcome; D000099226:Dolutegravir
D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000099226:Dolutegravir