135LB
Maraviroc (MVC) Pharmacokinetics (PK) in Blood Plasma (BP), Genital Tract (GT) Fluid and Tissue in Healthy Female Volunteers
J Dumond1, Kristine Patterson*1, A Pecha1, R Werner1, E Andrews2, B Damle2, R Tressler2, J Worsley3, K Boggess1, and A Kashuba1
1Univ of North Carolina at Chapel Hill, US; 2Pfizer Inc, New York, NY, US; and 3Pfizer Global R&D, Sandwich, Kent, UK
Background: This study
reports the plasma and GT PK of MVC, a new CCR5 antagonist recently approved
for use in treatment-experienced patients with R5-tropic HIV infection. The
pharmacology of antiretrovirals (ARVs) in the GT provides insight into the development
of ARV resistance in this sanctuary site and sexual transmission of HIV.
Methods: An open-label PK
study was performed in 12 HIV sero-negative women receiving MVC 300mg BID for 7 days. Eight paired BP and directly aspirated cervicovaginal fluid (CVF) samples
were collected over a 12 hr interval on Day 1 and 7, and at 24, 48, and 72 hrs
after the final dose on Day 7. BP and CVF trough samples were collected prior
to a.m. doses on Days 2-6. Vaginal tissue biopsy (VTB) samples were collected
once per subject at 2, 4, 8, or 12 hrs post-dose on Day 7 (3 subjects/time
point). MVC concentrations were measured by validated LC/MS/MS assays. Data
were analyzed by noncompartmental methods.
Results: The mean (SD) PK
parameters for MVC are shown below.
|
Parameters
|
Day 1*
|
Day 7*
|
|
BP
|
CVF
|
BP
|
CVF
|
VTB***
|
|
Cmax (ng/mL)
|
584 (259)
|
813 (559)
|
662 (242)
|
1452 (1361)
|
781
|
|
Tmax (hr)**
|
2 (1-3)
|
6 (4-12)
|
3 (1-4)
|
6 (0-12)
|
4
|
|
AUCτ (ng*hr/mL)
|
1991 (518)
|
4655 (3661)
|
2648 (798)
|
9629 (7819)
|
4992
|
* N = 10 to 12 subjects
** Median (range)
*** Units for VTB Cmax (ng/gm)
and AUCτ ( ng*hr/gm)
MVC was detectable in CFV with
concentrations reaching or exceeding plasma concentrations 4 hr after a single
oral dose. Steady-state concentration of MVC in BP and CVF appeared be reached
by Day 2 based on trough values. The accumulation ratio based on AUCτ,
(Day 7/Day 1) was 1.3 and 2.4 for BP and CVF, respectively. The AUCτ
ratio for CVF / BP was 2.5 and 3.9 on Days 1 and 7, respectively. On Day 7, VTB
concentrations were detectable in all samples, and the AUCτ in VTB was 1.9-fold
higher than BP. Once MVC was discontinued, CVF concentrations declined in
parallel to BP.
Conclusions: This is the
first study to investigate simultaneous MVC exposure in BP, CVF and VTB. MVC exposures
in CVF and VTB were higher than those observed in BP. These data indicate that
MVC has the potential to be studied as an oral agent for HIV prophylaxis.
|
