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Cervicovaginal and Rectal Fluid as a Surrogate Marker of Antiretroviral Tissue Concentration: Implications for Clinical Trial Design
- Publication Year :
- 2016
- Publisher :
- The University of North Carolina at Chapel Hill University Libraries, 2016.
-
Abstract
- BACKGROUND Quantifying tissue drug concentrations can yield important information during drug development, but complicates pharmacokinetic study design. Mucosal fluids collected by direct aspiration (cervicovaginal fluid; CVF) or swab (rectal fluid; RF) might be used as tissue concentration surrogates, but these relationships are not well characterized. METHODS Forty-nine healthy women, given a single oral dose of tenofovir, maraviroc, emtricitabine, or raltegravir at 50%-200% of the treatment dose, provided 13 plasma, 12 CVF, 12 RF and one cervical, vaginal and rectal tissue biopsy over 48 hours. Relationships between these paired samples were characterized by linear and multiple linear regression. Adjusted r values were used to select the final predictive models. RESULTS CVF exposure increased linearly with dose for all antiretrovirals (r(2) ≥ 0.23, P ≤ 0.02) except raltegravir (r(2) = 0.08, P = 0.19). In RF, only emtricitabine increased linearly with dose (r(2) = 0.27, P = 0.01). For all antiretrovirals, CVF and RF concentrations significantly correlated with mucosal tissue concentrations (female genital tract r(2) ≥ 0.37, rectal tissue (2)r ≥ 0.50, P ≤ 0.001). In the final multivariate models, plasma and fluid concentrations were both associated with FGT concentrations for all antiretrovirals (r(2) ≥ 0.81, P < 0.001). The same was noted for rectal tissue (r(2) ≥ 0.58, P < 0.001) except for tenofovir, for which RF alone was predictive of tissue concentration (r(2) = 0.91, P < 0.001). CONCLUSIONS Mucosal fluids were positively correlated with tissue concentrations and including plasma concentrations improved the regression models in most cases. Dose linearity in CVF, but not RF, suggests a saturation process in lower gastrointestinal tract tissue. These findings suggest that mucosal fluid and plasma concentrations may be used for qualitative inference of tissue concentrations for these antiretrovirals.
- Subjects :
- 0301 basic medicine
Adult
medicine.medical_specialty
Anti-HIV Agents
030106 microbiology
Rectum
Cervix Uteri
Emtricitabine
Gastroenterology
Article
Raltegravir Potassium
Maraviroc
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Pharmacokinetics
Cyclohexanes
Internal medicine
Medicine
Humans
Pharmacology (medical)
030212 general & internal medicine
Tenofovir
Clinical Trials as Topic
business.industry
Surrogate endpoint
Triazoles
Raltegravir
Healthy Volunteers
Body Fluids
Infectious Diseases
medicine.anatomical_structure
chemistry
Vagina
Female
business
Biomarkers
medicine.drug
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....c9558fb5414cfe434b9b3a26a780341d
- Full Text :
- https://doi.org/10.17615/tbzg-k418