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Cervicovaginal and Rectal Fluid as a Surrogate Marker of Antiretroviral Tissue Concentration: Implications for Clinical Trial Design.

Cervicovaginal and Rectal Fluid as a Surrogate Marker of Antiretroviral Tissue Concentration: Implications for Clinical Trial Design.
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Cottrell ML, Prince HM, Allmon A, Mollan KR, Hudgens MG, Sykes C, White N, Malone S, Dellon ES, Madanick RD, Shaheen NJ, Patterson KB, Kashuba AD,


Cottrell ML, Prince HM, Allmon A, Mollan KR, Hudgens MG, Sykes C, White N, Malone S, Dellon ES, Madanick RD, Shaheen NJ, Patterson KB, Kashuba AD, (click to view)

Cottrell ML, Prince HM, Allmon A, Mollan KR, Hudgens MG, Sykes C, White N, Malone S, Dellon ES, Madanick RD, Shaheen NJ, Patterson KB, Kashuba AD,

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Journal of acquired immune deficiency syndromes (1999) 72(5) 498-506 doi 10.1097/QAI.0000000000000996

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 ≥ 0.23, P ≤ 0.02) except raltegravir (r = 0.08, P = 0.19). In RF, only emtricitabine increased linearly with dose (r = 0.27, P = 0.01). For all antiretrovirals, CVF and RF concentrations significantly correlated with mucosal tissue concentrations (female genital tract r ≥ 0.37, rectal tissue 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 ≥ 0.81, P < 0.001). The same was noted for rectal tissue (r ≥ 0.58, P < 0.001) except for tenofovir, for which RF alone was predictive of tissue concentration (r = 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.

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