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Cervicovaginal and Rectal Fluid as a Surrogate Marker of Antiretroviral Tissue Concentration: Implications for Clinical Trial Design.
J Acquir Immune Defic Syndr. 2016 08 15; 72(5):498-506.JA

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.

Authors+Show Affiliations

*Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC; †University of North Carolina at Chapel Hill School of Medicine, Division of Infectious Diseases, Chapel Hill, NC; and ‡University of North Carolina at Chapel Hill, Gillings School of Global Public Health, Department of Biostatistics, Chapel Hill, NC.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

26999532

Citation

Cottrell, Mackenzie L., et al. "Cervicovaginal and Rectal Fluid as a Surrogate Marker of Antiretroviral Tissue Concentration: Implications for Clinical Trial Design." Journal of Acquired Immune Deficiency Syndromes (1999), vol. 72, no. 5, 2016, pp. 498-506.
Cottrell ML, Prince HM, Allmon A, et al. Cervicovaginal and Rectal Fluid as a Surrogate Marker of Antiretroviral Tissue Concentration: Implications for Clinical Trial Design. J Acquir Immune Defic Syndr. 2016;72(5):498-506.
Cottrell, M. L., Prince, H. M., Allmon, A., Mollan, K. R., Hudgens, M. G., Sykes, C., White, N., Malone, S., Dellon, E. S., Madanick, R. D., Shaheen, N. J., Patterson, K. B., & Kashuba, A. D. (2016). Cervicovaginal and Rectal Fluid as a Surrogate Marker of Antiretroviral Tissue Concentration: Implications for Clinical Trial Design. Journal of Acquired Immune Deficiency Syndromes (1999), 72(5), 498-506. https://doi.org/10.1097/QAI.0000000000000996
Cottrell ML, et al. Cervicovaginal and Rectal Fluid as a Surrogate Marker of Antiretroviral Tissue Concentration: Implications for Clinical Trial Design. J Acquir Immune Defic Syndr. 2016 08 15;72(5):498-506. PubMed PMID: 26999532.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cervicovaginal and Rectal Fluid as a Surrogate Marker of Antiretroviral Tissue Concentration: Implications for Clinical Trial Design. AU - Cottrell,Mackenzie L, AU - Prince,Heather M A, AU - Allmon,Andrew, AU - Mollan,Katie R, AU - Hudgens,Michael G, AU - Sykes,Craig, AU - White,Nicole, AU - Malone,Stephanie, AU - Dellon,Evan S, AU - Madanick,Ryan D, AU - Shaheen,Nicholas J, AU - Patterson,Kristine B, AU - Kashuba,Angela D M, PY - 2016/3/22/entrez PY - 2016/3/22/pubmed PY - 2017/6/1/medline SP - 498 EP - 506 JF - Journal of acquired immune deficiency syndromes (1999) JO - J. Acquir. Immune Defic. Syndr. VL - 72 IS - 5 N2 - 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. SN - 1944-7884 UR - https://www.unboundmedicine.com/medline/citation/26999532/Cervicovaginal_and_Rectal_Fluid_as_a_Surrogate_Marker_of_Antiretroviral_Tissue_Concentration:_Implications_for_Clinical_Trial_Design_ L2 - http://dx.doi.org/10.1097/QAI.0000000000000996 DB - PRIME DP - Unbound Medicine ER -