Jeremiah D Momper1, Jiajia Wang2, Alice Stek3, David E Shapiro2, Gwendolyn B Scott4, Mary E Paul5, Irma L Febo6, Sandra Burchett7, Elizabeth Smith8, Nahida Chakhtoura9, Kayla Denson10, Kittipong Rungruengthanakit11, Kathleen George12, Derek Z Yang1, Edmund V Capparelli1, Mark Mirochnick13, Brookie M Best1. 1. University of California, San Diego, La Jolla, CA. 2. Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston, MA. 3. University of Southern California, Los Angeles, CA. 4. University of Miami Miller School of Medicine, Miami, FL. 5. Baylor College of Medicine, Houston, TX. 6. University of Puerto Rico, School of Medicine, San Juan, PR. 7. Harvard Medical School and Boston Children's Hospital, Boston, MA. 8. National Institute of Allergy and Infectious Diseases. 9. National Institute of Child Health and Human Development, Bethesda, MD. 10. Frontier Science & Technology Research Foundation, Inc, Amherst, NY, USA. 11. Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand. 12. Family Health International, Durham, NC. 13. Boston University, Boston, MA, USA.
Abstract
OBJECTIVE: To evaluate darunavir and cobicistat pharmacokinetics during pregnancy compared with postpartum and in infant washout samples after delivery. DESIGN: Nonrandomized, open-label, parallel-group, multicenter phase-IV prospective study of darunavir and cobicistat pharmacokinetics in pregnant women with HIV and their children in the United States. METHODS: Intensive steady-state 24-h pharmacokinetic profiles were performed after administration of 800 mg of darunavir and 150 mg of cobicistat orally in fixed dose combination once-daily during the second trimester, third trimester, and postpartum. Infant washout samples were collected after birth. Darunavir and cobicistat were measured in plasma by validated HPLC-UV and liquid chromatography with tandem mass spectrometry detection (LC-MS)/MS assays, respectively. A two-tailed Wilcoxon signed-rank test (α = 0.10) was employed for paired within-participant comparisons. RESULTS: A total of 29 pregnant women receiving darunavir and cobicistat once-daily enrolled in the study. Compared with paired postpartum data, darunavir AUC0--24 was 53% lower in the second trimester [n = 12, P = 0.0024, geometric mean of ratio (GMR)=0.47, 90% confidence interval (CI) 0.33 - 0.68] and 56% lower in the third trimester (n = 18, P < 0.0001, GMR = 0.44, 90% CI 0.36 - 0.54), whereas cobicistat AUC0--24 was 50% lower in the second trimester (n = 12, P = 0.0024, GMR = 0.50, 90% CI 0.36-0.69) and 56% lower in the third trimester (n = 18, P < 0.0001, GMR = 0.44, 90% CI 0.35-0.55). Placental transfer of darunavir and cobicistat was limited. CONCLUSION: Standard darunavir/cobicistat dosing during pregnancy results in significantly lower exposure during pregnancy, which may increase the risk of virologic failure and perinatal transmission.
OBJECTIVE: To evaluate darunavir and cobicistat pharmacokinetics during pregnancy compared with postpartum and in infant washout samples after delivery. DESIGN: Nonrandomized, open-label, parallel-group, multicenter phase-IV prospective study of darunavir and cobicistat pharmacokinetics in pregnant women with HIV and their children in the United States. METHODS: Intensive steady-state 24-h pharmacokinetic profiles were performed after administration of 800 mg of darunavir and 150 mg of cobicistat orally in fixed dose combination once-daily during the second trimester, third trimester, and postpartum. Infant washout samples were collected after birth. Darunavir and cobicistat were measured in plasma by validated HPLC-UV and liquid chromatography with tandem mass spectrometry detection (LC-MS)/MS assays, respectively. A two-tailed Wilcoxon signed-rank test (α = 0.10) was employed for paired within-participant comparisons. RESULTS: A total of 29 pregnant women receiving darunavir and cobicistat once-daily enrolled in the study. Compared with paired postpartum data, darunavir AUC0--24 was 53% lower in the second trimester [n = 12, P = 0.0024, geometric mean of ratio (GMR)=0.47, 90% confidence interval (CI) 0.33 - 0.68] and 56% lower in the third trimester (n = 18, P < 0.0001, GMR = 0.44, 90% CI 0.36 - 0.54), whereas cobicistat AUC0--24 was 50% lower in the second trimester (n = 12, P = 0.0024, GMR = 0.50, 90% CI 0.36-0.69) and 56% lower in the third trimester (n = 18, P < 0.0001, GMR = 0.44, 90% CI 0.35-0.55). Placental transfer of darunavir and cobicistat was limited. CONCLUSION: Standard darunavir/cobicistat dosing during pregnancy results in significantly lower exposure during pregnancy, which may increase the risk of virologic failure and perinatal transmission.
Authors: Jeremiah D Momper; Brookie M Best; Jiajia Wang; Edmund V Capparelli; Alice Stek; Emily Barr; Martina L Badell; Edward P Acosta; Murli Purswani; Elizabeth Smith; Nahida Chakhtoura; Kyunghun Park; Sandra Burchett; David E Shapiro; Mark Mirochnick Journal: AIDS Date: 2018-11-13 Impact factor: 4.177
Authors: Yong Wang; Zhigang Liu; Joseph S Brunzelle; Iulia A Kovari; Tamaria G Dewdney; Samuel J Reiter; Ladislau C Kovari Journal: Biochem Biophys Res Commun Date: 2011-08-17 Impact factor: 3.575
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Authors: Edward P Acosta; Arlene Bardeguez; Carmen D Zorrilla; Russell Van Dyke; Michael D Hughes; Sharon Huang; Lisa Pompeo; Alice M Stek; Jane Pitt; D Heather Watts; Elizabeth Smith; Eleanor Jiménez; Lynne Mofenson Journal: Antimicrob Agents Chemother Date: 2004-02 Impact factor: 5.191
Authors: Kristina M Brooks; Mauricio Pinilla; Alice M Stek; David E Shapiro; Emily Barr; Irma L Febo; Mary E Paul; Jaime G Deville; Kathleen George; Kevin Knowles; Kittipong Rungruengthanakit; Renee Browning; Nahida Chakhtoura; Edmund V Capparelli; Mark Mirochnick; Brookie M Best Journal: J Acquir Immune Defic Syndr Date: 2022-07-01 Impact factor: 3.771
Authors: Jeremiah D Momper; Jiajia Wang; Alice Stek; David E Shapiro; Kathleen M Powis; Mary E Paul; Martina L Badell; Renee Browning; Nahida Chakhtoura; Kayla Denson; Kittipong Rungruengthanakit; Kathleen George; Edmund V Capparelli; Mark Mirochnick; Brookie M Best Journal: J Acquir Immune Defic Syndr Date: 2022-03-01 Impact factor: 3.771