Jonathan T Su1, Ryan S Teller1, Priya Srinivasan2, Jining Zhang3, Amy Martin2, Samuel Sung1, James M Smith2, Patrick F Kiser4,5. 1. Department of Biomedical Engineering, Northwestern University, 2145 Sheridan Road, Tech E310, Evanston, Illinois, 60208, USA. 2. Centers for Disease Control and Prevention, Atlanta, Georgia, USA. 3. Total Solutions Inc., Atlanta, Georgia, USA. 4. Department of Biomedical Engineering, Northwestern University, 2145 Sheridan Road, Tech E310, Evanston, Illinois, 60208, USA. Patrick.kiser@northwestern.edu. 5. Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA. Patrick.kiser@northwestern.edu.
Abstract
PURPOSE: Design of intravaginal rings (IVRs) for delivery of antiretrovirals is often guided by in vitro release under sink conditions, based on the assumption that in vivo release will follow a similar release profile. METHODS: We conducted a dose-ranging study in the female reproductive tract of pigtail macaques using matrix IVRs containing IQP-0528, a poorly soluble but highly potent antiretroviral drug with an IC90 of 146 ng/mL. These IVRs consisted of drug-loaded segments, 15.6% IQP-0528 in Tecoflex 85A, comprising either all, half, or a quarter of the entire ring. RESULTS: In vitro release under sink conditions demonstrates loading-proportional release, with a cumulative 30-day release of 48.5 ± 2.2 mg for our 100% loaded ring, 24.8 ± .36 mg from our 50% loaded ring, and 13.99 ± 1.58 mg from our 25% loaded ring. In vivo, while drug concentration in vaginal fluid is well in excess of IQP-0528's EC90, we find no statistical difference between the different ring loadings in either swab drug levels or drug released from our rings. CONCLUSIONS: We show that in vitro release may not accurately reflect in vivo release, particularly for poorly soluble drugs. All tested loadings of our IVRs are capable of delivering IQP-0528 well in excess of the IC90.
PURPOSE: Design of intravaginal rings (IVRs) for delivery of antiretrovirals is often guided by in vitro release under sink conditions, based on the assumption that in vivo release will follow a similar release profile. METHODS: We conducted a dose-ranging study in the female reproductive tract of pigtail macaques using matrix IVRs containing IQP-0528, a poorly soluble but highly potent antiretroviral drug with an IC90 of 146 ng/mL. These IVRs consisted of drug-loaded segments, 15.6% IQP-0528 in Tecoflex 85A, comprising either all, half, or a quarter of the entire ring. RESULTS: In vitro release under sink conditions demonstrates loading-proportional release, with a cumulative 30-day release of 48.5 ± 2.2 mg for our 100% loaded ring, 24.8 ± .36 mg from our 50% loaded ring, and 13.99 ± 1.58 mg from our 25% loaded ring. In vivo, while drug concentration in vaginal fluid is well in excess of IQP-0528's EC90, we find no statistical difference between the different ring loadings in either swab drug levels or drug released from our rings. CONCLUSIONS: We show that in vitro release may not accurately reflect in vivo release, particularly for poorly soluble drugs. All tested loadings of our IVRs are capable of delivering IQP-0528 well in excess of the IC90.
Authors: Anthony S Ham; Lisa Cencia Rohan; Ashlee Boczar; Lu Yang; Karen W Buckheit; Robert W Buckheit Journal: Pharm Res Date: 2012-03-06 Impact factor: 4.200
Authors: Ryan S Teller; David C Malaspina; Rachna Rastogi; Justin T Clark; Igal Szleifer; Patrick F Kiser Journal: J Control Release Date: 2015-12-23 Impact factor: 9.776
Authors: Alamelu Mahalingam; Adam P Simmons; Shweta R Ugaonkar; Karen M Watson; Charlene S Dezzutti; Lisa C Rohan; Robert W Buckheit; Patrick F Kiser Journal: Antimicrob Agents Chemother Date: 2011-01-18 Impact factor: 5.191
Authors: Priya Srinivasan; Jining Zhang; Amy Martin; Kristin Kelley; Janet M McNicholl; Robert W Buckheit; James M Smith; Anthony S Ham Journal: Antimicrob Agents Chemother Date: 2016-06-20 Impact factor: 5.191
Authors: G J Gatto; A Krovi; L Li; I Massud; A Holder; J Gary; P Mills; J Mitchell; E Luecke; Z R Demkovich; W Heneine; J G García-Lerma; M A Marzinke; R M Brand; C W Dobard; L M Johnson; A Van Der Straten Journal: Front Pharmacol Date: 2022-07-19 Impact factor: 5.988