A Dose Ranging Pharmacokinetic Evaluation of IQP-0528 Released from Intravaginal Rings in Non-Human Primates

• Published in: Pharmaceutical research 2017-10, Vol.34 (10), p.2163-2171
• Main Authors: Su, Jonathan T., Teller, Ryan S., Srinivasan, Priya, Zhang, Jining, Martin, Amy, Sung, Samuel, Smith, James M., Kiser, Patrick F.
• Format: Article
• Language: English
• Subjects: Administration, Intravaginal; Analysis; Animals; Anti-HIV Agents - administration & dosage; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacokinetics; Antiretroviral agents; Antiviral agents; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Body Fluids - chemistry; Contraceptive Devices, Female; Dose-Response Relationship, Drug; Drug Delivery Systems; Drug dosages; Drug Liberation; Female; Highly active antiretroviral therapy; HIV-1 - drug effects; Humans; Macaca nemestrina; Medical Law; Pharmacokinetics; Pharmacology/Toxicology; Pharmacy; Polymers; Primates; Pyrimidinones - administration & dosage; Pyrimidinones - chemistry; Pyrimidinones - pharmacokinetics; Reproductive system; Research Paper; Solubility; Vagina
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-017-2224-1

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 IC 90 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 EC 90 , 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 IC 90 .