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

Jonathan T. Su; Ryan S. Teller; Priya Srinivasan; Jining Zhang; Amy Martin; Samuel Sung; James M. Smith; Patrick F. Kiser

doi:10.1007/s11095-017-2224-1

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

Jonathan T. Su, Ryan S. Teller, Priya Srinivasan, Jining Zhang, Amy Martin, Samuel Sung, James M. Smith, Patrick F. Kiser^*

^*Corresponding author for this work

Biomedical Engineering

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

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.

Original language	English (US)
Pages (from-to)	2163-2171
Number of pages	9
Journal	Pharmaceutical Research
Volume	34
Issue number	10
DOIs	https://doi.org/10.1007/s11095-017-2224-1
State	Published - Oct 1 2017

Funding

This work was supported by NIH U19AI03461. IQP-0528 was provided by ImQuest BioSciences. We acknowledge the following members of the CDC DHAP Laboratory Branch/Preclinical Evaluation Team for their contributions to our nonhuman primate research: David Garber, James Mitchell, Shanon Ellis, Frank Deyounks and Kristen Kelley. We thank Angela Fought for helpful discussion of the statistical analysis. The findings and conclusions in this paper are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. This work was supported by NIH U19AI03461. IQP-0528 was provided by ImQuest BioSciences. We acknowledge the following members of the CDC DHAP Laboratory Branch/ Preclinical Evaluation Team for their contributions to our nonhuman primate research: David Garber, James Mitchell, Shanon Ellis, Frank Deyounks and Kristen Kelley. We thank Angela Fought for helpful discussion of the statistical analysis. The findings and conclusions in this paper are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

Keywords

IQP-0528
intravaginal rings
macaque
pharmacokinetics

ASJC Scopus subject areas

Pharmacology (medical)
Molecular Medicine
Biotechnology
Pharmacology
Pharmaceutical Science
Organic Chemistry

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10.1007/s11095-017-2224-1

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

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{\textquoteright}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.",

keywords = "IQP-0528, intravaginal rings, macaque, pharmacokinetics",

author = "Su, {Jonathan T.} and Teller, {Ryan S.} and Priya Srinivasan and Jining Zhang and Amy Martin and Samuel Sung and Smith, {James M.} and Kiser, {Patrick F.}",

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AU - Zhang, Jining

AU - Martin, Amy

AU - Sung, Samuel

AU - Smith, James M.

AU - Kiser, Patrick F.

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N2 - 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.

AB - 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.

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

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