Pharmacokinetic Modeling to Guide Preclinical Development of an Islatravir-Eluting Reservoir-Style Biodegradable Implant for Long-Acting HIV PrEP
Long-acting injectable cabotegravir is more effective than daily oral PrEP at preventing HIV transmission due to improved adherence, but requires bi-monthly large-volume intramuscular injections. Subcutaneous (SC) contraceptive implants can be formulated with antiretrovirals for extended-duration HI...
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| Format: | Article |
| Language: | English |
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MDPI AG
2024-01-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/16/2/201 |
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| author | Talisa S. Kinsale Mackenzie L. Cottrell Linying Li Rhonda Brand Greg Gatto Ellen Luecke Chasity Norton Archana Krovi Julie B. Dumond Gauri Rao Shekhar Yeshwante Brian Van Horne Ariane Van Der Straten Angela D. M. Kashuba Leah M. Johnson |
| author_facet | Talisa S. Kinsale Mackenzie L. Cottrell Linying Li Rhonda Brand Greg Gatto Ellen Luecke Chasity Norton Archana Krovi Julie B. Dumond Gauri Rao Shekhar Yeshwante Brian Van Horne Ariane Van Der Straten Angela D. M. Kashuba Leah M. Johnson |
| author_sort | Talisa S. Kinsale |
| collection | DOAJ |
| description | Long-acting injectable cabotegravir is more effective than daily oral PrEP at preventing HIV transmission due to improved adherence, but requires bi-monthly large-volume intramuscular injections. Subcutaneous (SC) contraceptive implants can be formulated with antiretrovirals for extended-duration HIV PrEP. Islatravir (ISL) is a first-in-class, investigational antiretroviral with pharmacologic properties well-suited for implant delivery. We performed preclinical studies for the development of a reservoir-style, poly(ε-caprolactone) ISL-eluting implant by conducting a single-dose SC ISL dose-ranging pharmacokinetic (PK) study of 0.1, 0.3, and 1 mg/kg in adult Wistar rats. Non-compartmental analysis was conducted, and dose proportionality assessed for ISL plasma and intracellular islatravir-triphosphate (ISL-tp). Population PK models estimated ISL’s unit impulse response to deconvolve ISL-implant in vivo absorption rate (mg/day) and cumulative mass (mg) from published rat plasma PK (<i>n</i> = 10). Drug release was interpreted using four kinetic models. Dose proportionality was affirmed for ISL and ISL-tp. A first-order, two-compartment model fitted the SC ISL bolus data. Mean (SD) absorption rate from 0 to 154 days was 0.072 ± 0.024 mg/day, and cumulative mass at 154 days was 8.67 ± 3.22 mg. ISL absorption was well-described by zero-order (r<sup>2</sup> = 0.95) and Ritger–Peppas (r<sup>2</sup> = 0.98). Our zero-order ISL-release poly(ε-caprolactone) implant is projected to achieve clinical PK above ISL-tp’s PrEP efficacy threshold. Continued development for HIV PrEP applications is warranted. |
| first_indexed | 2024-03-07T22:17:51Z |
| format | Article |
| id | doaj.art-5e3b180f2a7545f595dc9df71e45e098 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-07T22:17:51Z |
| publishDate | 2024-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-5e3b180f2a7545f595dc9df71e45e0982024-02-23T15:31:04ZengMDPI AGPharmaceutics1999-49232024-01-0116220110.3390/pharmaceutics16020201Pharmacokinetic Modeling to Guide Preclinical Development of an Islatravir-Eluting Reservoir-Style Biodegradable Implant for Long-Acting HIV PrEPTalisa S. Kinsale0Mackenzie L. Cottrell1Linying Li2Rhonda Brand3Greg Gatto4Ellen Luecke5Chasity Norton6Archana Krovi7Julie B. Dumond8Gauri Rao9Shekhar Yeshwante10Brian Van Horne11Ariane Van Der Straten12Angela D. M. Kashuba13Leah M. Johnson14Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USADivision of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USABiomedical Technologies RTI International, 3040 E. Cornwallis Road, Research Triangle Park, NC 27709, USAMagee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA 15213, USAGlobal Public Health Impact Center, RTI International, Research Triangle Park, NC 27709, USAGlobal Public Health Impact Center, RTI International, Research Triangle Park, NC 27709, USABiomedical Technologies RTI International, 3040 E. Cornwallis Road, Research Triangle Park, NC 27709, USABiomedical Technologies RTI International, 3040 E. Cornwallis Road, Research Triangle Park, NC 27709, USADivision of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USADivision of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USADivision of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USADivision of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USACenter for AIDS Prevention Studies (CAPS), Department of Medicine, University of California San Francisco, San Francisco, CA 94104, USADivision of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USABiomedical Technologies RTI International, 3040 E. Cornwallis Road, Research Triangle Park, NC 27709, USALong-acting injectable cabotegravir is more effective than daily oral PrEP at preventing HIV transmission due to improved adherence, but requires bi-monthly large-volume intramuscular injections. Subcutaneous (SC) contraceptive implants can be formulated with antiretrovirals for extended-duration HIV PrEP. Islatravir (ISL) is a first-in-class, investigational antiretroviral with pharmacologic properties well-suited for implant delivery. We performed preclinical studies for the development of a reservoir-style, poly(ε-caprolactone) ISL-eluting implant by conducting a single-dose SC ISL dose-ranging pharmacokinetic (PK) study of 0.1, 0.3, and 1 mg/kg in adult Wistar rats. Non-compartmental analysis was conducted, and dose proportionality assessed for ISL plasma and intracellular islatravir-triphosphate (ISL-tp). Population PK models estimated ISL’s unit impulse response to deconvolve ISL-implant in vivo absorption rate (mg/day) and cumulative mass (mg) from published rat plasma PK (<i>n</i> = 10). Drug release was interpreted using four kinetic models. Dose proportionality was affirmed for ISL and ISL-tp. A first-order, two-compartment model fitted the SC ISL bolus data. Mean (SD) absorption rate from 0 to 154 days was 0.072 ± 0.024 mg/day, and cumulative mass at 154 days was 8.67 ± 3.22 mg. ISL absorption was well-described by zero-order (r<sup>2</sup> = 0.95) and Ritger–Peppas (r<sup>2</sup> = 0.98). Our zero-order ISL-release poly(ε-caprolactone) implant is projected to achieve clinical PK above ISL-tp’s PrEP efficacy threshold. Continued development for HIV PrEP applications is warranted.https://www.mdpi.com/1999-4923/16/2/201HIV preventionpreexposure prophylaxisantiretroviral agentsislatravirextended-durationlong-acting implant |
| spellingShingle | Talisa S. Kinsale Mackenzie L. Cottrell Linying Li Rhonda Brand Greg Gatto Ellen Luecke Chasity Norton Archana Krovi Julie B. Dumond Gauri Rao Shekhar Yeshwante Brian Van Horne Ariane Van Der Straten Angela D. M. Kashuba Leah M. Johnson Pharmacokinetic Modeling to Guide Preclinical Development of an Islatravir-Eluting Reservoir-Style Biodegradable Implant for Long-Acting HIV PrEP Pharmaceutics HIV prevention preexposure prophylaxis antiretroviral agents islatravir extended-duration long-acting implant |
| title | Pharmacokinetic Modeling to Guide Preclinical Development of an Islatravir-Eluting Reservoir-Style Biodegradable Implant for Long-Acting HIV PrEP |
| title_full | Pharmacokinetic Modeling to Guide Preclinical Development of an Islatravir-Eluting Reservoir-Style Biodegradable Implant for Long-Acting HIV PrEP |
| title_fullStr | Pharmacokinetic Modeling to Guide Preclinical Development of an Islatravir-Eluting Reservoir-Style Biodegradable Implant for Long-Acting HIV PrEP |
| title_full_unstemmed | Pharmacokinetic Modeling to Guide Preclinical Development of an Islatravir-Eluting Reservoir-Style Biodegradable Implant for Long-Acting HIV PrEP |
| title_short | Pharmacokinetic Modeling to Guide Preclinical Development of an Islatravir-Eluting Reservoir-Style Biodegradable Implant for Long-Acting HIV PrEP |
| title_sort | pharmacokinetic modeling to guide preclinical development of an islatravir eluting reservoir style biodegradable implant for long acting hiv prep |
| topic | HIV prevention preexposure prophylaxis antiretroviral agents islatravir extended-duration long-acting implant |
| url | https://www.mdpi.com/1999-4923/16/2/201 |
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