Research

13 pages, 1474 KiB

Open AccessArticle

Pharmacokinetic Modeling to Guide Preclinical Development of an Islatravir-Eluting Reservoir-Style Biodegradable Implant for Long-Acting HIV PrEP

by 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 and Leah M. Johnson

Pharmaceutics 2024, 16(2), 201; https://doi.org/10.3390/pharmaceutics16020201 - 30 Jan 2024

Viewed by 865

Abstract

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 [...] Read more.

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 (n = 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 (r² = 0.95) and Ritger–Peppas (r² = 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. Full article

(This article belongs to the Special Issue HIV/AIDS Prevention Formulation Design and Optimization and Its Pharmacokinetic-Pharmacodynamic Evaluation)

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23 pages, 4095 KiB

Open AccessEditor’s ChoiceArticle

A Bilayer Microarray Patch (MAP) for HIV Pre-Exposure Prophylaxis: The Role of MAP Designs and Formulation Composition in Enhancing Long-Acting Drug Delivery

by Lalitkumar K. Vora, Ismaiel A. Tekko, Fabiana Volpe Zanutto, Akmal Sabri, Robert K. M. Choy, Jessica Mistilis, Priscilla Kwarteng, Courtney Jarrahian, Helen O. McCarthy and Ryan F. Donnelly

Pharmaceutics 2024, 16(1), 142; https://doi.org/10.3390/pharmaceutics16010142 - 20 Jan 2024

Viewed by 1028

Abstract

Microarray patches (MAPs) have shown great potential for efficient and patient-friendly drug delivery through the skin; however, improving their delivery efficiency for long-acting drug release remains a significant challenge. This research provides an overview of novel strategies aimed at enhancing the efficiency of [...] Read more.

Microarray patches (MAPs) have shown great potential for efficient and patient-friendly drug delivery through the skin; however, improving their delivery efficiency for long-acting drug release remains a significant challenge. This research provides an overview of novel strategies aimed at enhancing the efficiency of MAP delivery of micronized cabotegravir sodium (CAB Na) for HIV pre-exposure prophylaxis (PrEP). The refinement of microneedle design parameters, including needle length, shape, density, and arrangement, and the formulation properties, such as solubility, viscosity, polymer molecular weight, and stability, are crucial for improving penetration and release profiles. Additionally, a bilayer MAP optimization step was conducted by diluting the CAB Na polymeric mixture to localize the drug into the tips of the needles to enable rapid drug deposition into the skin following MAP application. Six MAP designs were analyzed and investigated with regard to delivery efficiency into the skin in ex vivo and in vivo studies. The improved MAP design and formulations were found to be robust and had more than 30% in vivo delivery efficiency, with plasma levels several-fold above the therapeutic concentration over a month. Repeated weekly dosing demonstrated the robustness of MAPs in delivering a consistent and sustained dose of CAB. In summary, CAB Na MAPs were able to deliver therapeutically relevant levels of drug. Full article

(This article belongs to the Special Issue HIV/AIDS Prevention Formulation Design and Optimization and Its Pharmacokinetic-Pharmacodynamic Evaluation)

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15 pages, 2183 KiB

Open AccessArticle

Physiologically Based Pharmacokinetic Modelling of Cabotegravir Microarray Patches in Rats and Humans

by Hannah Kinvig, Rajith K. R. Rajoli, Henry Pertinez, Lalitkumar K. Vora, Fabiana Volpe-Zanutto, Ryan F. Donnelly, Steve Rannard, Charles Flexner, Marco Siccardi and Andrew Owen

Pharmaceutics 2023, 15(12), 2709; https://doi.org/10.3390/pharmaceutics15122709 - 30 Nov 2023

Cited by 1 | Viewed by 924

Abstract

Microarray patches (MAPs) are currently under investigation as a self-administered, pain-free alternative used to achieve long-acting (LA) drug delivery. Cabotegravir is a potent antiretroviral that has demonstrated superior results over current pre-exposure prophylaxis (PrEP) regimens. This study aimed to apply physiologically based pharmacokinetic [...] Read more.

Microarray patches (MAPs) are currently under investigation as a self-administered, pain-free alternative used to achieve long-acting (LA) drug delivery. Cabotegravir is a potent antiretroviral that has demonstrated superior results over current pre-exposure prophylaxis (PrEP) regimens. This study aimed to apply physiologically based pharmacokinetic (PBPK) modelling to describe the pharmacokinetics of the dissolving bilayer MAP platform and predict the optimal dosing strategies for a once-weekly cabotegravir MAP. A mathematical description of a MAP was implemented into a PBPK model, and empirical models were utilised for parameter estimation. The intradermal PBPK model was verified against previously published in vivo rat data for intramuscular (IM) and MAP administration, and in vivo human data for the IM administration of LA cabotegravir. The verified model was utilised for the prediction of 300 mg, 150 mg and 75 mg once-weekly MAP administration in humans. Cabotegravir plasma concentrations >4 × protein-adjusted 90% inhibitory concentration (PA-IC₉₀) (0.664 µg/mL) and >8 × PA-IC₉₀ (1.33 µg/mL) were set as targets. The 75 mg, 150 mg and 300 mg once-weekly cabotegravir MAP regimens were predicted to sustain plasma concentrations >4 × PA-IC_90, while the 300 mg and 150 mg regimens achieved plasma concentrations >8 × PA-IC₉₀. These data demonstrate the potential for a once-weekly cabotegravir MAP using practical patch sizes for humans and inform the further development of cabotegravir MAPs for HIV PrEP. Full article

(This article belongs to the Special Issue HIV/AIDS Prevention Formulation Design and Optimization and Its Pharmacokinetic-Pharmacodynamic Evaluation)

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17 pages, 2735 KiB

Open AccessArticle

Pharmacokinetic Study of Islatravir and Etonogestrel Implants in Macaques

by Michele B. Daly, Andres Wong-Sam, Linying Li, Archana Krovi, Gregory J. Gatto, Chasity Norton, Ellen H. Luecke, Victoria Mrotz, Catalina Forero, Mackenzie L. Cottrell, Amanda P. Schauer, Joy Gary, Josilene Nascimento-Seixas, James Mitchell, Ariane van der Straten, Walid Heneine, J. Gerardo Garcίa-Lerma, Charles W. Dobard and Leah M. Johnson

Pharmaceutics 2023, 15(12), 2676; https://doi.org/10.3390/pharmaceutics15122676 - 26 Nov 2023

Viewed by 1161

Abstract

The prevention of HIV and unintended pregnancies is a public health priority. Multi-purpose prevention technologies capable of long-acting HIV and pregnancy prevention are desirable for women. Here, we utilized a preclinical macaque model to evaluate the pharmacokinetics of biodegradable ε-polycaprolactone implants delivering the [...] Read more.

The prevention of HIV and unintended pregnancies is a public health priority. Multi-purpose prevention technologies capable of long-acting HIV and pregnancy prevention are desirable for women. Here, we utilized a preclinical macaque model to evaluate the pharmacokinetics of biodegradable ε-polycaprolactone implants delivering the antiretroviral islatravir (ISL) and the contraceptive etonogestrel (ENG). Three implants were tested: ISL-62 mg, ISL-98 mg, and ENG-33 mg. Animals received one or two ISL-eluting implants, with doses of 42, 66, or 108 µg of ISL/day with or without an additional ENG-33 mg implant (31 µg/day). Drug release increased linearly with dose with median [range] plasma ISL levels of 1.3 [1.0–2.5], 1.9 [1.2–6.3] and 2.8 [2.3–11.6], respectively. The ISL-62 and 98 mg implants demonstrated stable drug release over three months with ISL-triphosphate (ISL-TP) concentr54ations in PBMCs above levels predicted to be efficacious for PrEP. Similarly, ENG implants demonstrated sustained drug release with median [range] plasma ENG levels of 495 [229–1110] pg/mL, which suppressed progesterone within two weeks and showed no evidence of altering ISL pharmacokinetics. Two of the six ISL-98 mg implants broke during the study and induced implant-site reactions, whereas no reactions were observed with intact implants. We show that ISL and ENG biodegradable implants are safe and yield sufficient drug levels to achieve prevention targets. The evaluation of optimized implants with increased mechanical robustness is underway for improved durability and vaginal efficacy in a SHIV challenge model. Full article

(This article belongs to the Special Issue HIV/AIDS Prevention Formulation Design and Optimization and Its Pharmacokinetic-Pharmacodynamic Evaluation)

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15 pages, 2237 KiB

Open AccessArticle

Preclinical Evaluation of Long-Acting Emtricitabine Semi-Solid Prodrug Nanoparticle Formulations

by Paul Curley, James J. Hobson, Neill J. Liptrott, Edward Makarov, Amer Al-khouja, Lee Tatham, Christopher A. W. David, Helen Box, Megan Neary, Joanne Sharp, Henry Pertinez, David Meyers, Charles Flexner, Caren L. Freel Meyers, Larisa Poluektova, Steve Rannard and Andrew Owen

Pharmaceutics 2023, 15(7), 1835; https://doi.org/10.3390/pharmaceutics15071835 - 27 Jun 2023

Cited by 1 | Viewed by 1251

Abstract

Long-acting injectable (LAI) formulations promise to deliver patient benefits by overcoming issues associated with non-adherence. A preclinical assessment of semi-solid prodrug nanoparticle (SSPN) LAI formulations of emtricitabine (FTC) is reported here. Pharmacokinetics over 28 days were assessed in Wistar rats, New Zealand white [...] Read more.

Long-acting injectable (LAI) formulations promise to deliver patient benefits by overcoming issues associated with non-adherence. A preclinical assessment of semi-solid prodrug nanoparticle (SSPN) LAI formulations of emtricitabine (FTC) is reported here. Pharmacokinetics over 28 days were assessed in Wistar rats, New Zealand white rabbits, and Balb/C mice following intramuscular injection. Two lead formulations were assessed for the prevention of an HIV infection in NSG-cmah^−/− humanised mice to ensure antiviral activities were as anticipated according to the pharmacokinetics. Cmax was reached by 12, 48, and 24 h in rats, rabbits, and mice, respectively. Plasma concentrations were below the limit of detection (2 ng/mL) by 21 days in rats and rabbits, and 28 days in mice. Mice treated with SSPN formulations demonstrated undetectable viral loads (700 copies/mL detection limit), and HIV RNA remained undetectable 28 days post-infection in plasma, spleen, lung, and liver. The in vivo data presented here demonstrate that the combined prodrug/SSPN approach can provide a dramatically extended pharmacokinetic half-life across multiple preclinical species. Species differences in renal clearance of FTC mean that longer exposures are likely to be achievable in humans than in preclinical models. Full article

(This article belongs to the Special Issue HIV/AIDS Prevention Formulation Design and Optimization and Its Pharmacokinetic-Pharmacodynamic Evaluation)

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13 pages, 2509 KiB

Open AccessArticle

Dose-Ranging Plasma and Genital Tissue Pharmacokinetics and Biodegradation of Ultra-Long-Acting Cabotegravir In Situ Forming Implant

by Isabella C. Young, Allison L. Thorson, Roopali Shrivastava, Craig Sykes, Amanda P. Schauer, Mackenzie L. Cottrell, Angela D. M. Kashuba and Soumya Rahima Benhabbour

Pharmaceutics 2023, 15(5), 1487; https://doi.org/10.3390/pharmaceutics15051487 - 13 May 2023

Cited by 1 | Viewed by 1175

Abstract

HIV continues to affect millions of men and women worldwide. The development of long-acting injectables for HIV prevention can overcome adherence challenges with daily oral prevention regimens by reducing dosing frequency and stigma. We previously developed an ultra-long-acting injectable, biodegradable, and removeable in [...] Read more.

HIV continues to affect millions of men and women worldwide. The development of long-acting injectables for HIV prevention can overcome adherence challenges with daily oral prevention regimens by reducing dosing frequency and stigma. We previously developed an ultra-long-acting injectable, biodegradable, and removeable in situ forming implant (ISFI) with cabotegravir (CAB) that demonstrated protection after multiple rectal SHIV challenges in female macaques. Here, we sought to further characterize CAB ISFI pharmacokinetics (PK) in mice by assessing the effect of dose and number of injections on CAB PK, time to completion of CAB release and polymer degradation, long-term genital tissue PK, and CAB PK tail after implant removal. CAB concentrations in plasma were above the benchmark for protection for 11–12 months with proportionality between dose and drug exposure. CAB ISFI exhibited high concentrations in vaginal, cervical, and rectal tissues for up to 180 days. Furthermore, depots were easily retrievable up to 180 days post-administration with up to 34% residual CAB and near complete (85%) polymer degradation quantified in depots ex vivo. After depot removal, results demonstrated a median 11-fold decline in CAB plasma concentrations across all doses. Ultimately, this study provided critical PK information for the CAB ISFI formulation that could aid in its future translation to clinical studies. Full article

(This article belongs to the Special Issue HIV/AIDS Prevention Formulation Design and Optimization and Its Pharmacokinetic-Pharmacodynamic Evaluation)

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Review

Jump to: Research, Other

42 pages, 6282 KiB

Open AccessEditor’s ChoiceReview

Polymer Delivery Systems for Long-Acting Antiretroviral Drugs

by Mohammad Ullah Nayan, Sudipta Panja, Ashrafi Sultana, Lubaba A. Zaman, Lalitkumar K. Vora, Brady Sillman, Howard E. Gendelman and Benson Edagwa

Pharmaceutics 2024, 16(2), 183; https://doi.org/10.3390/pharmaceutics16020183 - 28 Jan 2024

Viewed by 1061

Abstract

The success of long-acting (LA) drug delivery systems (DDSs) is linked to their biocompatible polymers. These are used for extended therapeutic release. For treatment or prevention of human immune deficiency virus type one (HIV-1) infection, LA DDSs hold promise for improved regimen adherence [...] Read more.

The success of long-acting (LA) drug delivery systems (DDSs) is linked to their biocompatible polymers. These are used for extended therapeutic release. For treatment or prevention of human immune deficiency virus type one (HIV-1) infection, LA DDSs hold promise for improved regimen adherence and reduced toxicities. Current examples include Cabenuva, Apretude, and Sunlenca. Each is safe and effective. Alternative promising DDSs include implants, prodrugs, vaginal rings, and microarray patches. Each can further meet patients’ needs. We posit that the physicochemical properties of the formulation chemical design can optimize drug release profiles. We posit that the strategic design of LA DDS polymers will further improve controlled drug release to simplify dosing schedules and improve regimen adherence. Full article

(This article belongs to the Special Issue HIV/AIDS Prevention Formulation Design and Optimization and Its Pharmacokinetic-Pharmacodynamic Evaluation)

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Other

Jump to: Research, Review

11 pages, 2920 KiB

Open AccessPerspective

Preclinical and Early Clinical Development of Tenofovir Alafenamide/Elvitegravir Topical Inserts for Effective On-Demand Vaginal and Rectal HIV Prevention

by M. Melissa Peet, Vivek Agrahari, Meredith R. Clark and Gustavo F. Doncel

Pharmaceutics 2024, 16(3), 348; https://doi.org/10.3390/pharmaceutics16030348 - 01 Mar 2024

Viewed by 825

Abstract

HIV/AIDS remains a global public health issue, and products available for the prevention of HIV infections are limited, especially those for short-acting, on-demand, user-controlled applications. Topical inserts are products that can be applied vaginally or rectally and have been explored as drug delivery [...] Read more.

HIV/AIDS remains a global public health issue, and products available for the prevention of HIV infections are limited, especially those for short-acting, on-demand, user-controlled applications. Topical inserts are products that can be applied vaginally or rectally and have been explored as drug delivery systems. To fill the gap in the HIV prevention product pipeline, CONRAD has developed a topical insert containing tenofovir alafenamide fumarate (TAF) and elvitegravir (EVG), two potent and synergistic antiretrovirals, as a simple, low-cost, and discreet option that can be self-administered vaginally and/or rectally, before and after coitus. In this review, we have described the development path of the TAF/EVG insert up to its current point in clinical testing, highlighting findings from acceptability, preclinical safety, pharmacokinetics, and efficacy evaluations and early clinical studies. In summary, the TAF/EVG inserts are stable, easy to manufacture, low-cost, acceptable, and show highly promising preclinical and clinical results for on-demand topical pre- or post-exposure HIV prevention. Full article

(This article belongs to the Special Issue HIV/AIDS Prevention Formulation Design and Optimization and Its Pharmacokinetic-Pharmacodynamic Evaluation)

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