2-Hydroxypropyl-β-cyclodextrin-enhanced pharmacokinetics of cabotegravir from a nanofluidic implant for HIV pre-exposure prophylaxis

Fernanda P. Pons-Faudoa, Antons Sizovs, Nicola Di Trani, Jesus Paez-Mayorga, Giacomo Bruno, Jessica Rhudy, Madhuri Manohar, Kevin Gwenden, Cecilia Martini, Corrine Ying Xuan Chua, Greta Varchi, Mark A Marzinke, Alessandro Grattoni

Research output: Contribution to journalArticle

Abstract

Preexposure prophylaxis (PrEP) with antiretrovirals (ARV) can prevent human immunodeficiency virus (HIV) transmission, but its efficacy is highly dependent on strict patient adherence to daily dosing regimen. Long-acting (LA) ARV formulations or delivery systems that reduce dosing frequency may increase adherence and thus PrEP efficacy. While cabotegravir (CAB) long-acting injectable (CAB LA), an integrase strand transfer inhibitor (INSTI), reduces dosing frequency to bimonthly injections, variable pharmacokinetics (PK) between patients and various adverse reactions necessitate improvement in delivery methods. Here we developed a subcutaneously implantable nanofluidic device for the sustained delivery of CAB formulated with 2-hydroxypropyl-β-cyclodextrin (βCAB) and examined the pharmacokinetics (PK) in Sprague-Dawley rats for 3 months in comparison to CAB. Our study demonstrated βCAB treatment group maintained clinically-relevant plasma CAB concentrations 2 times above the protein-adjusted concentration that inhibits viral replication by 90% (2 × PA-IC90) and drug penetration into tissues relevant to HIV-1 transmission. Further, we successfully fitted plasma CAB concentrations into a PK model (R2 = 0.9999) and determined CAB apparent elimination half-life of 47 days. Overall, our data shows the potential of sustained release of βCAB via a nanofluidic implant for long-term PrEP delivery, warranting further investigation for efficacy against HIV infections.

Original languageEnglish (US)
Pages (from-to)89-96
Number of pages8
JournalJournal of Controlled Release
Volume306
DOIs
StatePublished - Jul 28 2019

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Cyclodextrins
Pharmacokinetics
HIV
Integrases
Injections
Virus Diseases
Patient Compliance
Sprague Dawley Rats
Half-Life
HIV-1
Equipment and Supplies
Pharmaceutical Preparations
Pre-Exposure Prophylaxis
Proteins
Therapeutics

Keywords

  • Cabotegravir
  • Formulation
  • HIV
  • Implant
  • PrEP

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

2-Hydroxypropyl-β-cyclodextrin-enhanced pharmacokinetics of cabotegravir from a nanofluidic implant for HIV pre-exposure prophylaxis. / Pons-Faudoa, Fernanda P.; Sizovs, Antons; Di Trani, Nicola; Paez-Mayorga, Jesus; Bruno, Giacomo; Rhudy, Jessica; Manohar, Madhuri; Gwenden, Kevin; Martini, Cecilia; Chua, Corrine Ying Xuan; Varchi, Greta; Marzinke, Mark A; Grattoni, Alessandro.

In: Journal of Controlled Release, Vol. 306, 28.07.2019, p. 89-96.

Research output: Contribution to journalArticle

Pons-Faudoa, FP, Sizovs, A, Di Trani, N, Paez-Mayorga, J, Bruno, G, Rhudy, J, Manohar, M, Gwenden, K, Martini, C, Chua, CYX, Varchi, G, Marzinke, MA & Grattoni, A 2019, '2-Hydroxypropyl-β-cyclodextrin-enhanced pharmacokinetics of cabotegravir from a nanofluidic implant for HIV pre-exposure prophylaxis', Journal of Controlled Release, vol. 306, pp. 89-96. https://doi.org/10.1016/j.jconrel.2019.05.037
Pons-Faudoa, Fernanda P. ; Sizovs, Antons ; Di Trani, Nicola ; Paez-Mayorga, Jesus ; Bruno, Giacomo ; Rhudy, Jessica ; Manohar, Madhuri ; Gwenden, Kevin ; Martini, Cecilia ; Chua, Corrine Ying Xuan ; Varchi, Greta ; Marzinke, Mark A ; Grattoni, Alessandro. / 2-Hydroxypropyl-β-cyclodextrin-enhanced pharmacokinetics of cabotegravir from a nanofluidic implant for HIV pre-exposure prophylaxis. In: Journal of Controlled Release. 2019 ; Vol. 306. pp. 89-96.
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abstract = "Preexposure prophylaxis (PrEP) with antiretrovirals (ARV) can prevent human immunodeficiency virus (HIV) transmission, but its efficacy is highly dependent on strict patient adherence to daily dosing regimen. Long-acting (LA) ARV formulations or delivery systems that reduce dosing frequency may increase adherence and thus PrEP efficacy. While cabotegravir (CAB) long-acting injectable (CAB LA), an integrase strand transfer inhibitor (INSTI), reduces dosing frequency to bimonthly injections, variable pharmacokinetics (PK) between patients and various adverse reactions necessitate improvement in delivery methods. Here we developed a subcutaneously implantable nanofluidic device for the sustained delivery of CAB formulated with 2-hydroxypropyl-β-cyclodextrin (βCAB) and examined the pharmacokinetics (PK) in Sprague-Dawley rats for 3 months in comparison to CAB. Our study demonstrated βCAB treatment group maintained clinically-relevant plasma CAB concentrations 2 times above the protein-adjusted concentration that inhibits viral replication by 90{\%} (2 × PA-IC90) and drug penetration into tissues relevant to HIV-1 transmission. Further, we successfully fitted plasma CAB concentrations into a PK model (R2 = 0.9999) and determined CAB apparent elimination half-life of 47 days. Overall, our data shows the potential of sustained release of βCAB via a nanofluidic implant for long-term PrEP delivery, warranting further investigation for efficacy against HIV infections.",
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AU - Pons-Faudoa, Fernanda P.

AU - Sizovs, Antons

AU - Di Trani, Nicola

AU - Paez-Mayorga, Jesus

AU - Bruno, Giacomo

AU - Rhudy, Jessica

AU - Manohar, Madhuri

AU - Gwenden, Kevin

AU - Martini, Cecilia

AU - Chua, Corrine Ying Xuan

AU - Varchi, Greta

AU - Marzinke, Mark A

AU - Grattoni, Alessandro

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N2 - Preexposure prophylaxis (PrEP) with antiretrovirals (ARV) can prevent human immunodeficiency virus (HIV) transmission, but its efficacy is highly dependent on strict patient adherence to daily dosing regimen. Long-acting (LA) ARV formulations or delivery systems that reduce dosing frequency may increase adherence and thus PrEP efficacy. While cabotegravir (CAB) long-acting injectable (CAB LA), an integrase strand transfer inhibitor (INSTI), reduces dosing frequency to bimonthly injections, variable pharmacokinetics (PK) between patients and various adverse reactions necessitate improvement in delivery methods. Here we developed a subcutaneously implantable nanofluidic device for the sustained delivery of CAB formulated with 2-hydroxypropyl-β-cyclodextrin (βCAB) and examined the pharmacokinetics (PK) in Sprague-Dawley rats for 3 months in comparison to CAB. Our study demonstrated βCAB treatment group maintained clinically-relevant plasma CAB concentrations 2 times above the protein-adjusted concentration that inhibits viral replication by 90% (2 × PA-IC90) and drug penetration into tissues relevant to HIV-1 transmission. Further, we successfully fitted plasma CAB concentrations into a PK model (R2 = 0.9999) and determined CAB apparent elimination half-life of 47 days. Overall, our data shows the potential of sustained release of βCAB via a nanofluidic implant for long-term PrEP delivery, warranting further investigation for efficacy against HIV infections.

AB - Preexposure prophylaxis (PrEP) with antiretrovirals (ARV) can prevent human immunodeficiency virus (HIV) transmission, but its efficacy is highly dependent on strict patient adherence to daily dosing regimen. Long-acting (LA) ARV formulations or delivery systems that reduce dosing frequency may increase adherence and thus PrEP efficacy. While cabotegravir (CAB) long-acting injectable (CAB LA), an integrase strand transfer inhibitor (INSTI), reduces dosing frequency to bimonthly injections, variable pharmacokinetics (PK) between patients and various adverse reactions necessitate improvement in delivery methods. Here we developed a subcutaneously implantable nanofluidic device for the sustained delivery of CAB formulated with 2-hydroxypropyl-β-cyclodextrin (βCAB) and examined the pharmacokinetics (PK) in Sprague-Dawley rats for 3 months in comparison to CAB. Our study demonstrated βCAB treatment group maintained clinically-relevant plasma CAB concentrations 2 times above the protein-adjusted concentration that inhibits viral replication by 90% (2 × PA-IC90) and drug penetration into tissues relevant to HIV-1 transmission. Further, we successfully fitted plasma CAB concentrations into a PK model (R2 = 0.9999) and determined CAB apparent elimination half-life of 47 days. Overall, our data shows the potential of sustained release of βCAB via a nanofluidic implant for long-term PrEP delivery, warranting further investigation for efficacy against HIV infections.

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