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

Research output: Contribution to journalArticle

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

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

PMID: 31136811

Altmetrics

Cite this

Standard

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, 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

Harvard

Pons-Faudoa, FP, Sizovs, A, Di Trani, N, Paez-Mayorga, J, Bruno, G, Rhudy, J, Manohar, M, Gwenden, K, Martini, C, Chua, YX, 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

APA

Pons-Faudoa, F. P., Sizovs, A., Di Trani, N., Paez-Mayorga, J., Bruno, G., Rhudy, J., ... Grattoni, A. (2019). 2-Hydroxypropyl-β-cyclodextrin-enhanced pharmacokinetics of cabotegravir from a nanofluidic implant for HIV pre-exposure prophylaxis. Journal of Controlled Release, 306, 89-96. https://doi.org/10.1016/j.jconrel.2019.05.037

Vancouver

Pons-Faudoa FP, Sizovs A, Di Trani N, Paez-Mayorga J, Bruno G, Rhudy J et al. 2-Hydroxypropyl-β-cyclodextrin-enhanced pharmacokinetics of cabotegravir from a nanofluidic implant for HIV pre-exposure prophylaxis. Journal of Controlled Release. 2019 Jul 28;306:89-96. https://doi.org/10.1016/j.jconrel.2019.05.037

Author

Pons-Faudoa, Fernanda P. ; Sizovs, Antons ; Di Trani, Nicola ; Paez-Mayorga, Jesus ; Bruno, Giacomo ; Rhudy, Jessica ; Manohar, Madhuri ; Gwenden, Kevin ; Martini, Cecilia ; Chua, 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.

BibTeX

@article{450220f3c300499c8acd2fee33b1c3ba,
title = "2-Hydroxypropyl-β-cyclodextrin-enhanced pharmacokinetics of cabotegravir from a nanofluidic implant for HIV pre-exposure prophylaxis",
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.",
keywords = "Cabotegravir, Formulation, HIV, Implant, PrEP",
author = "Pons-Faudoa, {Fernanda P.} and Antons Sizovs and {Di Trani}, Nicola and Jesus Paez-Mayorga and Giacomo Bruno and Jessica Rhudy and Madhuri Manohar and Kevin Gwenden and Cecilia Martini and Chua, {Ying Xuan} and Greta Varchi and Marzinke, {Mark A.} and Alessandro Grattoni",
year = "2019",
month = "7",
day = "28",
doi = "10.1016/j.jconrel.2019.05.037",
language = "English (US)",
volume = "306",
pages = "89--96",
journal = "Journal of Controlled Release",
issn = "0168-3659",
publisher = "Elsevier",

}

RIS

TY - JOUR

T1 - 2-Hydroxypropyl-β-cyclodextrin-enhanced pharmacokinetics of cabotegravir from a nanofluidic implant for HIV pre-exposure prophylaxis

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, Ying Xuan

AU - Varchi, Greta

AU - Marzinke, Mark A.

AU - Grattoni, Alessandro

PY - 2019/7/28

Y1 - 2019/7/28

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.

KW - Cabotegravir

KW - Formulation

KW - HIV

KW - Implant

KW - PrEP

UR - http://www.scopus.com/inward/record.url?scp=85066797018&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85066797018&partnerID=8YFLogxK

U2 - 10.1016/j.jconrel.2019.05.037

DO - 10.1016/j.jconrel.2019.05.037

M3 - Article

VL - 306

SP - 89

EP - 96

JO - Journal of Controlled Release

T2 - Journal of Controlled Release

JF - Journal of Controlled Release

SN - 0168-3659

ER -

ID: 49555064