Effects of Injection Volume and Route of Administration on Dolutegravir In Situ Forming Implant Pharmacokinetics.

Jordan B Joiner,Mackenzie L Cottrell,Soumya Rahima Benhabbour,Jasmine L King,Angela D M Kashuba,Paul A Dayton,Sarah Anne Howard,Roopali Shrivastava

doi:10.3390/pharmaceutics14030615

Jordan B Joiner, Mackenzie L Cottrell + Show 6 more

Open Access

https://doi.org/10.3390/pharmaceutics14030615

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Abstract

Due to the versatility of the in situ forming implant (ISFI) drug delivery system, it is crucial to understand the effects of formulation parameters for clinical translation. We utilized ultrasound imaging and pharmacokinetics (PK) in mice to understand the impact of administration route, injection volume, and drug loading on ISFI formation, degradation, and drug release in mice. Placebo ISFIs injected subcutaneously (SQ) with smaller volumes (40 L) exhibited complete degradation within 30–45 days, compared to larger volumes (80 L), which completely degraded within 45–60 days. However, all dolutegravir (DTG)-loaded ISFIs along the range of injection volumes tested (20–80 L) were present at 90 days post-injection, suggesting that DTG can prolong ISFI degradation. Ultrasound imaging showed that intramuscular (IM) ISFIs flattened rapidly post administration compared to SQ, which coincides with the earlier Tmax for drug-loaded IM ISFIs. All mice exhibited DTG plasma concentrations above four times the protein-adjusted 90% inhibitory concentration (PA-IC90) throughout the entire 90 days of the study. ISFI release kinetics best fit to zero order or diffusion-controlled models. When total administered dose was held constant, there was no statistical difference in drug exposure regardless of the route of administration or number of injections.

Highlights

There has been a surge in development of long-acting injectable formulations for a wide variety of sustained release applications, marked by the recently Food and DrugAdministration (FDA)-approved Cabenuva for human immunodeficiency virus (HIV)treatment [1]
Several past and recent works have sought to understand the effects of in situ forming implant (ISFI) properties on drug release using novel methods such as magnetic resonance imaging (MRI), ultrasound imaging, and ultraviolet imaging; to our knowledge, no works have studied the effect of ISFI formation and degradation via multiple routes of administration and varying injection volumes [2–6]
We previously demonstrated the utility of ultrasound imaging to noninvasively assess ISFI formation and bioerosion [14]

Summary

Introduction

There has been a surge in development of long-acting injectable formulations for a wide variety of sustained release applications, marked by the recently Food and Drug. This formulation consists of two gluteal IM injections of cabotegravir and rilpivirine suspensions, setting a precedent for injection of multiple formulations to sustain drug release. There is a need to understand the nuances in ISFI formation and degradation with varying injection sites and volumes. Several past and recent works have sought to understand the effects of ISFI properties on drug release using novel methods such as magnetic resonance imaging (MRI), ultrasound imaging, and ultraviolet imaging; to our knowledge, no works have studied the effect of ISFI formation and degradation via multiple routes of administration (including IM) and varying injection volumes [2–6]. This work has improved our understanding of how existing ISFI formulations work, and will serve as a guide for future development.

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