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

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

doi:10.3390/pharmaceutics14030615

Cited by 9 publications

(6 citation statements)

References 20 publications

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“…During optimization and building on our prior work, all CAB ISFI formulations were generated using an FDA-approved biodegradable polymer consisting of 50:50 PLGA, which enables ultra-long release of antiretrovirals from ISFIs 20,21,29 and has a favorable degradation profile including eliciting complete degradation within a few months 30,31 . This degradation profile is ideal to ensure complete polymer degradation prior to subsequent ISFI injections to prevent polymer accumulation.…”

Section: Optimization Of Cab Isfi and In Vitro Drug Releasementioning

confidence: 99%

Ultra-long-acting in-situ forming implants with cabotegravir protect female macaques against rectal SHIV infection

et al. 2023

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Ultra-long-acting delivery platforms for HIV pre-exposure prophylaxis (PrEP) may increase adherence and maximize public health benefit. We report on an injectable, biodegradable, and removable in-situ forming implant (ISFI) that is administered subcutaneously and can release the integrase inhibitor cabotegravir (CAB) above protective benchmarks for more than 6 months. CAB ISFIs are well-tolerated in female mice and female macaques showing no signs of toxicity or chronic inflammation. In macaques, median plasma CAB concentrations exceed established PrEP protection benchmarks within 3 weeks and confer complete protection against repeated rectal SHIV challenges. Implant removal via a small incision in 2 macaques at week 12 results in a 7- to 48-fold decrease in plasma CAB levels within 72 hours. Modeling to translate CAB ISFI dosing suggests that a 3 mL injection would exceed protective benchmarks in humans for over 5 months post administration. Our results support the clinical advancement of CAB ISFIs for ultra-long-acting PrEP in humans.

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Section: Optimization Of Cab Isfi and In Vitro Drug Releasementioning

confidence: 99%

Ultra-long-acting in-situ forming implants with cabotegravir protect female macaques against rectal SHIV infection

et al. 2023

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“…However, absorption kinetics may differ between gluteal and alternative routes of administration, which may be influenced by differences in muscle‐fat tissue composition and other yet unidentified variables. Finally, new ultra‐long‐acting technologies are on the horizon with the potential to extend drug dosing intervals 41,42 by up to a year, thereby improving the convenience of the HIV prevention and treatment.…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics of Cabotegravir Following Oral Administration and Long‐Acting Intramuscular Injection in Real‐World People with HIV

Thoueille,

Saldanha,

Schaller

et al. 2024

Clin Pharma and Therapeutics

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Long‐acting cabotegravir has been studied mainly in the stringent framework of clinical trials, which does not necessarily reflect the situation of people with HIV (PWH) in routine clinical settings. The present population pharmacokinetic analysis aims to build real‐world reference percentile curves of cabotegravir concentrations, accounting for patient‐related factors that may affect cabotegravir exposure. The second objective is to simulate whether dosing interval adjustments of cabotegravir could be considered in specific subpopulations. Overall, 238 PWH contributed to 1,038 cabotegravir levels (186 during the initial oral administration phase and 852 after intramuscular injection). Cabotegravir pharmacokinetics was best described using a one‐compartment model with distinct first order‐absorption for oral and intramuscular administrations, and identical volume and clearance. Our model showed almost 40% faster absorption and 30% higher clearance than previously reported, resulting in a time to steady‐state of 8 months and an elimination half‐life of 4.6 weeks for long‐acting cabotegravir. Sex and body mass index significantly influenced absorption, and bodyweight affected clearance. Model‐based simulations showed that cabotegravir trough concentrations in females were 25% lower 4 weeks after the intramuscular loading dose, but 42% higher during the late maintenance phase. Finally, simulations indicated that in females, despite significantly higher cabotegravir concentrations, longer intervals between injections may not consistently ensure levels above the 4‐fold protein‐adjusted 90% inhibitory target concentration.

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“…Accessible surface area can also be controlled by the microfractures or surface roughness of the API. In addition, injection volume and injection site could also affect the in vivo release of the API [43].…”

Section: Drug Repurposing -Advances Scopes and Opportunities In Drug ...mentioning

confidence: 99%

Utilizing 505(b)(2) Regulatory Pathway for New Drug Applications: An Overview on the Advanced Formulation Approach and Challenges

Chen¹,

Zhang²,

Wang³

et al. 2023

Drug Repurposing - Advances, Scopes and Opportunities in Drug Discovery

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More than 50% of approved drugs on the market contain poorly water-soluble APIs, which typically are associated with poor bioavailability, suboptimal drug delivery, ineffective drug efficacy, and side effects. This creates a huge opportunity in generating 505(b)(2) products, which address unmet medical needs by applying formulation technologies to overcome those difficulties. A key feature of the 505(b)(2) pathway is the 505(b)(2) sponsor can rely upon clinical data or literature produced by other companies. The 505(b)(2) pathway allows manufacturers to acquire FDA approval without performing all the work required with a traditional NDA. The 505(b)(2) strategy can be an option to improve existing drug products with a new indication, dosage form, dosing regimen, strength, combination with other products, new route of administration, elimination of food effect, switching from a prescription drugs (Rx) to an over-the-counter (OTC), non-prescription product that differs from the OTC monograph, and orphan drug indications. Both generic and brand companies are turning to more complex 505(b)(2) products to avoid the commoditized generic competition. Revitalization of older marketed drug products using innovative drug delivery technologies or platforms can provide new marketing exclusivity and new patent protection, and thus offer an effective tool for product life cycle management.

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

Cited by 9 publications

References 20 publications

Ultra-long-acting in-situ forming implants with cabotegravir protect female macaques against rectal SHIV infection

Ultra-long-acting in-situ forming implants with cabotegravir protect female macaques against rectal SHIV infection

Population Pharmacokinetics of Cabotegravir Following Oral Administration and Long‐Acting Intramuscular Injection in Real‐World People with HIV

Utilizing 505(b)(2) Regulatory Pathway for New Drug Applications: An Overview on the Advanced Formulation Approach and Challenges

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