Strengths, weaknesses, opportunities and challenges for long acting injectable therapies: Insights for applications in HIV therapy

Abstract

Advances in solid drug nanoparticle technologies have resulted in a number of long-acting (LA) formulations with the potential for once monthly or longer administration. Such formulations offer great utility for chronic diseases, particularly when a lack of medication compliance may be detrimental to treatment response. Two such formulations are in clinical development for HIV but the concept of LA delivery has its origins in indications such as schizophrenia and contraception. Many terms have been utilised to describe the LA approach and standardisation would be beneficial. Ultimately, definitions will depend upon specific indications and routes of delivery, but for HIV we propose benchmarks that reflect perceived clinical benefits and available data on patient attitudes. Specifically, we propose dosing intervals of ≥ 1 week, ≥ 1 month or ≥ 6 months, for oral, injectable or implantable strategies, respectively. This review focuses upon the critical importance of potency in achieving the LA outcome for injectable formulations and explores established and emerging technologies that have been employed across indications. Key technological challenges such as the need for consistency and ease of administration for drug combinations, are also discussed. Finally, the review explores the gaps in knowledge regarding the pharmacology of drug release from particulate-based LA injectable suspensions. A number of hypotheses are discussed based upon available data relating to local drug metabolism, active transport systems, the lymphatics, macrophages and patient-specific factors. Greater knowledge of the mechanisms that underpin drug release and protracted exposure will help facilitate further development of this strategy to achieve the promising clinical benefits.

Long-acting formulations for the treatment of latent tuberculous infection: opportunities and challenges

“…This is especially true for existing oral anti-TB drugs, many of which lack the right balance of water solubilty, lipophilicity, half-life and potency. 16 Management of adverse effects may be more challenging with LA injectable formulations as they cannot be immediately discontinued, and the physicochemical properties that make them suitable for LA injectables also negate the option of dialysis or other strategies to remove the drug. New drug delivery technologies, such as removable solid or semi-solid implants, may alleviate many of these problems by providing options that are readily removable.…”

“…Since parenteral delivery avoids the gastrointestinal tract and first pass metabolism, it is conceivable that the magnitude of some transporter or enzyme-mediated drug-drug interactions or pharmacogenetic variability may be less with long-acting formulations, but this remains to be seen and will require careful evaluation. 16 …”

“…Recently, it was proposed that a candidate should achieve at least once weekly, once monthly, or once 6-monthly dosing to qualify as LA when considering oral, injection, or implant, respectively, in the context of HIV. 16 Thus, the application of the term should be strongly considered in the context of the specific indication for which a new medicine is being developed, and for TB this has informed the target product profile (TPP) discussed below.…”

“…Broadly, LA injectable medicines have been explored utilizing either intramuscular or subcutaneous administration of oil-based solutions, drug-encapsulated in polymer microparticles, in-situ formation of gels or solid/semi-solid structures, or drug particle suspensions. 16 The recent paradigm for LA injectables has emerged from the delivery of antipsychotic drugs such as paliperidone palmitate, 18 which involve intramuscular administration of solid drug nanoparticle (SDN) suspensions. Indeed, the exciting new developments for HIV prevention and therapy have involved the formation of SDNs of rilpivirine and cabotegravir, by the process of wet-bead milling.…”

Advancements in nano-enabled therapeutics for neuroHIV management

“…The strengths, weaknesses, opportunities, and challenges of LA-injectable therapies for HIV have been described excellently by Owen and Rannard. 6 The pharmacology and formulation of LA Ctg were described in a comprehensive review presented by Trezza et al 7 The authors concluded that the pharmacologic profile of Ctg has great potential for the treatment and prevention of HIV-1 infection. This drug exhibited half-life of 40 days and showed therapeutic action at a low dose.…”