Recent Publications

The latest research and clinical studies being done in long-acting, extended release drugs for HIV and TB.

Long-Acting Drugs and Formulations for the Treatment and Prevention of HIV

Date: 
11/6/20
Citation: 

Flexner C, Owen A, Siccardi M, Swindells S. Long-Acting Drugs and Formulations for the Treatment and Prevention of HIV,
International Journal of Antimicrobial Agents,2020, 106220,ISSN 0924-8579.

Long acting and extended-release formulations represent one of the most important approaches to improving the treatment and prevention of chronic HIV infection. Long acting small molecules and monoclonal antibodies have demonstrated potent anti-HIV activity in early and late stage clinical trials. Strategies to manage toxicities and falling drug concentrations after missed doses, as well as primary and secondary resistance to current drugs and monoclonal antibodies are important considerations.

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Performance and Stability of Tenofovir Alafenamide Formulations within Subcutaneous Biodegradable Implants for HIV Pre-Exposure Prophylaxis (PrEP)

Date: 
11/5/20
Citation: 

Li L, Johnson LM, Krovi SA, Demkovich ZR, van der Straten A. Performance and Stability of Tenofovir Alafenamide Formulations within Subcutaneous Biodegradable Implants for HIV Pre-Exposure Prophylaxis (PrEP). Pharmaceutics. 2020; 12(11):1057.

A critical need exists to develop diverse biomedical strategies for the widespread use of HIV Pre-Exposure Prophylaxis (HIV PrEP). This manuscript describes a subcutaneous reservoir-style implant for long-acting delivery of tenofovir alafenamide (TAF) for HIV PrEP. We detail key parameters of the TAF formulation that affect implant performance, including TAF ionization form, the selection of excipient and the exposure to aqueous conditions. Both in-vitro studies and shelf stability tests demonstrate enhanced performance for TAF freebase (TAFFB) in this long-acting implant platform, as TAFFB maintains higher chemical stability than the TAF hemifumarate salt (TAFHF). 

Application of Clinical Pharmacology Principles in Drug Development of Modified-Release Products: Leveraging Exposure-Response Information to Support Approval

Date: 
11/3/20
Citation: 

AbuAsal BS, Hamed SS, Ahmed MA, Al-Mansour L, Uppoor R, Mehta M. Application of Clinical Pharmacology Principles in Drug Development of Modified-Release Products: Leveraging Exposure-Response Information to Support Approval. J Clin Pharmacol. 2020 Nov;60(11):1441-1452. doi: 10.1002/jcph.1637. Epub 2020 May 26. PMID: 32453882.

The development of modified-release (MR) drug products aims to address a clinical need such as improving patient compliance. There are multiple pathways and development strategies for the registration and approval of MR products. The development strategy of an MR product is usually dependent on the availability and pharmacokinetic/pharmacodynamics (PK/PD) characteristics of the reference drug product, that is, an immediate-release (IR) product or a reference MR. Compared with a reference IR product, an MR product is likely to have a different PK profile over the least common dosing time due to unequal dosing intervals. In case of differences in PK profiles between the MR product and the reference product, confirmatory efficacy and safety studies may be needed to support registration. 

Novel Long-Acting Drug Combination Nanoparticles Composed of Gemcitabine and Paclitaxel Enhance Localization of Both Drugs in Metastatic Breast Cancer Nodules

Date: 
9/23/20
Citation: 

Yu J, Mu Q, Perazzolo S, Griffin JI, Zhu L, McConnachie LA, Shen DD, Ho RJ. Novel Long-Acting Drug Combination Nanoparticles Composed of Gemcitabine and Paclitaxel Enhance Localization of Both Drugs in Metastatic Breast Cancer Nodules. Pharm Res. 2020 Sep 23;37(10):197. doi: 10.1007/s11095-020-02888-8. PMID: 32968837.

 GT DcNPs were evaluated based on particle size and drug association efficiency (AE%). The effect of DcNP on GT plasma time-course and tissue distribution was characterized in mice and a pharmacokinetic model was developed. A GT distribution study into cancer nodules (derived from 4 T1 cells) was performed.

Exploration into the opinions of patients with HIV, healthcare professionals and the lay public of the use of microneedles in clinical practice: highlighting the translational potential for their role in HIV infection

Date: 
9/18/20
Citation: 

Moffatt K, Quinn C, McCague PJ, Donnelly RF. Exploration into the opinions of patients with HIV, healthcare professionals and the lay public of the use of microneedles in clinical practice: highlighting the translational potential for their role in HIV infection. Drug Deliv Transl Res. 2020 Sep 18. doi: 10.1007/s13346-020-00848-8. Epub ahead of print. PMID: 32946042.

Poor adherence to oral antiretroviral therapy (ART) remains an important challenge in the treatment of HIV. Microneedles (MN) potentially could offer a non-invasive long-acting (LA) delivery approach, avoiding the need for daily dosing of ART. However, this claim has yet to be explored amongst its potential end-users. The aim of this mixed methods study was to investigate the perspectives from various end-users surrounding the translation of MN technology to general clinical practice, with a particular focus on delivery of ART. Quantitative postal questionnaires were distributed amongst healthcare professionals (HCPs) and the lay public (LP). A total of 208 responses were obtained (HCP, 69; LP, 139), with a completion rate of 34.7%. The consensus on MN technology was positive from both demographics (HCP, 97.1%; LP, 98.6%), with further strong support of postulated MN use within HIV (HCP, 97.1%; LP, 98.6%). 

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A year-long extended release nanoformulated cabotegravir prodrug

Date: 
8/15/20
Citation: 

Kulkarni TA, Bade AN, Sillman B, et al. A year-long extended release nanoformulated cabotegravir prodrug. Nat Mater. 2020;19(8):910-920. doi:10.1038/s41563-020-0674-z

Long-acting cabotegravir (CAB) extends antiretroviral drug administration from daily to monthly. However, dosing volumes, injection site reactions and health-care oversight are obstacles towards a broad usage. The creation of poloxamer-coated hydrophobic and lipophilic CAB prodrugs with controlled hydrolysis and tissue penetrance can overcome these obstacles. To such ends, fatty acid ester CAB nanocrystal prodrugs with 14, 18 and 22 added carbon chains were encased in biocompatible surfactants named NMCAB, NM2CAB and NM3CAB and tested for drug release, activation, cytotoxicity, antiretroviral activities, pharmacokinetics and biodistribution.

Translating Cell and Gene Biopharmaceutical Products for Health and Market Impact. Product Scaling From Clinical to Marketplace: Lessons Learned and Future Outlook

Date: 
8/15/20
Citation: 

Bak A, Friis KP, Wu Y, Ho RJY. Translating Cell and Gene Biopharmaceutical Products for Health and Market Impact. Product Scaling From Clinical to Marketplace: Lessons Learned and Future Outlook. J Pharm Sci. 2019 Oct;108(10):3169-3175. doi: 10.1016/j.xphs.2019.05.027. Epub 2019 May 29. PMID: 31150697.

Cell and gene therapies have the potential to be curative for severe disease states such as cancer or incurable orphan genetic diseases. Despite the promise, there are only few such therapies available, although more are appearing in pharmaceutical pipelines. A major culprit limiting a fast translation from preclinical research to the clinic and the market is chemistry, manufacturing and control. The root cause is that most cell and gene therapies currently are personalized in form of ex vivo manipulated cells. This approach stands in sharp contrast to the population-based approach seen for small molecules and protein therapeutics. Therefore, it warrants a different approach to product manufacturing, testing, release, regulatory submissions, and product distribution.

Controlled Solvent Removal from Antiviral Drugs and Excipients in Solution Enables the Formation of Novel Combination Multi-Drug-Motifs in Pharmaceutical Powders Composed of Lopinavir, Ritonavir and Tenofovir

Date: 
8/10/20
Citation: 

Yu J, Yu D, Lane S, McConnachie L, Ho RJY. Controlled Solvent Removal from Antiviral Drugs and Excipients in Solution Enables the Formation of Novel Combination Multi-Drug-Motifs in Pharmaceutical Powders Composed of Lopinavir, Ritonavir and Tenofovir. J Pharm Sci. 2020 Aug 10:S0022-3549(20)30434-2. doi: 10.1016/j.xphs.2020.08.003. Epub ahead of print. PMID: 32791073.

Diverging physicochemical properties of HIV drug combinations are challenging to formulate as a single dosage form. We have found that 2-to-4 hydrophilic and hydrophobic HIV drugs in combination can be stabilized with lipid excipients under a controlled solvent removal process to form a novel pharmaceutical powder distinct from typical amorphous material. This discovery has enabled production of a drug combination nanoparticle (DcNP) powder composed of 3 HIV drugs-water-insoluble lopinavir (LogP = 4.7) and ritonavir (LogP = 5.6) and water-soluble tenofovir (LogP = -1.6). 

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Integrated Multi-stakeholder Systems Thinking Strategy: Decision-making with Biopharmaceutics Risk Assessment Roadmap (BioRAM) to Optimize Clinical Performance of Drug Products

Date: 
7/27/20
Citation: 

Selen A, Müllertz A, Kesisoglou F, Ho RJY, Cook JA, Dickinson PA, Flanagan T. Integrated Multi-stakeholder Systems Thinking Strategy: Decision-making with Biopharmaceutics Risk Assessment Roadmap (BioRAM) to Optimize Clinical Performance of Drug Products. AAPS J. 2020 Jul 27;22(5):97. doi: 10.1208/s12248-020-00470-z. PMID: 32719954.

Decision-making in drug development benefits from an integrated systems approach, where the stakeholders identify and address the critical questions for the system through carefully designed and performed studies. Biopharmaceutics Risk Assessment Roadmap (BioRAM) is such a systems approach for application of systems thinking to patient focused and timely decision-making, suitable for all stages of drug discovery and development. We described the BioRAM therapy-driven drug delivery framework, strategic roadmap, and integrated risk assessment instrument (BioRAM Scoring Grid) in previous publications (J Pharm Sci 103:3377-97, 2014; J Pharm Sci 105:3243-55, 2016).

Pharmacokinetics, Safety and Tolerability of Long-Acting Parenteral Intramuscular Injection Formulations of Doravirine

Date: 
6/5/20
Citation: 

Yee KL, Mittal S, Fan L, et al. Pharmacokinetics, safety and tolerability of long-acting parenteral intramuscular injection formulations of doravirine [published online ahead of print, 2020 Jun 5]. J Clin Pharm Ther. 2020;10.1111/jcpt.13182. doi:10.1111/jcpt.13182. PMID: 32501541.

Doravirine is a non-nucleoside reverse transcriptase inhibitor indicated for the treatment of human immunodeficiency virus (HIV)-1 infection. This phase 1 study in healthy adults investigated the pharmacokinetics, safety and tolerability of long-acting parenteral (LAP) microsuspension formulations of doravirine administered as an intramuscular (IM) injection.

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