LEAP Publications

Creating demand for long-acting formulations for the treatment and prevention of HIV, tuberculosis, and viral hepatitis

Date:

1/1/19

Citation:

Flexner C, Thomas DL, Swindells S. Creating demand for long-acting formulations for the treatment and prevention of HIV, tuberculosis, and viral hepatitis. Curr Opin HIV AIDS. 2019 Jan;14(1):13-20. doi: 10.1097/COH.0000000000000510. PMID: 30394948.

Long-acting drugs and formulations have radically altered the management of several important and common medical conditions, including chronic schizophrenia, osteoporosis, and contraception. In all three of the aforementioned circumstances, extended-release injectable versions of approved oral drugs are commonly used in settings where there is a need to improve adherence and/or convenience for the patient. In principle, any innovations that reduce the frequency of drug administration improve adherence. However, in this review ‘long-acting’ refers to an alteration in the delivery of a medication that results in dosing intervals of at least 1 week for oral medications, at least 1 month for injectable formulations, and at least 6 months for implants.

Modelling the long-acting administration of anti-tuberculosis agents using PBPK: a proof of concept study

Date:

8/1/18

Citation:

Rajoli RKR, Podany AT, Moss DM, Swindells S, Flexner C, Owen A, Siccardi M. Modelling the long-acting administration of anti-tuberculosis agents using PBPK: a proof of concept study. Int J Tuberc Lung Dis. 2018 Aug 1;22(8):937-944. doi: 10.5588/ijtld.17.0515. PMID: 29991405; PMCID: PMC6166436.

Tuberculosis (TB) remains a global pandemic and is one of the top ten leading causes of death worldwide, however early diagnosis and anti-TB therapy have saved over 49 million lives between 2000 and 2015. Individuals with latent TB infection (LTBI) along with immunosuppression, including neonates, infants, elderly and patients co-infected with HIV are at higher risk of developing active TB infection. Progression of LTBI to active TB is 12 to 20 times higher in HIV-infected persons than in those who are HIV-uninfected.

Antiretroviral implants for treatment and prevention of HIV infection

Date:

7/1/18

Citation:

Flexner C. Antiretroviral implants for treatment and prevention of HIV infection. Curr Opin HIV AIDS. 2018 Jul;13(4):374-380. doi: 10.1097/COH.0000000000000470. PMID: 29794816.

Current antiretroviral drugs and formulations have, for the most part, achieved optimal antiviral efficacy and tolerability. However, adherence with daily oral pill taking remains the most important barrier to long-term suppression of HIV replication and prevention of the emergence of drug-resistant virus variants. Patients who experience even short periods of nonadherence are in danger of losing the health benefits of antiretroviral therapy, and narrowing their choices for future treatment. This is true whether antiretroviral drugs are taken for treatment or prevention of infection.

In Silico Dose Prediction for Long-Acting Rilpivirine and Cabotegravir Administration to Children and Adolescents

Date:

2/1/18

Citation:

Rajoli RKR, Back DJ, Rannard S, Meyers CF, Flexner C, Owen A, Siccardi M. In Silico Dose Prediction for Long-Acting Rilpivirine and Cabotegravir Administration to Children and Adolescents. Clin Pharmacokinet. 2018 Feb;57(2):255-266. doi: 10.1007/s40262-017-0557-x. PMID: 28540638; PMCID: PMC5701864.

Long-acting injectable antiretrovirals represent a pharmacological alternative to oral formulations and an innovative clinical option to address adherence and reduce drug costs. Clinical studies in children and adolescents are characterised by ethical and logistic barriers complicating the identification of dose optimisation. Physiologically-based pharmacokinetic modelling represents a valuable tool to inform dose finding prior to clinical trials. The objective of this study was to simulate potential dosing strategies for existing long-acting injectable depot formulations of cabotegravir and rilpivirine in children and adolescents (aged 3-18 years) using physiologically-based pharmacokinetic modelling.

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

Date:

2/1/18

Citation:

Swindells S, Siccardi M, Barrett SE, Olsen DB, Grobler JA, Podany AT, Nuermberger E, Kim P, Barry CE, Owen A, Hazuda D, Flexner C. Long-acting formulations for the treatment of latent tuberculous infection: opportunities and challenges. Int J Tuberc Lung Dis. 2018 Feb 1;22(2):125-132. doi: 10.5588/ijtld.17.0486. PMID: 29506608; PMCID: PMC6103451.

The World Health Organization (WHO) strategy to end the global tuberculosis (TB) epidemic can only be accomplished by dramatic acceleration of early diagnosis of TB, preventive treatment of those at risk for disease progression, and treatment of all patients with TB. Of the 23% of the world’s population allegedly infected with latent tuberculosis infection (LTBI), less than 5% are diagnosed and treated, therefore diagnosis and management of LTBI is a crucial intervention for TB elimination.

Long-acting injectable atovaquone nanomedicines for malaria prophylaxis

Date:

1/22/18

Citation:

Bakshi RP, Tatham LM, Savage AC, Tripathi AK, Mlambo G, Ippolito MM, Nenortas E, Rannard SP, Owen A, Shapiro TA. Long-acting injectable atovaquone nanomedicines for malaria prophylaxis. Nat Commun. 2018 Jan 22;9(1):315. doi: 10.1038/s41467-017-02603-z. PMID: 29358624; PMCID: PMC5778127.

Every year, Plasmodium falciparum malaria afflicts hundreds of millions of people and kills hundreds of thousands of children. Despite considerable success in reducing the worldwide prevalence of malaria, its incidence in visitors to endemic areas has continued to rise steadily and for unprotected travellers to west Africa the risk of malaria is 3.4% mo−1. Though promising advances are being made, as of yet no malaria vaccine can reliably impart high levels of long-lived protection. Antimalarial drugs thus continue to provide an essential component of malaria prophylaxis. Unfortunately, however, the requirement for daily or weekly oral drug-dosing regimens is commonly associated with noncompliance.

Why a universal antiretroviral regimen?

Date:

7/1/17

Citation:

Flexner CW, Clayden P, Venter WDF. Why a universal antiretroviral regimen? Curr Opin HIV AIDS. 2017 Jul;12(4):315-317. doi: 10.1097/COH.0000000000000390. PMID: 28486340; PMCID: PMC5722220.

In 2015, with its "Treat all" recommendation, World Health Organization (WHO) removed all restrictions on eligibility for antiretroviral treatment (ART) among HIV positive people. WHO estimates that by the end of 2018, 20 million people worldwide will be receiving combination ART. An additional 15–17 million will be in need of ART but unable to access or afford it. Most of the existing supply of antiretrovirals (ARVs) is provided through international agencies, such as PEPFAR and the Global Fund, or governments of low- and middle-income countries (LMICs), all of which face stable or shrinking health care budgets.

Universal antiretroviral regimens: thinking beyond one-pill-once-a-day

Date:

7/1/17

Citation:

Jacobson JM, Flexner CW. Universal antiretroviral regimens: thinking beyond one-pill-once-a-day. Curr Opin HIV AIDS. 2017 Jul;12(4):343-350. doi: 10.1097/COH.0000000000000374. PMID: 28368868; PMCID: PMC5753590.

Orally-administered combination antiretroviral drug therapy has had impressive success in suppressing viral replication in HIV-infected individuals and largely protecting them from the complications of HIV-1 infection. Incomplete recovery of the CD4 T cell population and residual immune impairment, mild neurocognitive dysfunction, and a continued risk of cardiovascular and other “non-AIDS” events, all associated with persistent immune activation, remain as problems. But, by and large, the morbidities and mortality from HIV disease have greatly diminished. Furthermore, oral regimens have become simpler and less toxic over time, so that several well tolerated one-pill-a-day coformulated single tablet regimens (STRs) are now available.

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

Date:

8/1/16

Citation:

Owen A, Rannard S. Strengths, weaknesses, opportunities and challenges for long acting injectable therapies: Insights for applications in HIV therapy. Adv Drug Deliv Rev. 2016 Aug 1;103:144-156. doi: 10.1016/j.addr.2016.02.003. Epub 2016 Feb 23. PMID: 26916628; PMCID: PMC4935562.

The HIV/AIDS epidemic remains a major public health threat and approximately 36.9 million [34.3 million–41.4 million] people worldwide are estimated to be infected. In 2014, AIDS claimed an estimated 1.2 million [980 000–1.6 million] lives globally, with 2 million [1.9 million–2.2 million] people being newly infected in the same year. Worldwide, around 15.8 million people were accessing antiretroviral therapy in June 2015, constituting ~41% of adults and ~32% of children infected with the virus [1]. Antiretroviral therapy (ART) currently involves co-administration of drugs to simultaneously inhibit multiple viral targets, maximising inhibition of viral replication whilst minimising drug resistance.

Drug Delivery Strategies and Systems for HIV/AIDS Pre-Exposure Prophylaxis (PrEP) and Treatment

Date:

12/10/15

Citation:

Nelson AG, Zhang X, Ganapathi U, Szekely Z, Flexner CW, Owen A, Sinko PJ. Drug delivery strategies and systems for HIV/AIDS pre-exposure prophylaxis and treatment. J Control Release. 2015 Dec 10;219:669-680. doi: 10.1016/j.jconrel.2015.08.042. Epub 2015 Aug 24. PMID: 26315816; PMCID: PMC4879940.

The year 2016 will mark an important milestone - the 35th anniversary of the first reported cases of HIV/AIDS. Antiretroviral Therapy (ART) drug regimens are widely considered to be one of the greatest achievements in therapeutic drug research. In fact, ART has transformed healthcare for HIV-infected people from a terminal illness where patients quickly progress from HIV infection to AIDS and serious opportunistic infections to today, where HIV infection is widely regarded as a chronic disease. Unfortunately, the discontinuation of ART or the development of drug resistance results in rapid viral rebound. The lack of widespread successful preventive measures and the inability to eradicate HIV from infected cells highlight the significant healthcare challenges and DD opportunities that remain today.

LEAP Publications

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