Long-acting injectable antiretrovirals for HIV treatment and prevention

William R Spreen, David A Margolis, John C Pottage Jr, William R Spreen, David A Margolis, John C Pottage Jr

Abstract

Purpose of review: Long-acting antiretroviral (ARV) drugs may improve adherence to therapy and extend opportunities for therapeutic or prophylactic intervention to underserved patient populations. This review focuses on recent advances in the development of small molecule long-acting injectable ARV agents.

Recent findings: The need for combination ART and physicochemical and dosing limitations of current ARV drugs impede attempts to redevelop them as long-acting injectable formulations. However, the intrinsic properties of rilpivirine, a nonnucleoside reverse transcriptase inhibitor, and GSK1265744, an HIV-1 integrase strand transfer inhibitor, have enabled crystalline nanoparticle formulations to progress to clinical trials.

Summary: Investigational long-acting injectable nanoformulations of rilpivirine and GSK1265744 are clinical-stage development candidates. Complementary pharmacologic properties of both agents - different mechanisms of action, resistance profiles, metabolic pathways, lack of drug interactions and low daily oral doses - offer the potential for combination use. Phase I studies of the pharmacokinetics and safety of each long-acting formulation alone and in combination indicate that a monthly dosing regimen is possible for HIV treatment. An ongoing phase IIb trial of oral GSK1265744 and oral rilpivirine is evaluating this two-drug regimen for maintenance of virologic suppression; results will inform future studies using the injectable formulations. Additional preclinical and clinical studies indicate a potential use of each agent for HIV pre-exposure prophylaxis.

Figures

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FIGURE 1
FIGURE 1
Mean plasma levels of GSK1265744 over time following single-dose administration of long-acting formulation . GSK1265744 (200 mg/ml) was administered as a single IM (gluteal) or SC (abdominal) injection or equally divided IM or SC injection. Each cohort comprised eight healthy adult patients (six active/two placebo). The dashed line represents the plasma PA-IC90 value for GSK1265744 against wild-type HIV-1 of 0.166 μg/ml.

References

    1. Joint United Nations Programme on HIV/AIDS (UNAIDS) Global report: UNAIDS report on the global AIDS epidemic 2012. Geneva, Switzerland:UNAIDS; 2012
    1. Grant RM, Lama JR, Anderson PL, et al. for the iPrEx Study Team Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med 2010; 363:2587–2599
    1. Baeten JM, Donnell D, Ndase P, et al. for the Partners PrEP Study Team Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med 2012; 367:399–410
    1. Thigpen MC, Kebaabetswe PM, Paxton LA, et al. for the TDF2 Study Group Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med 2012; 367:423–434
    1. US Food and Drug Administration Press release: FDA approves first drug for reducing the risk of sexually acquired HIV infection. Silver Spring, MD: US Food and Drug Administration; 16 July 2012. [Accessed on 24 July 2013]
    1. Van Damme L, Corneli A, Ahmed K, et al. for the FEM-PrEP Study Group Preexposure prophylaxis for HIV infection among African women. N Engl J Med 2012; 367:411–422
    1. Marrazzo J, Ramjee G, Nair G, et al. Preexposure prophylaxis for HIV in women: daily oral tenofovir, oral tenofovir/emtricitabine, or vaginal tenofovir gel in the VOICE study (MTN 003) [Abstract no. 26LB]. 20th Conference on Retroviruses and Opportunistic Infections; Atlanta, GA 2013
    1. Westhoff C. Depot-medroxyprogesterone acetate injection (Depo-Provera®): a highly effective contraceptive option with proven long-term safety. Contraception 2003; 68:75–87
    1. Adams CE, Fenton MKP, Quraishi S, David AS. Systematic meta-review of depot antipsychotic drugs for people with schizophrenia. B J Psychiatry 2001; 179:290–299
    1. Schooler NR. Relapse and rehospitalization: comparing oral and depot antipsychotics. J Clin Psychiatry 2003; 64 Suppl 16:14–17
    1. Nowacek A, Miller S, McMillan R, et al. NanoART synthesis, characterization, uptake, release and toxicology for human monocyte-macrophage drug delivery. Nanomedicine (Lond) 2009; 4:903–917
    1. Puligujja P, et al. Macrophage folate receptor-targeted antiretroviral therapy facilitates drug entry, retention, antiretroviral activities and biodistribution for reduction of human immunodeficiency virus infections. Nanomedicine 2013

    2. Authors describe the manufacture and in-vitro testing of polymer-coated ARV nanoparticles as a method to enhance macrophage uptake, retention and antiviral activity.

    1. Gautam N, Roy U, Balkundi S, et al. Preclinical pharmacokinetics and tissue distribution of long-acting nanoformulated antiretroviral therapy. Antimicrob Agents Chemother 2013; 57:3110–3120

    2. Nanoformulated atazanavir and ritonavir are prepared and evaluated in mice and monkey; results demonstrate blood and tissue drug concentrations are enhanced and prolonged compared with native drug.

    1. Bruno CJ, Jacobson JM. Ibalizumab: an anti-CD4 monoclonal antibody for the treatment of HIV-1 infection. J Antimicrob Chemother 2010; 65:1839–1841
    1. Ford S, Gould E, Chen S, et al. Lack of pharmacokinetic (PK) interaction between rilpivirine and the integrase inhibitors, dolutegravir and S/GSK1265744 [Abstract no. A-1249]. 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy; San Francisco, CA 2012
    1. Underwood M, St Clair M, Johns B, et al. S/GSK1265744: a next generation integrase inhibitor (INI) with activity against raltegravir-resistant clinical isolates [Abstract no. MOAA0103]. 28th International AIDS Conference; Vienna, Austria 2010
    1. Yoshinaga T, Kobayashi M, Seki T, et al. Antiviral characteristics of S/GSK1265744, an HIV integrase inhibitor (INI) dosed by oral or long-acting parenteral injection [Abstract no. H-550]. 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy; San Francisco, CA; 2012
    1. Min S, DeJesus E, McCurdy L, et al. Pharmacokinetics (PK) and safety in healthy and HIV-infected subjects and short-term antiviral efficacy of S/GSK1265744, a next generation once daily HIV integrase inhibitor [Abstract no. H-1228]. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy; San Francisco, CA; 2009
    1. Spreen W, Ford S, Chen S, et al. Pharmacokinetics, safety and tolerability of the HIV integrase inhibitor S/GSK1265744 long acting parenteral nanosuspension following single dose administration to healthy adults [Abstract no. TUPE040]. 19th International AIDS Conference; Washington, DC; 2012
    1. ViiV Healthcare Dose ranging study of GSK1265744 plus nucleoside reverse transcriptase inhibitors for induction of human immunodeficiency virus-1 (HIV-1) virologic suppression followed by virologic suppression maintenance by GSK1265744 plus rilpivirine. Bethesda, MD: National Library of Medicine; 2012. [Accessed on 24 July 2013]
    1. Spreen W, Williams P, Margolis D, et al. First study of repeat dose co-administration of GSK1265744 and TMC278 long-acting parenteral nanosuspensions: pharmacokinetics, safety and tolerability in healthy adults [Abstract no. WEAB0103]. 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; Kuala Lumpur, Malaysia; 2013
    1. Ford S, Margolis D, Chen S, et al. Plasma and tissue GSK1265744 pharmacokinetics following long-acting parenteral administration in healthy male and female subjects [Abstract no. O_02]. 14th International Workshop on Clinical Pharmacology of HIV Therapy; Amsterdam, the Netherlands; 2013.
    1. Andrews C, Gettie A, Russell-Lodrigue K, et al. Long-acting parenteral formulation of GSK1265744 protects macaques against repeated intrarectal challenges with SHIV [Abstract no. 24LB]. 20th Conference on Retroviruses and Opportunistic Infections; Atlanta, GA; 2013
    1. Baert L, van ’t Klooster G, Dries W, et al. Development of a long-acting injectable formulation with nanoparticles of rilpivirine (TMC278) for HIV treatment. Eur J Pharm Biopharm 2009; 72:502–508

    2. Authors describe development and preclinical proof of concept studies of injectable nanoformulation of rilpivirine.

    1. Van ’t Klooster G, Hoeben E, Borghys H, et al. Pharmacokinetics and disposition of rilpivirine (TMC278) nanosuspension as a long-acting injectable antiretroviral formulation. Antimicrob Agents Chemother 2010; 54:2042–2050

    2. Preclinical experiments in rats and dogs demonstrate a rilpivirine 200 nanometer particle size injectable suspension provides drug release for up to 6 months. Drug concentrations in lymphoid tissues exceeded plasma concentrations suggesting macrophage uptake of nanoparticles and a secondary depot source of drug release. In addition, first human pharmacokinetic study of TMC278 long-acting injection is reported.

    1. Verloes R, van ’t Klooster G, Baert L, et al. TMC278 long acting - a parenteral nanosuspension formulation that provides sustained clinically relevant plasma concentrations in HIV-negative volunteers. 17th International AIDS Conference; Mexico City, Mexico; 2008
    1. Jackson A, Else L, Tjia J, et al. Rilpivirine-LA formulation: pharmacokinetics in plasma, genital tract in HIV-females and rectum in males [Abstract no. 35]. 19th Conference on Retroviruses and Opportunistic Infections; Seattle WA; 2012

Source: PubMed

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