Pharmacokinetic testing of a first-generation cabotegravir prodrug in rhesus macaques

&NA; Long-acting antiretrovirals can improve therapy and prevention for HIV-1 infection. Current long-acting cabotegravir (CAB LAP) can be administered every other month. Previously, we demonstrated that a myristoylated CAB prodrug encased in poloxamer 407 provided extended plasma drug concentrations. We now demonstrate that this first-generation nanoformulated prodrug can sustain plasma CAB concentrations above the protein-adjusted 90% inhibitory concentration for 4 months in rhesus macaques. A 2.5-fold extension in CAB half-life and a 1.6-fold increase in area under the concentration–time curve were observed compared with CAB LAP.

[1]  H. Gendelman,et al.  Creation of a long-acting nanoformulated dolutegravir , 2018, Nature Communications.

[2]  H. Gendelman,et al.  Creation of a nanoformulated cabotegravir prodrug with improved antiretroviral profiles , 2017, Biomaterials.

[3]  H. Gendelman,et al.  Pharmacokinetics of a Long-Acting Nanoformulated Dolutegravir Prodrug in Rhesus Macaques , 2017, Antimicrobial Agents and Chemotherapy.

[4]  D. Podzamczer,et al.  Long-acting intramuscular cabotegravir and rilpivirine in adults with HIV-1 infection (LATTE-2): 96-week results of a randomised, open-label, phase 2b, non-inferiority trial , 2017, The Lancet.

[5]  J. Gallant,et al.  Safety and tolerability of long-acting cabotegravir injections in HIV-uninfected men (ECLAIR): a multicentre, double-blind, randomised, placebo-controlled, phase 2a trial. , 2017, The lancet. HIV.

[6]  D. Ho,et al.  Cabotegravir long acting injection protects macaques against intravenous challenge with SIVmac251 , 2017, AIDS.

[7]  R. Shafer,et al.  HIV-1 drug resistance and resistance testing. , 2016, Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases.

[8]  N. Ford,et al.  Patient-Reported Barriers to Adherence to Antiretroviral Therapy: A Systematic Review and Meta-Analysis , 2016, PLoS medicine.

[9]  G. Treisman,et al.  Neuropsychiatric Effects of HIV Antiviral Medications , 2016, Drug Safety.

[10]  F. Vidal,et al.  Switching antiretroviral regimes for the treatment of HIV: safety implications , 2016, Expert opinion on drug safety.

[11]  J. Troya,et al.  Safety and Tolerability: Current Challenges to Antiretroviral Therapy for the Long-Term Management of HIV Infection. , 2016, AIDS reviews.

[12]  S. Piscitelli,et al.  Formulation and pharmacology of long-acting cabotegravir , 2015, Current opinion in HIV and AIDS.

[13]  M. Markowitz,et al.  GSK1265744 Demonstrates Robust In Vitro Activity Against Various Clades of HIV-1 , 2015, Journal of acquired immune deficiency syndromes.

[14]  D. Ho,et al.  A long-acting integrase inhibitor protects female macaques from repeated high-dose intravaginal SHIV challenge , 2015, Science Translational Medicine.

[15]  W. Heneine,et al.  The long-acting integrase inhibitor GSK744 protects macaques from repeated intravaginal SHIV challenge , 2015, Science Translational Medicine.

[16]  S. Piscitelli,et al.  Pharmacokinetics, Safety, and Tolerability With Repeat Doses of GSK1265744 and Rilpivirine (TMC278) Long-Acting Nanosuspensions in Healthy Adults , 2014, Journal of acquired immune deficiency syndromes.

[17]  D. Ho,et al.  Long-Acting Integrase Inhibitor Protects Macaques from Intrarectal Simian/Human Immunodeficiency Virus , 2014, Science.

[18]  W. Spreen,et al.  Long-acting injectable antiretrovirals for HIV treatment and prevention , 2013, Current opinion in HIV and AIDS.

[19]  Lei Wang,et al.  Prevention of HIV-1 infection with early antiretroviral therapy. , 2011, The New England journal of medicine.

[20]  C. Katlama,et al.  HIV-Infected Adults With a CD4 Cell Count Greater Than 500 Cells/mm3 on Long-Term Combination Antiretroviral Therapy Reach Same Mortality Rates as the General Population , 2007, Journal of acquired immune deficiency syndromes.

[21]  E. Vittinghoff,et al.  Combination antiretroviral therapy and recent declines in AIDS incidence and mortality. , 1999, The Journal of infectious diseases.