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Hiv and pharmacokinetics

Rada M Savic, Prasanna Jagannathan, Richard Kajubi, Liusheng Huang, Nan Zhang, Moses Were, Abel Kakuru, Mary K Muhindo, Norah Mwebaza, Erika Wallender, Tamara D Clark, Bishop Opira, Moses Kamya, Diane V Havlir, Philip J Rosenthal, Grant Dorsey, Francesca T Aweeka
Background: Dihydroartemsinin-piperaquine is highly efficacious as intermittent preventive therapy for malaria during pregnancy (IPTp). Determining associations between piperaquine exposure, malaria risk, and adverse birth outcomes informs optimal dosing strategies. Methods: HIV-uninfected pregnant women were enrolled in a placebo-controlled trial of IPTp at 12-20 weeks gestation and randomized to: sulfadoxine-pyrimethamine every 8 weeks (n=106), dihydroartemsinin-piperaquine every 8 weeks (n=94), or dihydroartemsinin-piperaquine every 4 weeks (n=100) during pregnancy...
March 14, 2018: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Luděk Eyer, Radim Nencka, Erik de Clercq, Katherine Seley-Radtke, Daniel Růžek
Nucleoside analogs represent the largest class of small molecule-based antivirals, which currently form the backbone of chemotherapy of chronic infections caused by HIV, hepatitis B or C viruses, and herpes viruses. High antiviral potency and favorable pharmacokinetics parameters make some nucleoside analogs suitable also for the treatment of acute infections caused by other medically important RNA and DNA viruses. This review summarizes available information on antiviral research of nucleoside analogs against arthropod-borne members of the genus Flavivirus within the family Flaviviridae, being primarily focused on description of nucleoside inhibitors of flaviviral RNA-dependent RNA polymerase, methyltransferase, and helicase/NTPase...
January 2018: Antiviral Chemistry & Chemotherapy
Ahizechukwu C Eke, Nahida Chakhtoura, Angela Kashuba, Brookie M Best, Craig Sykes, Jiajia Wang, Alice M Stek, Elizabeth Smith, Samantha Calabrese, Edmund V Capparelli, Mark Mirochnick
BACKGROUND: Concentrations of antiretrovirals (ARVs) in the genital tract play a key role in pre-exposure prophylaxis. This study aims to describe rilpivirine (Edurant) concentrations in the genital tract in pregnant and postpartum women. METHODS: International Maternal Pediatric Adolescent AIDS Clinical Trials Protocol P1026s is an ongoing, prospective study of antiretroviral pharmacokinetics (PK) in HIV infected pregnant women that include a cohort receiving rilpivirine combination regimen...
March 8, 2018: Journal of Acquired Immune Deficiency Syndromes: JAIDS
Erik Mogalian, Luisa M Stamm, Anu Osinusi, Diana M Brainard, Gong Shen, Kah Hiing John Ling, Anita Mathias
Background: Combining antiviral regimens in the HCV/HIV coinfected population can be complex as they share overlapping mechanisms for elimination that may result in potential drug interactions. The pharmacokinetics, safety, and tolerability of concomitantly administered sofosbuvir/velpatasvir (SOF/VEL) with multiple commonly prescribed antiretroviral (ARV) regimens were evaluated. Methods: Healthy volunteers were enrolled into two phase 1, open-label, randomized, multiple-dose, cross-over studies...
March 7, 2018: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Stein Schalkwijk, Rob Ter Heine, Angela C Colbers, Alwin D R Huitema, Paolo Denti, Kelly E Dooley, Edmund Capparelli, Brookie M Best, Tim R Cressey, Rick Greupink, Frans G M Russel, Mark Mirochnick, David M Burger
BACKGROUND: Reducing the dose of efavirenz can improve safety, reduce costs, and increase access for patients with HIV infection. According to the World Health Organization, a similar dosing strategy for all patient populations is desirable for universal roll-out; however, it remains unknown whether the 400 mg daily dose is adequate during pregnancy. METHODS: We developed a mechanistic population pharmacokinetic model using pooled data from women included in seven studies (1968 samples, 774 collected during pregnancy)...
March 8, 2018: Clinical Pharmacokinetics
Nagsen Gautam, Zhiyi Lin, Mary G Banoub, Nathan A Smith, Audai Maayah, JoEllyn McMillan, Howard E Gendelman, Yazen Alnouti
Nucleoside reverse transcriptase inhibitors (NRTIs) require intracellular phosphorylation to active triphosphate (TP) nucleotide metabolites before they can inhibit the HIV reverse transcriptase. However, monitoring these pharmacologically active TP metabolites is challenging due to their instability and their low concentrations at the pg/ml levels in blood and tissues. The combination of lamivudine (3TC) and abacavir (ABC) is one of the first lines for HIV therapy. Therefore, a sensitive, selective, accurate, and precise LC-MS/MS method was developed and validated for the simultaneous quantification of 3TC- and ABC-TP metabolites in mouse blood and tissues...
February 20, 2018: Journal of Pharmaceutical and Biomedical Analysis
Elisa Colella, Dario Cattaneo, Laura Galli, Sara Baldelli, Emilio Clementi, Massimo Galli, Adriano Lazzarin, Antonella Castagna, Stefano Rusconi, Vincenzo Spagnuolo
The 96-week results of the Monotherapy Once a Day with Atazanavir/r (MODAt) study [NCT01511809] showed an inferior virological efficacy of atazanavir (ATV)/ritonavir monotherapy versus triple therapy, which was promptly retrieved by the reintroduction of nucleoside/nucleotide inhibitors of reverse transcriptase [N(n)RTIs]. We aimed to identify potential relationships between ATV exposure and clinical outcome in HIV-1 subjects treated with ATV/ritonavir monotherapy [ATV/r 300/100mg] versus ATV/ritonavir triple therapy [ATV/r 300/100mg+2NRTIs]...
March 2, 2018: New Microbiologica
JoEllen M McMillan, Denise A Cobb, Zhiyi Lin, Mary G Banoub, Raghubendra S Dagur, Amanda A Branch Woods, Weimin Wang, Edward Makarov, Ted Kocher, Poonam S Joshi, Rolen M Quadros, Donald W Harms, Samuel M Cohen, Howard E Gendelman, Channabasavaiah B Gurumurthy, Santhi Gorantla, Larisa Y Poluektova
Antiretroviral drug (ARV) metabolism is linked largely to hepatic cytochrome P450 (CYP) activity. One ARV drug class known to be metabolized by intestinal and hepatic CYP3A are the protease inhibitors (PI). Plasma drug concentrations in are boosted by CYP3A inhibitors such as cobisistat and ritonavir (RTV). Studies of such drug-drug interactions are limited as the enzyme pathways are human specific. While immune-deficient mice reconstituted with human cells are an excellent model to study ARVs during human immunodeficiency virus type 1 (HIV-1) infection, they cannot reflect human drug metabolism...
February 23, 2018: Journal of Pharmacology and Experimental Therapeutics
Elaine Tseng, Gwendolyn D Fate, Gregory S Walker, Theunis C Goosen, R Scott Obach
Maraviroc (MVC) is an CCR5 co-receptor antagonist indicated in combination with other antiretroviral agents for the treatment of CCR5-tropic human immunodefinciency virus-1 (HIV-1) infection. In this study, the metabolism of MVC was investigated in human liver microsomes to delineate the relative roles of CYP3A4 and CYP3A5. MVC is metabolized to five hydroxylated metabolites, all of which were biosynthesized and identified using mass and NMR spectroscopy. The sites of metabolism were the 2- and 3-positions of the 4,4-difluorocyclohexyl moiety and the methyl of the triazole moiety...
February 23, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Diane E T Bastiaans, Sibyl P M Geelen, Eline G Visser, Michiel van der Flier, Clementien L Vermont, Angela P H Colbers, Monique Roukens, David M Burger, Annemarie M C van Rossum
In this multicenter pharmacokinetic study in HIV-infected children (6-12 years), we validated the approved once-daily darunavir/ritonavir dosing recommendations.The geometric mean darunavir area under the plasma concentration-time curve was 63.1, substantially lower than the mean value observed in adults. However, all trough levels were adequate and short-term virological outcome was good. These data support the use of the darunavir/ritonavir once-daily dosing recommendations.
February 22, 2018: Pediatric Infectious Disease Journal
Aubrey L Presnell, Oranat Chuchuen, Morgan G Simons, Jason R Maher, David F Katz
The prophylactic activity of antiretroviral drugs applied as microbicides against sexually transmitted HIV is dependent upon their concentrations in infectable host cells. Within mucosal sites of infection (e.g., vaginal and rectal mucosa), those cells exist primarily in the stromal layer of the tissue. Traditional pharmacokinetic studies of these drugs have been challenged by poor temporal and spatial specificity. Newer techniques to measure drug concentrations, involving Raman spectroscopy, have been limited by laser penetration depth into tissue...
February 21, 2018: Drug Delivery and Translational Research
Nithya Srinivas, Kaitlyn Maffuid, Angela D M Kashuba
Despite contributing significantly to the burden of global disease, the translation of new treatment strategies for diseases of the central nervous system (CNS) from animals to humans remains challenging, with a high attrition rate in the development of CNS drugs. The failure of clinical trials for CNS therapies can be partially explained by factors related to pharmacokinetics/pharmacodynamics (PK/PD), such as lack of efficacy or improper selection of the initial dosage. A focused assessment is needed for CNS-acting drugs in first-in-human studies to identify the differences in PK/PD from animal models, as well as to choose the appropriate dose...
February 20, 2018: Clinical Pharmacokinetics
Sébastien Landry, Chi-Nan Chen, Nimish Patel, Alice Tseng, Richard G Lalonde, Denis Thibeault, Steven Sanche, Nancy L Sheehan
Therapeutic drug monitoring (TDM) constitutes a compelling approach for the optimization of antiretroviral therapy in treatment-experienced HIV-1 patients. While various inhibitory indices have been proposed to predict virologic outcome, there is a lack of consensus on the clinical value of TDM. Here, we report the comparative results of TDM in 14 HIV-1-infected patients who had previously received at least two different PI-based regimens and who initiated darunavir (DRV)-based salvage therapy. Pharmacokinetic/pharmacodynamics (PK/PD) parameters were calculated for each subject...
February 16, 2018: Antiviral Research
Niloufar Marsousi, Youssef Daali, Pierre Fontana, Jean-Luc Reny, Virginie Ancrenaz-Sirot, Alexandra Calmy, Serge Rudaz, Jules Alexandre Desmeules, Caroline Flora Samer
BACKGROUND AND OBJECTIVES: Prasugrel and clopidogrel are inhibitors of the ADP-P 2 Y 12 platelet receptor used in acute coronary syndrome patients. They require bioactivation via isoenzymes such as cytochrome P450 (CYP) 3A4, CYP2C19 and CYP2B6. Ritonavir and cobicistat are potent CYP3A inhibitors, prescribed as pharmacokinetic (PK) enhancers in the treatment of human immunodeficiency virus (HIV) infection. METHODS: In this study, the impact of boosted antiretroviral therapies (ARTs) on the PK of clopidogrel and prasugrel active metabolites (AMs), and on the efficacy of prasugrel and clopidogrel, were evaluated in a randomized crossover clinical trial...
February 16, 2018: Clinical Pharmacokinetics
Joseph S Redman, J Nicholas Francis, Robert Marquardt, Damon Papac, Alan L Mueller, Debra M Eckert, Brett D Welch, Michael S Kay
Peptides often suffer from short in vivo half-lives due to proteolysis and renal clearance that limit their therapeutic potential in many indications, necessitating pharmacokinetic (PK) enhancement. D-peptides, composed of mirror-image D-amino acids, overcome proteolytic degradation but are still vulnerable to renal filtration due to their small size. If renal filtration could be slowed, D-peptides would be promising therapeutic agents for infrequent dosing, such as in extended-release depots. Here, we tether a diverse set of PK-enhancing cargoes to our potent, protease-resistant D-peptide HIV entry inhibitor, PIE12-trimer...
February 13, 2018: Molecular Pharmaceutics
Pamela Hummert, Teresa L Parsons, Laura M Ensign, Thuy Hoang, Mark A Marzinke
BACKGROUND: The nucleotide reverse transcriptase inhibitor tenofovir (TFV) is widely administered in a disoproxil prodrug form (tenofovir disoproxil fumarate, TDF) for HIV management and prevention. Recently, novel prodrugs tenofovir alafenamide fumarate (TAF) and hexadecyloxypropyl tenofovir (CMX157) have been pursued for HIV treatment while minimizing adverse effects associated with systemic TFV exposure. Dynamic and sensitive bioanalytical tools are required to characterize the pharmacokinetics of these prodrugs in systemic circulation...
February 8, 2018: Journal of Pharmaceutical and Biomedical Analysis
John C Kraft, Lisa A McConnachie, Josefin Koehn, Loren Kinman, Jianguo Sun, Ann C Collier, Carol Collins, Danny D Shen, Rodney J Y Ho
Existing oral antiretroviral (ARV) agents have been shown in human studies to exhibit limited lymph node penetration and lymphatic drug insufficiency. As lymph nodes are a reservoir of HIV, it is critical to deliver and sustain effective levels of ARV combinations in these tissues. To overcome lymph node drug insufficiency of oral combination ARV therapy (cART), we developed and reported a long-acting and lymphocyte-targeting injectable that contains three ARVs-hydrophobic lopinavir (LPV) and ritonavir (RTV), and hydrophilic tenofovir (TFV)-stabilized by lipid excipients in a nanosuspension...
February 9, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
Lopamudra Dutta, Biswajit Mukherjee, Tapash Chakraborty, Malay Kumar Das, Laboni Mondal, Sanchari Bhattacharya, Raghuvir H Gaonkar, Mita Chatterjee Debnath
Delivering highly water soluble drugs across blood-brain barrier (BBB) is a crucial challenge for the formulation scientists. A successful therapeutic intervention by developing a suitable drug delivery system may revolutionize treatment across BBB. Efforts were given here to unravel the capability of a newly developed fatty acid combination (stearic acid:oleic acid:palmitic acid = 8.08:4.13:1) (ML) as fundamental component of nanocarrier to deliver highly water soluble zidovudine (AZT) as a model drug into brain across BBB...
November 2018: Drug Delivery
Saghi Sepehri, Sepehr Soleymani, Rezvan Zabihollahi, Mohammad R Aghasadeghi, Mehdi Sadat, Lotfollah Saghaie, Hamid R Memarian, Afshin Fassihi
A series of tetrahydropyrimidine derivatives (2a-l) were designed, synthesized and screened for anti-HIV-1 properties based on the structures of HIV-1 gp41 binding site inhibitors, NB-2 and NB-64. A computational study was performed to predict the pharmacodynamics, pharmacokinetics and drug-likeness features of the studied molecules. Docking studies revealed that the carboxylic acid group in the molecules forms salt bridges with either Lys574 or Arg579. Physiochemical properties (e.g. molecular weight, number of hydrogen bond donors, number of hydrogen bond acceptors and number of rotatable bonds) of the synthesized compounds confirmed and exhibited that these compounds were within the range set by Lipinski's rule of five...
February 6, 2018: Chemistry & Biodiversity
Brady Sillman, Aditya N Bade, Prasanta K Dash, Biju Bhargavan, Ted Kocher, Saumi Mathews, Hang Su, Georgette D Kanmogne, Larisa Y Poluektova, Santhi Gorantla, JoEllyn McMillan, Nagsen Gautam, Yazen Alnouti, Benson Edagwa, Howard E Gendelman
Potent antiretroviral activities and a barrier to viral resistance characterize the human immunodeficiency virus type one (HIV-1) integrase strand transfer inhibitor dolutegravir (DTG). Herein, a long-acting parenteral DTG was created through chemical modification to improve treatment outcomes. A hydrophobic and lipophilic modified DTG prodrug is encapsulated into poloxamer nanoformulations (NMDTG) and characterized by size, shape, polydispersity, and stability. Retained intracytoplasmic NMDTG particles release drug from macrophages and attenuate viral replication and spread of virus to CD4+ T cells...
February 6, 2018: Nature Communications
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