Kashyap Patel1,2, Carl M Kirkpatrick2, Keith A Nieforth1, Sushmita Chanda3, Qingling Zhang3, Matthew McClure3, John Fry3, Julian A Symons3, Lawrence M Blatt3, Leo Beigelman3, John P DeVincenzo4, Dymphy R Huntjens5, Patrick F Smith1. 1. d3 Medicine, A Certara Company, Parsippany, NJ, USA. 2. Centre for Medicine Use and Safety, Monash University, Melbourne, VIC, Australia. 3. Alios BioPharma Inc, a Janssen Pharmaceutical Company of Johnson and Johnson, South San Francisco, CA, USA. 4. Departments of Pediatrics and Microbiology, Immunology and Biochemistry, University of Tennessee Center for Health Sciences, and Children's Foundation Research Institute at LeBonheur Children's Hospital, Memphis, TN, USA. 5. Janssen R&D, Janssen Pharmaceutica NV, Beerse, Belgium.
Abstract
Background: Respiratory syncytial virus (RSV) causes high morbidity, with mortality rates approaching or exceeding that of influenza in adult and infant patient populations, respectively. Lumicitabine (ALS-008176 or JNJ-64041575) is an oral nucleoside analogue prodrug in clinical development to treat RSV infections. This prodrug converts to plasma-circulating ALS-8112, and then to the 5'-active nucleoside triphosphate (NTP) form within host cells. We conducted an RSV-A challenge study in healthy adults to evaluate lumicitabine's activity during an active RSV infection. Objectives: To develop a semi-mechanistic mathematical model describing RSV kinetics, and the pharmacokinetics (PK) and pharmacodynamics (PD) of lumicitabine during treatment. Methods:Nasopharyngeal viral load and concentrations of ALS-8112 and ALS-8144 (uridine metabolite) were measured frequently over the study duration. Population viral kinetic and PK/PD models were developed using NONMEM. The RSV life-cycle was described using a target-cell-limited model that included a physiological delay. Results: The estimated clearances of ALS-8112 and ALS-8144 were 54.2 and 115 L/h/70 kg, respectively. A semi-physiological model was linked to predict ALS-8112 conversion to active intracellular NTP. Extensive and rapid RSV reduction occurred after lumicitabine treatment (EC50 = 1.79 μM), with >99% viral inhibition at 2 h after loading dose. Simulated NTP exposures and time to EC50 attainment suggested that rapid therapeutic effects and reduced dosing frequency are achievable in adult and paediatric patients. Conclusions: The semi-mechanistic model characterizes RSV kinetics and the antiviral effectiveness of lumicitabine in an adult challenge population. This model is applicable to guide dose selection in adult and paediatric patients.
RCT Entities:
Background: Respiratory syncytial virus (RSV) causes high morbidity, with mortality rates approaching or exceeding that of influenza in adult and infantpatient populations, respectively. Lumicitabine (ALS-008176 or JNJ-64041575) is an oral nucleoside analogue prodrug in clinical development to treat RSV infections. This prodrug converts to plasma-circulating ALS-8112, and then to the 5'-active nucleoside triphosphate (NTP) form within host cells. We conducted an RSV-A challenge study in healthy adults to evaluate lumicitabine's activity during an active RSV infection. Objectives: To develop a semi-mechanistic mathematical model describing RSV kinetics, and the pharmacokinetics (PK) and pharmacodynamics (PD) of lumicitabine during treatment. Methods: Nasopharyngeal viral load and concentrations of ALS-8112 and ALS-8144 (uridine metabolite) were measured frequently over the study duration. Population viral kinetic and PK/PD models were developed using NONMEM. The RSV life-cycle was described using a target-cell-limited model that included a physiological delay. Results: The estimated clearances of ALS-8112 and ALS-8144 were 54.2 and 115 L/h/70 kg, respectively. A semi-physiological model was linked to predict ALS-8112 conversion to active intracellular NTP. Extensive and rapid RSV reduction occurred after lumicitabine treatment (EC50 = 1.79 μM), with >99% viral inhibition at 2 h after loading dose. Simulated NTP exposures and time to EC50 attainment suggested that rapid therapeutic effects and reduced dosing frequency are achievable in adult and paediatric patients. Conclusions: The semi-mechanistic model characterizes RSV kinetics and the antiviral effectiveness of lumicitabine in an adult challenge population. This model is applicable to guide dose selection in adult and paediatric patients.
Authors: Darren Wethington; Olivia Harder; Karthik Uppulury; William C L Stewart; Phylip Chen; Tiffany King; Susan D Reynolds; Alan S Perelson; Mark E Peeples; Stefan Niewiesk; Jayajit Das Journal: J R Soc Interface Date: 2019-11-27 Impact factor: 4.118
Authors: Craig R Rayner; Patrick F Smith; David Andes; Kayla Andrews; Hartmut Derendorf; Lena E Friberg; Debra Hanna; Alex Lepak; Edward Mills; Thomas M Polasek; Jason A Roberts; Virna Schuck; Mark J Shelton; David Wesche; Karen Rowland-Yeo Journal: Clin Pharmacol Ther Date: 2021-03-09 Impact factor: 6.875