Respiratory syncytial virus-A dynamics and the effects of lumicitabine, a nucleoside viral replication inhibitor, in experimentally infected humans

• Published in: Journal of antimicrobial chemotherapy 2019-02, Vol.74 (2), p.442-452
• Main Authors: Patel, Kashyap, Kirkpatrick, Carl M, Nieforth, Keith A, Chanda, Sushmita, Zhang, Qingling, McClure, Matthew, Fry, John, Symons, Julian A, Blatt, Lawrence M, Beigelman, Leo, DeVincenzo, John P, Huntjens, Dymphy R, Smith, Patrick F
• Format: Article
• Language: English
• Subjects: Adult; Antiviral Agents - blood; Antiviral Agents - pharmacokinetics; Antiviral Agents - therapeutic use; Deoxycytidine - analogs & derivatives; Deoxycytidine - blood; Deoxycytidine - pharmacokinetics; Deoxycytidine - therapeutic use; Double-Blind Method; Healthy Volunteers; Humans; Models, Theoretical; Nasopharynx - virology; Respiratory Syncytial Virus Infections - drug therapy; Respiratory Syncytial Virus, Human - drug effects; Respiratory Syncytial Virus, Human - physiology; Viral Load - drug effects; Virus Replication - drug effects
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dky415

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.