807. Population PK/PD Modeling of Human Respiratory Syncytial Virus Infection and the Antiviral Effect of AL-8176
Session: Poster Abstract Session: Antimicrobial Agents: PK/PD Studies
Friday, October 9, 2015
Room: Poster Hall
  • AL-8176_PK-PD Modeling_ID Week 2015_Patel_JRD.pdf (905.9 kB)

    Background: Respiratory Syncytial Virus (RSV) is a common cause of morbidity and mortality in adult and pediatric populations.  AL-8176 is an oral nucleoside analog prodrug in development for the treatment of RSV infection in infants and adults. AL-8176 is metabolized to AL-8112, which is converted intracellularly to the active nucleotide triphosphate (NTP).  A Phase 2 challenge study in healthy volunteers (HV) was conducted to evaluate the antiviral activity of AL-8176 against RSV-A virus.


    Objectives: To develop a semi-mechanistic population PK/PD model to describe the time course of RSV infection and the antiviral effect of AL-8176.

    Methods: HV were inoculated with RSV-A and randomized to placebo (n=18) or AL-8176 (n=44) once positive for RSV by polymerase chain reaction (PCR). AL-8176 dosing regimens were Q12 x 5 days (i.e., 10 doses) and were:  one 750mg loading dose (LD) then nine 150mg maintenance doses (MD); 375mg Q12; and one 750mg LD then nine 500mg MD.  Nasal viral load and plasma concentrations of AL-8112 and AL-8144 (inactive metabolite) were measured frequently over the duration of the study.  Data were modeled using NONMEM 7.2. 


    Results: The kinetics of RSV was described using a 4-compartment model representing target epithelial (T), infected non-productive (I1), infected productive (I2) cells and virions (V). Two-compartment PK models characterized both AL-8112 and AL-8144 disposition, with clearance estimates of 54.2 L/h/70 kg and 115 L/h/70 kg, respectively. A semi-physiological model was linked to predict the conversion of AL-8112 to the active NTP in lung epithelial cells. Extensive and rapid dose-dependent reductions in RSV occurred after AL-8176 administration, with a sigmoid Emax model describing NTP inhibition (EC50 1.78 μM, RSE 11.5%).  AL-8176 inhibition of RSV replication 4 hours after the first 375mg dose and 750mg LD was estimated to be 96.6% and 99.4%, respectively. At steady-state, RSV inhibition was estimated to be > 99% for all dosing regimens evaluated. 


    Conclusion: A semi-mechanistic model has been developed that characterizes RSV kinetics and the antiviral effectiveness of AL-8176 in an adult HV challenge model.  The results of this model are being used to guide dose selection in adult and pediatric patient populations.

    Kashyap Patel, PhD1, Carl Kirkpatrick, PhD2, Keith Nieforth, PhD1, Sushmita Chanda, PhD3, Qingling Zhang, PhD3, Matthew Mcclure, MD3, John Fry, RN3, Julian Symons, D.Phil3, Lawrence Blatt, PhD3, Leo Beigelman, PhD3 and Patrick Smith, PharmD1, (1)D3 Medicine, Parsippany, NJ, (2)Monash University, Parkville, Australia, (3)Alios BioPharma Inc, South San Francisco, CA


    K. Patel, d3 Medicine: Consultant , Consulting fee

    C. Kirkpatrick, d3 Medicine: Consultant , Consulting fee

    K. Nieforth, d3 Medicine: Employee , Salary

    S. Chanda, Alios BioPharma: Employee , Salary

    Q. Zhang, Alios BioPharma: Employee , Salary

    M. Mcclure, Alios BioPharma: Employee , Salary

    J. Fry, Alios BioPharma: Employee , Salary

    J. Symons, Alios BioPharma: Employee , Salary

    L. Blatt, Alios BioPharma: Employee , Salary

    L. Beigelman, Alios BioPharma: Employee , Salary

    P. Smith, d3 Medicine: Employee , Salary

    Findings in the abstracts are embargoed until 12:01 a.m. PDT, Wednesday Oct. 7th with the exception of research findings presented at the IDWeek press conferences.