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.
K. Nieforth, d3 Medicine: Employee , Salary
S. Chanda, Alios BioPharma: Employee , Salary
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