Respiratory Syncytial Virus (RSV) causes severe respiratory infections and concomitant disease resulting in significant morbidity and mortality in infants, elderly, and immunocompromised adults. Vaccines, monoclonal antibodies, and small-molecule antivirals are now either available or in development to prevent and treat RSV infections. Although rodent and non-rodent preclinical animal models have been used to evaluate these emerging agents, there is still a need to improve our understanding of the pharmacokinetic (PK)-pharmacodynamic (PD) relationships within and between animal models to enable better design of human challenge studies and clinical trials. Herein, we report a PKPD evaluation of MRK-1, a novel small molecule non-nucleoside inhibitor of the RSV L polymerase protein, in the semi-permissive cotton rat and African green monkey models of RSV infection. These studies demonstrate a strong relationship between in vitro activity, in vivo drug exposure, and pharmacodynamic efficacy as well as revealing limitations of the cotton rat RSV model. Additionally, we report unexpected horizontal transmission of human RSV between co-housed African green monkeys, as well as a lack of drug specific resistant mutant generation. Taken together these studies further our understanding of these semi-permissive animal models and offer the potential for expansion of their preclinical utility in evaluating novel RSV therapeutic agents.