14 CLINICAL PHARMACOLOGY 14.1 Mechanism of Action Bamlanivimab is a recombinant neutralizing human IgG1κ monoclonal antibody (mAb) to the spike protein of SARS-CoV-2, and is unmodified in the Fc region. Bamlanivimab binds to spike protein with a dissociation constant KD = 0.071 nM and blocks spike protein attachment to the human ACE2 receptor with an IC value of 0.025 µg/mL. 50 14.2 Pharmacodynamics A Phase 2 trial evaluated bamlanivimab over a dose range of 1 to 10 times the recommended dose (700 to 7000 mg) of bamlanivimab in patients with mild to moderate COVID-19. A flat exposure-response relationship for efficacy was identified for bamlanivimab within this dose range, based on viral load and clinical outcomes. 14.3 Pharmacokinetics Pharmacokinetic profile of bamlanivimab is expected to be consistent with the profile of other IgG1 monoclonal antibodies. Special Populations: The PK of bamlanivimab was not affected by age, sex, race, disease severity or inflammation based on a population PK analysis. Body weight had no clinically relevant effect on the PK of bamlanivimab in adults with COVID-19 over the body weight range of 41 kg to 173 kg [see Use in Specific Populations (11.4, 11.7)]. Pediatric population The PK of bamlanivimab in pediatric patients have not been evaluated. Using modeling and simulation, the recommended dosing regimen is expected to result in comparable plasma exposures of bamlanivimab in pediatric patients ages 12 years of age or older who weigh at least 40 kg as observed in adult patients [see Use in Specific Populations (11.3)]. Patients with renal impairment Bamlanivimab is not eliminated intact in the urine, thus renal impairment is not expected to affect the exposure of bamlanivimab [see Use in Specific Populations (11.5)]. Patients with hepatic impairment Based on population PK analysis, patients with mild hepatic impairment had approximately 20% higher clearance than patients with normal hepatic function. This effect is statistically significant, but not clinically meaningful. Bamlanivimab has not been studied in patients with moderate or severe hepatic impairment [see Use in Specific Populations (11.6)]. Drug interactions: Bamlanivimab is not renally excreted or metabolized by cytochrome P450 enzymes; therefore, interactions with concomitant medications that are renally excreted or that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely [see Drug Interactions (10)]. 18