Population pharmacokinetics and pharmacodynamics of the neutralizing antibodies bamlanivimab and etesevimab in patients with mild to moderate COVID-19 infection.

Chigutsa, Emmanuel; O'Brien, Lisa; Ferguson-Sells, Lisa; Long, Amanda; Chien, Jenny

Bamlanivimab and etesevimab are neutralizing antibodies indicated for treatment of COVID-19 in patients with early mild or moderate disease. We present the use of pharmacokinetic-pharmacodynamic (PK/PD) modeling that characterizes the timecourse of viral load obtained from 2970 patients from two phase 2 clinical trials. The model was used for identification of optimal doses that would result in at least 90% of patients achieving serum drug concentrations that results in 90% of maximum drug effect (IC90) for at least 28 days. The serum IC90 (95% confidence interval) was estimated to be 4.2 (3.2, 4.3) µg/mL for bamlanivimab and 12.6 (9.7, 12.8) µg/mL for etesevimab. Observed clinical trial data confirmed PK and PK/PD model predictions that doses of 700 mg bamlanivimab and 1400 mg etesevimab would result in maximum reduction in viral load, with no additional effect seen at higher doses. No dose adjustment is recommended as age, sex, race, baseline viral load and hepatic impairment did not have a significant impact on the PK of the antibodies. Earlier drug administration resulted in greater reductions in viral load, demonstrating the importance of receiving treatment as soon as possible. Relative to placebo, typical reduction in viral load over a 7 day period was estimated to be 80 or 93% (drug administered 4 days or 1 days after the onset of symptoms, respectively), p<0.0001. PK/PD modeling and simulation was pivotal throughout the drug development and emergency use authorization process.