Bamlanivimab (Page 8 of 12)

14.2 Pharmacodynamics

A flat exposure-response relationship for efficacy was identified for bamlanivimab and etesevimab administered together within the dose range of 700 mg bamlanivimab and 1,400 mg etesevimab to 2,800 mg bamlanivimab and 2,800 mg etesevimab (4 and 2 times the authorized dose, respectively), based on clinical data and pharmacokinetic/pharmacodynamic modeling.

For post-exposure prophylaxis of COVID-19, a dose of 700 mg bamlanivimab and 1,400 mg etesevimab was supported based on clinical data and pharmacokinetic/pharmacodynamic modeling.

14.3 Pharmacokinetics

A summary of PK parameters of bamlanivimab and etesevimab following administration of a single dose of 700 mg bamlanivimab and 1,400 mg etesevimab is provided in Table 3. There is no change in PK of bamlanivimab or etesevimab administered alone or together suggesting there is no interaction between the two antibodies. There were no differences in PK of etesevimab between mild/moderate ambulatory participants and healthy participants.

Table 3: Pharmacokinetic Parameters of Bamlanivimab (BAM) and Etesevimab (ETE) Administered IV in Adults

Abbreviations: CV = coefficient of variation; Cmax = maximum concentration; AUCinf = area under the concentration versus time curve from zero to infinity; Vss = steady-state volume of distribution.
a N = number of subjects simulated using the PK model.
b The number of subjects for Vss, half-life, and clearance are based on a population PK model that included bamlanivimab doses up to 7,000 mg and etesevimab doses up to 2,800 mg.
	N	BAM(700 mg)	ETE(1400 mg)
Systemic Exposure
Geometric Mean (%CV) Cmax , mcg/mL	270	187 (41.7)	422 (41.2)
Geometric Mean (%CV) Cday 29 , mcg/mL	311 BAM; 320 ETE	25.7 (42.9)	116 (38.1)
Median (5th ,95th percentile) Cweek 8 , mcg/mL	1000a	10.1 (3.59, 22.9)	58.3 (26.8, 117)
Geometric Mean (%CV) AUCinf , mcg day/mL	499	2500 (28.0)	10600 (29.9)
Distribution
Geometric Mean (%CV) Vss (L)	1899 BAM; 1498 ETEb	6.59 (24.9)	5.78 (24.7)
Elimination
Geometric Mean (%CV) Elimination Half-Life (day)	1899 BAM; 1498 ETEb	20.9 (17.3)	32.6 (21.7)
Geometric Mean (%CV) Clearance (L/day)	1899 BAM; 1498 ETEb	0.274 (31.5)	0.134 (32.5)

Bamlanivimab and etesevimab are expected to be degraded into small peptides and component amino acids via catabolic pathways in the same manner as endogenous IgG antibodies.

Special Populations:

The PK profiles of bamlanivimab and etesevimab were not affected by age, sex, race, or disease severity based on a population PK analysis. Body weight had no clinically relevant effect on the PK of bamlanivimab or etesevimab 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 and etesevimab has been evaluated in 88 pediatric patients <18 years who received weight-based dosing [see Dosage and Administration (2.2)]. The data show that weight-based dosing in pediatric patients provides comparable plasma exposures to those observed in adults who received bamlanivimab 700 mg and etesevimab 1,400 mg. No dosage adjustment is recommended in pediatric patients <18 years who weigh at least 40 kg. Pediatric patients weighing less than 40 kg should be dosed on the basis of body weight [see Dosage and Administration (2.2, 2.4)]. The recommended dosing regimen for pediatric patients ≤12 kg is predicted to result in similar exposures when compared to exposures achieved in adults receiving bamlanivimab 700 mg and etesevimab 1,400 mg based on pharmacokinetic modeling and simulation. The youngest participant in the pediatric treatment trial was 10 months of age and weighed 8.6 kg [see Clinical Trials and Supporting Data for EUA (18.1)].

Table 4: Pharmacokinetic Parameters of Bamlanivimab (BAM) and Etesevimab (ETE) Administered IV in Pediatric Patients

Abbreviations: CV = coefficient of variation; Cmax = maximum concentration; AUCinf = area under the concentration versus time curve from zero to infinity.
Body Weight	≥40 kg	>20 to <40 kg	>12 to ≤20 kg	≤12 kg
BAM / ETE Dose	700 mg / 1400 mg	350 mg / 700 mg	175 mg / 350 mg	15 mg/kg / 30 mg/kg
BAM: Geometric Mean (%CV) [n]
Cmax , mcg/mL	235 (51.0) [52]	239 (39.1) [16]	243 (66.0) [7]	371 (9.8) [2]
Cday 29 , mcg/mL	26.8 (50.2) [34]	26.1 (32.5) [8]	23.0 (53.0) [3]	[0]
AUCinf , mcg day/mL	2760 (30.7) [66]	2780 (25.7) [20]	2430 (28.4) [9]	3000 (19.1) [3]
ETE: Geometric Mean (%CV) [n]
Cmax , mcg/mL	508 (50.6) [50]	444 (26.6) [14]	444 (64.9) [7]	831 (16.8) [2]
Cday 29 , mcg/mL	133 (46.8) [34]	138 (29.5) [8]	125 (51.5) [3]	[0]
AUCinf , mcg day/mL	12900 (32.4) [66]	12400 (23.2) [20]	11300 (29.6) [9]	13500 (13.0) [3]

Patients with renal impairment

Bamlanivimab and etesevimab are not eliminated intact in the urine. Renal impairment is not expected to impact the PK of bamlanivimab and etesevimab, since mAbs with molecular weight >69 kDa are known not to undergo renal elimination. Similarly, dialysis is not expected to impact the PK of bamlanivimab and etesevimab [see Use in Specific Populations (11.5)].

Patients with hepatic impairment

Based on population PK analysis, there is no significant difference in PK of bamlanivimab or etesevimab in patients with mild hepatic impairment compared to patients with normal hepatic function. Bamlanivimab and etesevimab have not been studied in patients with moderate or severe hepatic impairment [see Use in Specific Populations (11.6)].

Drug interactions:

Bamlanivimab and etesevimab are 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.