Projecting human pharmacokinetics of therapeutic antibodies from nonclinical data

Figures & data

Figure 1 Observed (•) and predicted pertuzumab serum concentration-time profiles [median (−), 2.5%, 97.5% quantile (−−)] in humans normalized by dose. Pertuzumab concentration-time profiles were scaled from cynomolgus monkey using Dedrick approach with exponent of 0.85 and 1 for CL and V, respectively. The predicted CL, V_ss and V_c for pertuzumab obtained by fitting compartmental modeling were 3.39 mL/kg/day, 69.8 mL/kg and 34.36 mL/kg, respectively, which is consistent with the observed values (CL = 3.31 mL/day/kg, V_ss = 70.0 mL/kg and V_c = 40.9 mL/kg).

Figure 2 Accuracy of allometric scaling of human clearance of 13 therapeutic mAbs from observed clearance using various scaling methods [(A) simple allometric scaling, (B) simple allometric scaling with maximum life potential as correction factor; (C) simple allometric scaling with brain weight as correction factor; (D) allometric scaling based on ROE (rule of exponent) for therapeutic Abs; (E) scaling from cynomolgus monkey using a fixed exponent of clearance of 0.85 (validation data set n = 9); (F) scaling from cynomolgus monkey using a fixed exponent of clearance of 0.85 (full data set n = 13)]. No rodent PK studies were conducted for GNE mAb U and GNE mAb W, therefore, only allometric scaling from cynomolgus monkey were performed for these two mAbs. The percent prediction error (%PE) is the difference between the estimated clearance and observed clearance divided by observed or predicted clearance ×100 for over-prediction (

) and under-prediction (■), respectively. The solid line represents %PE = 0. The dashed lines represent %PE = 100% or −100%.

Table 1 Predicted human clearance for different monoclonal antibodies using various scaling methods

Monoclonal Antibodya1,a2	CLobsf				Simple allometric scalingg			Maximum life potential (MLP) as correction factorg			Brain weight (BrW) as correction factorg			Rule of Exponents k		Scaling from cyno data using a fixed exponent of CL of 0.85
	mouse	rat	cyno	human	xh	CLpred	PBj	yh	CLpred	PHj	zh	CLpred	PEj	CLpred	PEj	wi	CLpred	PBj
Pertuzumab	7.02	8.93	5.15	3.31	0.939	4.87	47.1	13.5	3.79	14.5	1.94	3.42	11	4.87	47.1	0.832	3.29	−0.73
Bevacizumab	15.7	4.83	5.37	3.35	0.794	2.34	−43.1	1.21	1.82	−84.0	1.80	1.58	−112	2.34	−43.1	0.875	343	2.28
Trastuzumabc	7.80	ND	5.52	3.80	1.00	5.53	45.5	0.906	4.28	12.6	1.87	2.39	−60.0	NA	NA	0.783	3.52	−7.89
Onializuniab	3.12	6.67	4.32	2.40	1.06	6.31	163	1.47	4.91	105	2.06	4.25	77.1	4.25	77.1	0.733	2.76	14.9
ONE mAb S	5.50	8.00	8.72	5.57	1.09	11.9	114	1.50	9.29	66.8	2.09	8.04	44.3	8.04	44.3	0.850	5.56	−0.11
ONE mAb Td	ND	14.6	6.26	4.79	0.679	2.40	−99.6	1.31	4.34	−10.4	2.03	6.09	27.1	NA	NA	0.785	3.99	−19.9
ONE mAb Xb	10.3	11.6	8.62	4.40	0.966	8.37	90.2	1.38	6.44	46.4	1.97	5.54	25.9	8.37	90.2	0.776	5.50	25.00
ONE mAb Y	8.80	5.09	3.06	2.68	0.777	1.44	−86.1	1.20	1.24	−116	1.79	1.07	−150	1.44	−86.1	0.886	1.95	−37.3
ONE mAb Z	5.33	10.2	6.21	3.23	1.021	8.56	165	1.43	6.49	101	2.02	5.43	68	5.43	68	0.970	3.96	22.7
ONE mAb U e	ND	ND	2.36	2.16	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	0.956	1.51	−43.5
ONE mAb Vc	16.5	ND	4.34	3.08	0.741	2.00	−54	1.87	1.87	−64.7	1.74	1.8	−71	NA	NA	0.842	2.77	−11.2
GNE mAb We	ND	ND	11.5	6.00	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	0.804	7.34	22.3
Anti-CD40b	10.4	12.8	10.8	4.85	1.01	11.94	146	1.42	9.15	88.7	2.01	7.86	62.1	7.86	62.1	0.923	6.89	42.1

ND, no data; NA, not applicable.

a1 All antibodies except for GNE mAb T, GNE mAb X and GNE mAb U are humanized IgG antibodies. GNE mAb T is chimeric, and GNE mAb X and U are human antibodies.

a2 Used reported body weight for mice (20 g), rat (250 g) and cynomolgus monkeys (3.5 kg) except when indicated.

b Used the observed body weight in the study.

c Only mouse and monkey PK data were available. Regression was done based on two species.

d Only rat and monkey PK data were available. Regression was done based on two species.

e Only monkey PK data was available. No regression was done.

f CL values were obtained by two-compartmental analysis. CLs were reported as mean values for mouse, rat and monkeys. If anti-therapeutics antibody (ATA) has significant impacts on CL, only ATA negative animals were included for CL calculations, otherwise, all animals were included for CL calculations. CLs in humans were reported as typical values in population pharmacokinetics analysis, which include ATA positive and ATA negative subjects.

g regression R² > 0.96 for all molecules.

h simple allometric scaling: CL = a•BW^x; allometric scaling with MLP as correction factor: MLP•CL = b•BW^y; allometric scaling with BrW as correction factor: BrW•CL = c•BW^z; where a, b and c are the coefficient and x, y and z is the exponent of the allometric equation.

i the exponent w for the antibodies were back calculated based on the observed mean CL in cynomolgus monkeys and in humans. The mean ± SD of w was 0.847 ± 0.07.

j Percentage errors (PEs) are [(CL_h, predicted − CL_h, observed)/CL_h, observed] × 100% for over-prediction and [(CL_h, predicted − CL_h, observed)/CL_h, predicted] × 100% for under-prediction.

k Rule of exponents (ROE) proposed by Mahmood for mAbs was only applied to eight mAbs with preclinical PK data from three species available for the simple allometric scaling method: MLP as a correction factor is not needed when exponents of simple allometry are greater than 0.71 but less than 1; brain weight is required to improve the prediction of human CL when exponents of simple allometry are greater than 1.