A Mechanism-Based Pharmacokinetic/Pharmacodynamic Model for Bococizumab, a Humanized Monoclonal Antibody Against Proprotein Convertase Subtilisin/Kexin Type 9, and Its Application in Early Clinical Development.
Bococizumab (RN316/PF-04950615), a humanized monoclonal antibody, binds to secreted proprotein convertase subtilisin/kexin type 9 (PCSK9) and prevents its downregulation of low-density lipoprotein receptor, leading to improved clearance and reduction of low-density lipoprotein cholesterol (LDL-C) in plasma. A mechanism-based drug-target binding model was developed, accounting for bococizumab, PCSK9, and LDL-C concentrations and the effects of concomitant administration of statins. This model was utilized to better understand the pharmacokinetic/pharmacodynamic (PK/PD) data obtained from 3 phase 1 and 2 phase 2a clinical studies. First, simulations performed with this model demonstrated that the conventional method of the area-under-the-curve ratio for bioavailability determination underestimated the subcutaneous bioavailability of bococizumab due to its target-mediated disposition. Second, a covariate model component for statin effects on bococizumab PK/PD was characterized, including a description of the decreased baseline LDL-C, increased baseline PCSK9, and increased LDL-C lowering with concomitant use of statins. Last, the impact of the dosing regimens with and without a dose holiday on bococizumab's LDL-C-lowering effectiveness was shown to be predictable due to the well-characterized PK-PD relationship.
World Wide Research and Development, Pfizer Inc, San Diego, California.
Chandrasekhar
C
Udata
World Wide Research and Development, Pfizer Inc, San Diego, California.
Pamela D
PD
Garzone
World Wide Research and Development, Pfizer Inc, San Diego, California.
Barry
B
Gumbiner
World Wide Research and Development, Pfizer Inc, San Diego, California.
Tenshang
T
Joh
World Wide Research and Development, Pfizer Inc, San Diego, California.
Hong
H
Liang
World Wide Research and Development, Pfizer Inc, San Diego, California.
Kai-Hsin
KH
Liao
World Wide Research and Development, Pfizer Inc, San Diego, California.
Jason H
JH
Williams
World Wide Research and Development, Pfizer Inc, San Diego, California.
Xu
X
Meng
D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000924:Anticholesteremic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy; D008954:Models, Biological; D000071449:Proprotein Convertase 9 / Q000276:immunology*; D011485:Protein Binding
D061067:Antibodies, Monoclonal, Humanized; D000924:Anticholesteremic Agents; C000598888:bococizumab; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9
PCSK9; bococizumab; monoclonal antibody; pharmacokinetic/pharmacodynamic model; proprotein convertase subtilisin/kexin type 9