Pharmacokinetics and pharmacodynamics of CD4-anchoring bi-functional fusion inhibitor in monkeys.
OBJECTIVE
This study was to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of a chimeric protein, CD4-anchoring bi-functional fusion inhibitor (CD4-BFFI), in monkeys and assess the feasibility for HIV-1 treatment in humans.


METHODS
The serum concentrations of CD4-BFFI and CD4 receptors were determined and modeled using a target-mediated drug disposition (TMDD) model following intravenous administration of 1 or 10 mg/kg in monkeys. In vitro CD4 internalization was examined in human peripheral blood mononuclear cells.


RESULTS
Noncompartmental analysis showed a decrease in clearance (1.35 to 0.563 mL/h/kg) and an increase in half-lives (35 to 50 h) with increasing doses. Dose-dependent CD4 occupancy was observed. The TMDD model reasonably captured the PK/PD profiles and suggested greater degradation rate constant for the free CD4 than the bound CD4. In vitro assay showed CD4-BFFI did not reduce the internalization of cell surface CD4. The simulated serum concentrations of CD4-BFFI were 20-fold above its in vitro IC50 for HIV-1 at 3 mg/kg weekly or biweekly following subcutaneous administration in humans.


CONCLUSIONS
The TMDD modeling and in vitro CD4 internalization study indicate that CD4-BFFI does not induce CD4 internalization and CD4-BFFI short half-life is likely due to normal CD4 internalization. The simulated human PK supports CD4-BFFI as a promising anti-HIV-1 agent.
Department of Drug Metabolism and Pharmacokinetics, Roche Palo Alto, 3411 Hillview Avenue, Palo Alto, California, 94304, USA, liu.xingrong@gene.com.
Xingrong
X
Liu
Ying C
YC
Ou
Jun
J
Zhang
Ago
A
Ahene
Douglas
D
Clark
Su-Chun
SC
Hsieh
Matthew
M
Cooper
Changhua
C
Ji
D061605:Administration, Intravenous; D000818:Animals; D019380:Anti-HIV Agents / Q000097:blood / Q000276:immunology / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000097:blood / Q000276:immunology / Q000493:pharmacokinetics* / Q000494:pharmacology*; D015704:CD4 Antigens / Q000276:immunology*; D005260:Female; D000882:Haplorhini; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008297:Male; D008954:Models, Biological; D011993:Recombinant Fusion Proteins / Q000097:blood / Q000276:immunology / Q000493:pharmacokinetics* / Q000494:pharmacology*
D019380:Anti-HIV Agents; D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D011993:Recombinant Fusion Proteins