The application of mechanism-based PK/PD modeling in pharmacodynamic-based dose selection of muM17, a surrogate monoclonal antibody for efalizumab.
muM17 is an anti-mouse CD11a monoclonal antibody (mAb) developed as a surrogate molecule for assessing potential reproductive toxicities of efalizumab, an anti-human CD11a mAb approved for treatment of chronic moderate to severe plaque psoriasis. This article shows the use of a mechanism-based PK/PD model for muM17 to further support the determination of dose equivalency of muM17 in the mouse and efalizumab in humans based on CD11a expression on T-lymphocytes (PD). Patients in clinical studies received 1 mg/kg/week efalizumab subcutaneously for 12 weeks. In the mouse model, a single IV dose of 1 or 10 mg/kg or a single SC dose of 3, 5, or 10 mg/kg muM17 was administered. Drug concentrations and PD were quantitated using ELISA and flow cytometry (FACS) analyses, respectively. The PK/PD model of muM17 in mice was developed and was validated using sparse data from a separate multiple dose PK/PD study. The model was next used to simulate PD profiles with multiple dosing regimens mimicking those of the clinical dose of efalizumab. The model showed that 3 mg/kg/week SC administration of muM17 in mice is the minimum dose that can produce PD effects similar to those produced following 1 mg/kg/week SC of efalizumab in humans.
Wu
Benjamin
B
Department of Pharmacokinetic and Pharmacodynamic Sciences, Genentech, Inc., 1 DNA Way, MS 70, South San Francisco, CA 94080, USA.
Joshi
Amita
A
Ren
Song
S
Ng
Chee
C
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D040881:CD11a Antigen / Q000008:administration & dosage / Q000494:pharmacology*; D017321:Clinical Trials, Phase I as Topic; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007279:Injections, Subcutaneous; D051379:Mice; D008815:Mice, Inbred Strains; D008954:Models, Biological; D015337:Multicenter Studies as Topic; D011565:Psoriasis / Q000188:drug therapy; D015203:Reproducibility of Results; D012098:Reproduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D040881:CD11a Antigen; C472181:efalizumab