| Title |
Translational PK-PD modeling analysis of MCLA-128, a HER2/HER3 bispecific monoclonal antibody, to predict clinical efficacious exposure and dose
|
|---|---|
| Published in |
Investigational New Drugs, May 2018
|
| DOI | 10.1007/s10637-018-0593-x |
| Pubmed ID | |
| Authors |
Aurelia H. M. de Vries Schultink, Robert P. Doornbos, Alexander B. H. Bakker, Kees Bol, Mark Throsby, Cecile Geuijen, David Maussang, Jan H. M. Schellens, Jos H. Beijnen, Alwin D. R. Huitema |
| Abstract |
Introduction MCLA-128 is a bispecific monoclonal antibody targeting the HER2 and HER3 receptors. Pharmacokinetics (PK) and pharmacodynamics (PD) of MCLA-128 have been evaluated in preclinical studies in cynomolgus monkeys and mice. The aim of this study was to characterize the PK and PD of MCLA-128 and to predict a safe starting dose and efficacious clinical dose for the First-In-Human study. Methods A PK-PD model was developed based on PK data from cynomolgus monkeys and tumor growth data from a mouse JIMT-1 xenograft model. Allometric scaling was used to scale PK parameters between species. Simulations were performed to predict the safe and efficacious clinical dose, based on AUCs, receptor occupancies and PK-PD model simulations. Results MCLA-128 PK in cynomolgus monkeys was described by a two-compartment model with parallel linear and nonlinear clearance. The xenograft tumor growth model consisted of a tumor compartment with a zero-order growth rate and a first-order dying rate, both affected by MCLA-128. Human doses of 10 to 480 mg q3wk were predicted to show a safety margin of >10-fold compared to the cynomolgus monkey AUC at the no-observed-adverse-effect-level (NOAEL). Doses of ≥360 mg resulted in predicted receptor occupancies above 99% (Cmax and Cave). These doses showed anti-tumor efficacy in the PK-PD model. Conclusions This analysis predicts that a flat dose of 10 to 480 mg q3wk is suitable as starting dose for a First-in-Human study with MCLA-128. Flat doses ≥360 mg q3wk are expected to be efficacious in human, based on receptor occupancies and PK-PD model simulations. |
Mendeley readers
The data shown below were compiled from readership statistics for 42 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 42 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Researcher | 10 | 24% |
| Other | 4 | 10% |
| Student > Doctoral Student | 4 | 10% |
| Student > Postgraduate | 3 | 7% |
| Student > Ph. D. Student | 3 | 7% |
| Other | 5 | 12% |
| Unknown | 13 | 31% |
| Readers by discipline | Count | As % |
|---|---|---|
| Biochemistry, Genetics and Molecular Biology | 9 | 21% |
| Agricultural and Biological Sciences | 5 | 12% |
| Medicine and Dentistry | 4 | 10% |
| Pharmacology, Toxicology and Pharmaceutical Science | 3 | 7% |
| Immunology and Microbiology | 3 | 7% |
| Other | 4 | 10% |
| Unknown | 14 | 33% |
Attention Score in Context
This research output has an Altmetric Attention Score of 3. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 29 April 2021.
All research outputs
#7,555,516
of 23,047,237 outputs
Outputs from Investigational New Drugs
#328
of 1,175 outputs
Outputs of similar age
#131,040
of 327,168 outputs
Outputs of similar age from Investigational New Drugs
#7
of 18 outputs
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