Preclinical PK/PD Models of Tumor Response in Oncological Drug Development
Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
Introduction: Xiang et al./Jumbe et al. created preclinical pharmacokinetic-pharmacodynamic (PK/PD) models to describe the relationship between the concentration (PK) and the anti-tumor effect (PD) of the antibody based drugs MetMAb and T-DM1. PK/PD parameters for the models were measured from studies performed on mice. Xin et al./Gupta et al. tested MetMAb/T-DM1 on humans and determined human PK/PD parameters.
Aim: Identify (out of four regimens) a suitable dosing regimen for MetMAb/T-DM1 from a progression-free survival (PFS) point of view. This is to find a regimen that most effectively prevents disease progression and thereby contributes the most to the wellbeing of patients when used in the clinic. Another aim is to identify differences in PFS curves by comparing a simulated clinical dose of MetMAb/T-DM1 with a clinical dose in the literature. This is to evaluate weaknesses with the project’s methods.
Materials and Methods: PubMed was the main source of information. MLXPlore and NONMEM were used to simulate dosing regimens for MetMAb/T-DM1. PK data from human studies humans and PD data from mice studies were inputted into the PK/PD model for MetMAb/T-DM1 and four dose regimens were simulated. A clinical dose of 15.0 mg/kg/11.4 mg/kg with a Q3W (one dose every third week) dose regimen for MetMAb/T-DM1 was simulated and compared to observed clinical dose regimens found in the literature. Kaplan-Meier curves were used to show the average PFS values.
Results: Simulated MetMAb/T-DM1 regimens were 0.66/0.80 mg/kg with Q1W, 1.32/1.60 mg/kg with Q2W, 1.99/2.40 mg/kg with Q3W and 2.64/3.19 mg/kg with Q4W. Differences from a disease progression point of view were found when comparing the simulated regimens in this study with the regimens found in literature.
Conclusions: The Q4W dosing regimen was the best regimen for MetMAb/T-DM1 from a PFS point of view. The clinical simulations done in this project did not predict the observed data. Inability to simulate survival, and the fact that the used models are based on mice likely explained these differences.
Place, publisher, year, edition, pages
2014. , 36 p.
Oncology, tumor, T-DM1, MetMAb
Cancer and Oncology
IdentifiersURN: urn:nbn:se:uu:diva-229800OAI: oai:DiVA.org:uu-229800DiVA: diva2:737735
Subject / course
Bachelor of Science Programme in Pharmacy
Bender, Brendan, Doktorand
Hammarlund-Udenaes, Margareta, Professor