Qiuyang Zhang (1), Erqian Yu (1), Wanqiu Yang (2), Qingqing Xiao (2), Yan Ren (1)
1. Clinical Pharmacology, BeiGene (Shanghai) Co., Ltd., Shanghai, China; 2. Department of Pharmacometrics, Mosim Co., Ltd., Shanghai, China
Introduction: Cpd001 is an orally available, potent small molecule inhibitor of a closely related spectrum receptor tyrosine kinases (RTKs). RTKs are key regulators of signaling pathways leading to cell growth, survival, and migration. These kinases are found dysregulated in many cancers through overexpression, genetic alteration or co-expression with high affinity ligands. Multiple Cpd001 RTK targets are genetically altered in a variety of cancer indications and act as oncogenic drivers promoting cancer development and progression. The safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of Cpd001 are being explored in patient with advanced solid tumors. A population PK (popPK) model was built to summarize the currently available patient PK data, and preliminary exposure-response (E-R) analyses were performed to inform dose optimization in future clinical studies.
Objectives:
- To characterize the population trend and covariates of Cpd001 PK in patients with advanced solid tumors
- To explore the E-R relationships between Cpd001 exposure and safety as well as preliminary efficacy endpoints
Methods: Currently 77 patients have been treated with Cpd001 at dose levels of 80 mg or 120 mg for up to 5 cycles. Intensive blood samples were collected from 39 patients at pre-and 0.5-, 2-, 4-, 6-, 8-, 10-, 12-, 24-hr post dose (among which 12 and 24 hr time points are optional) on Cycle 1 Day 1 and Cycle 1 Day 21. Other blood samples are sparsely collected at pre- and 6-hr post dose. The plasma concentrations of Cpd001 were analyzed using LC-MS/MS. A total of 756 plasma concentration observations were available for model building using NONMEM (7.2, ICON, Maryland). A list of covariates (age, body weight, sex, liver and kidney functions, race and concomitant medications) were evaluated using a forward addition and backward elimination method.
The impact of model-simulated AUCss, Cmax,ss and Ctrough on efficacy endpoints (overall response rates (ORR), progression-free survival (PFS) and disease control rate (DCR) and time to response), safety endpoints (adverse events (AEs), and drug-related AEs of interest (hypertension, diarrhea, proteinuria, nausea, etc.) were explored. Semi-parametric Cox proportional hazard model and logistic regression model, as well as Graphics and descriptive statistics, were used to describe the potential relationships. Nested and non-nested models were compared based on objective function value and Akaike Information Criterion value, respectively.
Results: The PK of Cpd001 was adequately characterized by a one-compartment model with first-order absorption and elimination. GOF plots, bootstrap and pcVPC suggested the final model described the observed data well and had good predictability. The typical values of apparent clearance (CL/F), volume of distribution (V/F) and absorption rate constant were estimated to be 58.5 L/h, 1580 L, and 0.159 h-1, respectively. Age was identified as a significant covariate on V/F, which has no clinically relevant impact on AUCss. Terminal half-life of Cpd001 was not able to be accurately estimated with the current dataset because the elimination phase was not fully characterized (45.5% of the optional samples were not collected).
An increase in the probability of any grade and drug-related hypertension was observed when Cpd001 AUCss is greater than its median of 1824.76 ng*h/mL. The probability of causing nausea and drug-related nausea for patients with AUCss greater than its median (2151.93 ng*h/mL) tended to be higher. DCR was found to be significantly correlated with increased exposure with a plateau effect at AUCss >1770 ng*h/mL or Ctrough > 60 ng/mL.
Conclusions: A one-compartment model with first-order absorption and elimination was identified to adequately describe the PK of Cpd001. Age was identified as a covariate on V/F, which is unlikely to have clinical relevance.
No significant exposure-AE relationships were found except for the increased trends of hypertension and nausea in patients with higher AUCss. Such tendency should be interpreted with caution as the sample size is small.
The increase in DCR appeared to be associated with higher Cpd001 exposure with a plateau when AUCss > 1770 ng*h/mL or Ctrough > 60 ng/mL.
The popPK and E-R models will be further updated when more clinical data are collected, and the results will be used to support dose optimization for the following clinical studies in specific patient populations.
References:
[1] Blume-Jensen P., Hunter T., Oncogenic kinase signalling. Nature, 2001; 411:355-65
[2] Paul MK. and Mukhopadhyay AK., Tyrosine kinase- Role and significance in cancer. International Journal of Medical Sciences, 2004; 1(2):101-115.
[3] Reza M. The Relationship Among Pharmacokinetic Parameters: Effects of Altered Kinetics on the Drug Plasma Concentration-Time Profiles, American Journal of Pharmaceutical Education, 2004; 68 (2) Article 36.
Reference: PAGE () Abstr 9447 [www.page-meeting.org/?abstract=9447]
Poster: Drug/Disease Modelling - Oncology