Background AR-67 is a novel camptothecin analogue at early stages of drug development. The phase 1 clinical trial in cancer patients with solid tumors was completed and a population pharmacokinetic model (POP PK) was developed to facilitate further development of this investigational agent. Methods Pharmacokinetic data collected in the phase 1 clinical trial were utilized for the development of a population POP PK by implementing the non-linear mixed effects approach. Patient characteristics at study entry were evaluated as covariates in the model. Subjects (N = 26) were treated at nine dosage levels (1.2–12.4 mg/m2/day) on a daily × 5 schedule. Hematological toxicity data were modeled against exposure metrics. Results A two-compartment POP PK model best described the disposition of AR-67 by fitting a total of 328 PK observations from 25 subjects. Following covariate model selection, age remained as a significant covariate on central volume. The final model provided a good fit for the concentration versus time data and PK parameters were estimated with good precision. Clearance, inter-compartmental clearance, central volume and peripheral volume were estimated to be 32.2 L/h, 28.6 L/h, 6.83 L and 25.0 L, respectively. Finally, exposure-pharmacodynamic analysis using Emax models showed that plasma drug concentration versus time profiles are better predictors of AR-67-related hematologic toxicity were better predictors of leukopenia and thrombocytopenia, as compared to total dose. Conclusions A POP PK model was developed to characterize AR-67 pharmacokinetics and identified age as a significant covariate. Exposure PK metrics Cmax and AUC were shown to predict hematological toxicity. Further efforts to identify clinically relevant determinants of AR-67 disposition and effects in a larger patient population are warranted.
|Number of pages||13|
|Journal||Investigational New Drugs|
|State||Published - Dec 1 2019|
Bibliographical noteFunding Information:
We thank Dr. Thomas Burke (deceased) and his family, Drs. Dennis Curran, and Bradley Anderson for initiating the development of AR-67; Jamie Horn, Chris Houchins, Christopher Wilfong, Marynell Jenkins, Cynthia Leedham, Anne Schmidt, and Mark Stevens for facilitating this project, and all patients for their participation. Investigational new drug application enabling studies were funded by the Rapid Access to Intervention Development program at the National Cancer Institute.
© 2019, Springer Science+Business Media, LLC, part of Springer Nature.
- Performance status
- Population pharmacokinetics
ASJC Scopus subject areas
- Pharmacology (medical)