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In Vitro and In Vivo Evaluation of Photocontrolled Biologically Active Compounds - Potential Drug Candidates for Cancer Photopharmacology
Published on: September 29, 2023
Phase I dose-finding and pharmacokinetic trial of orally administered indibulin (D-24851) to patients with solid
I E L M Kuppens1, P O Witteveen, M Schot
1Department of Medical Oncology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066, CX Amsterdam, The Netherlands. isa_kuppens@hotmail.com
Abstract:
Indibulin is a synthetic small molecule which antitumor activity is based upon destabilization of microtubules. The primary study objectives were to determine the impact of fasted and fed condition on pharmacokinetic parameters, as well as the maximum tolerated dose of the oral drinking solution of indibulin administered once daily for 14 days every 3 weeks in patients with solid tumors. In the pilot food effect part, patients received a single dose of 20 mg indibulin on day-8 and -4, fasted or fed, in a randomized crossover design. In the dose-escalation part, patients received a single dose of indibulin on day-4. Three dose levels were evaluated: 20, 40 and 80 mg. After a washout period, patients received indibulin once daily for 14 days every 3 weeks (multiple dose part). Blood samples were collected in the pilot food effect- and in the dose escalation study. A total of 14 patients entered, of which 6 completed the food effect study. The ratio of indibulin (fed/fasted) in the food effect study for AUC(0-72) was estimated as 1.24 (P=0.082, 95%CI 0.96-1.41) and C(max) ratio was 0.89 (P=0.54, 95%CI 0.55-1.44). Interpatient variability was high. Higher peak plasma concentrations were reached under fasting conditions which was undesired regarding tolerability. Therefore the dose escalation study was continued under fed conditions. Dose limiting toxicities, nausea and vomiting, appeared to be related to the increased volume of the solvent lactic acid. This study is continued, evaluating indibulin administered as capsules on the recommended dose level of 60 mg daily for 14 days.
Insights
Indibulin
Area of Science:
- Pharmacology
- Oncology
- Drug Development
Background:
- Indibulin is a synthetic small molecule with antitumor activity.
- Its mechanism involves destabilizing microtubules.
- Oral indibulin's pharmacokinetics and tolerability were evaluated.
Purpose of the Study:
- To assess the impact of food on indibulin pharmacokinetics.
- To determine the maximum tolerated dose (MTD) of oral indibulin.
- To evaluate indibulin's safety and tolerability in solid tumor patients.
Main Methods:
- A randomized crossover design for food effect study (fasted vs. fed).
- Dose escalation to determine MTD.
- Multiple dose administration for 14 days every 3 weeks.
- Blood sample analysis for pharmacokinetic parameters.
Main Results:
- Food intake did not significantly alter indibulin's area under the curve (AUC).
- Peak plasma concentration (Cmax) was lower when fed, but interpatient variability was high.
- Higher peak concentrations under fasting conditions were associated with tolerability issues.
- Dose-limiting toxicities (nausea, vomiting) were linked to the solvent (lactic acid).
Conclusions:
- Indibulin's pharmacokinetic profile is influenced by food intake.
- Fasting conditions may lead to undesirable peak concentrations.
- Further studies are ongoing with indibulin capsules to optimize dosing and tolerability.
