Model-based prediction of nanoparticle and dissolved form ratios using total concentration data: a case study of...

Area of Science:

• Pharmacology
• Nanotechnology
• Clinical Pharmacology

Background:

• Irinotecan (CPT-11) is a prodrug for SN-38, but its clinical use is limited by poor conversion, tumor targeting, and toxicity.
• Nanoparticle formulations like SNB-101 aim to improve irinotecan delivery and reduce toxicity via the EPR effect.

Purpose of the Study:

• To develop a pharmacokinetic (PK) model to distinguish nanoparticle (NP) and dissolved (S) forms of irinotecan and SN-38.
• To characterize NP-to-S transitions and their contribution to total drug exposure from SNB-101.

Main Methods:

• Utilized total plasma concentration data from a Phase I clinical trial of SNB-101.
• Developed an 11-compartment PK model integrating prior knowledge and new clinical data.

Main Results:

• SNB-101 predominantly delivers SN-38 in nanoparticle form (NP-SN-38), accounting for over 80% of total SN-38 exposure.
• High NP-SN-38 exposure correlated with reduced systemic toxicity despite increased total SN-38 levels.

Conclusions:

• Reduced exposure to dissolved SN-38 and irinotecan contributes to SNB-101's favorable safety profile.
• This model-based approach highlights the value of distinguishing NP and S forms for predicting efficacy and toxicity of nanoparticle therapeutics.