A physiologically-based nanocarrier biopharmaceutics model to reverse-engineer the in vivo drug release

Over the years, a wide variety of nanomedicines has entered global markets, providing a blueprint for the emerging generics industry. They are characterized by a unique pharmacokinetic behavior difficult to explain with conventional methods. In the present approach a physiologically-based nanocarrier biopharmaceutics model has been developed. Providing a compartmental framework of the distribution and elimination of nanocarrier delivery systems, this model was applied to human clinical data of the drug products Doxil®, Myocet®, and AmBisome® as well as to the formulation prototypes Foslip® and NanoBB-1-Dox. A parameter optimization by differential evolution led to an accurate representation of the human data (AAFE < 2). For each formulation, separate half-lives for the carrier and the free drug as well as the drug release were calculated from the total drug concentration-time profile. In this context, a static in vitro set-up and the dynamic in vivo situation with a continuous infusion and accumulation of the carrier were simulated. For Doxil®, a total drug release ranging from 0.01 to 22.1% was determined. With the time of release exceeding the elimination time of the carrier, the major fraction was available for drug targeting. NanoBB-1-Dox released 76.2-77.8% of the drug into the plasma, leading to an accumulated fraction of approximately 20%. The mean residence time of encapsulated doxorubicin was 128 h for Doxil® and 0.784 h for NanoBB-1-Dox, giving the stealth liposomes more time to accumulate at the intended target site. For all other formulations, Myocet®, AmBisome®, and Foslip®, the major fraction of the dose was released into the blood plasma without being available for targeted delivery.