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 (R), Myocet (R), and AmBisome (R) as well as to the formulation prototypes Foslip (R) 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 (R), 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 (R) 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 (R), AmBisome (R), and Foslip (R), the major fraction of the dose was released into the blood plasma without being available for targeted delivery.