Predicting human pharmacokinetics of liposomal temoporfin using a hybrid in silico model.

Over the years, the performance of the liposomal formulations of temoporfin, Foslip® and Fospeg®, was investigated in a broad array of cell-based assays and preclinical animal models. So far, little attention has been paid to the influence of drug release and liposomal stability on the plasma concentration-time profile. The drug release is a key attribute which impacts product quality and the in vivo efficacy of nanocarrier formulations. In the present approach, the in vitro drug release and the drug-protein transfer of Foslip® and Fospeg® was determined using the dispersion releaser technology. To analyze the stability of both formulations in physiological fluids, nanoparticle tracking analysis was applied. A comparable drug release behavior and a high physical stability with a vesicle size of approximately 92 ± 2 nm for Foslip® and at 111 ± 5 nm for Fospeg® were measured. The development of a novel hybrid in silico model resulted in an optimal representation of the in vivo data. Based on the information available for previous formulations, the model enabled a prediction of the performance of Foslip® in humans. To verify the simulations, plasma concentration-time profiles of a phase I clinical trial were used. An absolute average fold error of 1.4 was achieved. Moreover, a deconvolution of the pharmacokinetic profile into different fractions relevant for the in vivo efficacy and safety was achieved. While the total plasma concentration reached a cmax of 2298 ng/mL after 0.72 h, the monomolecular drug accounted for a small fraction of the photosensitizer with a cmax of 321 ng/mL only.

A dialysis-based in vitro drug release assay to study dynamics of the drug-protein transfer of temoporfin liposomes.

Today, a growing number of nanotherapeutics is utilized to deliver poorly soluble compounds using the intravenous route of administration. The drug release and the direct transfer of the active pharmaceutical ingredient to serum proteins plays an important role in bioavailability and accumulation of the drug at the target site. It is closely related to the formation of a protein corona as well as the plasma protein binding of the compound. In the present study, two in vitro drug release methods, the flow-through cell and the dispersion releaser technology, were evaluated with regards to their capability to measure a time-resolved profile of the serum protein binding. In this context, the photosensitizer temoporfin and temoporfin-loaded liposomes were tested. While in the fine capillaries of the flow-through cell a rapid agglomeration of proteins occurred, the dispersion releaser technology in combination with the four-step model enabled the measurement of the transfer of drugs from liposomes to proteins. In presence of 10% of fetal calf serum approximately 20% of the model compound temoporfin were bound to serum proteins within the first 3 h. At higher serum concentration this binding remained stable for approximately 10 h.

Advanced in silico modeling explains pharmacokinetics and biodistribution of temoporfin nanocrystals in humans.

Foscan®, a formulation comprising temoporfin dissolved in a mixture of ethanol and propylene glycol, has been approved in Europe for palliative photodynamic therapy of squamous cell carcinoma of the head and neck. During clinical and preclinical studies it was observed that considering the administration route, the drug presents a rather atypical plasma profile as plasma concentration peaks delayed. Possible explanations, as for example the formation of a drug depot or aggregation after intravenous administration, are discussed in current literature. In the present study an advanced in silico model was developed and evaluated for the detailed description of Foscan® pharmacokinetics. Therefore, in vitro release data obtained from experiments with the dispersion releaser technology investigating dissolution pressures of various release media on the drug as well as in vivo data obtained from a clinical study were included into the in silico models. Furthermore, precipitation experiments were performed in presence of biorelevant media and precipitates were analyzed by nanoparticle tracking analysis. Size analysis and particle fraction were also incorporated in this model and a sensitivity analysis was performed. An optimal description of the in vivo situation based on in vitro release and particle characterization data was achieved, as demonstrated by an absolute average fold error of 1.21. This in vitro-in vivo correlation provides an explanation for the pharmacokinetics of Foscan® in humans.