Details

Autor(en) / Beteiligte

• Gao, Ge Fiona
• Ashtikar, Mukul
• Kojima, Ryo
• Yoshida, Takatsune
• Kaihara, Masanori
• Tajiri, Tomokazu
• Shanehsazzadeh, Saeed
• Modh, Harshvardhan
• Wacker, Matthias G.

Titel

Predicting drug release and degradation kinetics of long-acting microsphere formulations of tacrolimus for subcutaneous injection

Ist Teil von

• Journal of controlled release, 2021-01, Vol.329, p.372-384

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2021

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Today, tacrolimus represents a cornerstone of immunosuppressive therapy for liver and kidney transplants and remains subject of preclinical and clinical investigations, aiming at the development of long-acting depot formulations for subcutaneous injection. One major challenge arises from establishing in vitro-in vivo correlations due to the absence of meaningful in vitro methods predictive for the in vivo situation, together with a strong impact of multiple kinetic processes on the plasma concentration-time profile. In the present approach, two microsphere formulations were compared with regards to their in vitro release and degradation characteristics. A novel biorelevant medium provided the physiological ion and protein background. Release was measured using the dispersion releaser technology under accelerated conditions. A release of 100% of the drug from the carrier was achieved within 7 days. The capability of the in vitro performance assay was verified by the level A in vitro-in vivo correlation analysis. The contributions of in vitro drug release, drug degradation, diffusion rate and lymphatic transport to the absorption process were quantitatively investigated by means of a mechanistic modelling approach. The degradation rate, together with release and diffusion characteristics provides an estimate of the bioavailability and therefore can be a guide to future formulation development. [Display omitted] •DR technology detects release and degradation of tacrolimus in biorelevant medium.•State-of-the-art computational framework to evaluate dialysis experiments.•Capability to predict the in vivo performance confirmed by IVIVC of two formulations.•Pharmacokinetic data obtained in relevant species (cynomolgus monkeys).•PBB model elucidates relevant influences on bioavailability in subcutaneous tissue.