Pharmacokinetics of an Injectable Modified-Release 2-Hydroxyflutamide Formulation in the Human Prostate Gland Using a Semiphysiologically Based Biopharmaceutical Model
2014 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, Vol. 11, no 9, 3097-3111 p.Article in journal (Refereed) Published
The local distribution of 2-hydroxyflutamide (2-HOF) in prostate tissue after a single intraprostatic injection of a novel parenteral modified-release (MR) formulation in patients with localized prostate cancer was estimated using a semiphysiologically based biopharmaceutical model. Plasma concentration-time profiles for 2-HOF were acquired from a phase II study in 24 patients and the dissolution of the MR formulation was investigated in vitro. Human physiological values and the specific physicochemical properties of 2-HOF were obtained from the literature or calculated via established algorithms. A compartmental modeling approach was adopted for tissue and blood in the prostate gland, where the compartments were modeled as a series of concentric spherical shells contouring the centrally positioned depot formulation. Discrete fluid connections between the blood compartments were described by the representative flow of blood, whereas the mass transport of drug from tissue to tissue and tissue to blood was described by a one-dimensional diffusion approximation. An empirical dissolution approach was adopted for the release of 2-HOF from the formulation. The model adequately described the plasma concentration time profiles of 2-HOF.. Predictive simulations indicated that the local tissue concentration of 2-HOF within a distance of 5 mm from the depot formulation was approximately 40 times higher than that of unbound 2-HOF in plasma. The simulations also indicated that spreading the formulation throughout the prostate gland would expose more of the gland and increase the overall release rate of 2-HOF from the given dose. The increased release rate would initially increase the tissue and plasma concentrations but would also reduce the terminal half-life of 2-HOF in plasma. Finally, an in vitro in vivo correlation of the release of 2-HOF from the parenteral MR formulation was established. This study shows that intraprostatic 2-HOF concentrations are significantly higher than systemic plasma concentrations and that increased distribution of 2-HOF throughout the gland, using strategic imaging-guided administration, is possible. This novel parenteral MR formulation, thus, facilitates good pharmacological effect while minimizing the risk of side effects.
Place, publisher, year, edition, pages
2014. Vol. 11, no 9, 3097-3111 p.
prostate cancer, 2-hydroxyflutamide, Liproca Depot, physiological modeling, drug delivery
Pharmacology and Toxicology
IdentifiersURN: urn:nbn:se:uu:diva-233002DOI: 10.1021/mp5002813ISI: 000341230000013OAI: oai:DiVA.org:uu-233002DiVA: diva2:754550