Investigations of the mechanism behind the rapid absorption of nano-amorphous abiraterone acetate

Basa-Dénes, Orsolya; Solymosi, Tamás; Ötvös, Zsolt; Angi, Réka; Ujhelyi, Andrea; Jordán, Tamás; Heltovics, Gábor; Glavinas, Hristos

doi:10.1016/j.ejps.2019.01.001

Cited by 19 publications

(11 citation statements)

References 22 publications

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“…, enzyme adsorption, in vivo AbA/Ab precipitation, and the impact of microporosity on micellar formation). Rapid AbA release and dissolution followed by subsequent hydrolysis generates a supersaturation state of both AbA and its metabolite, Ab, in the media. , It has been reported that the supersaturation of Ab is more stable in vivo , whereas AbA supersaturation is highly unstable and, thus, is more prone to precipitation. , Furthermore, by increasing the degree of supersaturation, a higher driving force for precipitation is created . This clarifies the inferior in vivo performance achieved by MPS-C of the highest microporosity (247.0 m 2 /g).…”

Section: Resultsmentioning

confidence: 89%

“…Upon oral administration, dissolved AbA is rapidly hydrolyzed by esterase into the active drug Ab. ,, Both the prodrug (AbA) and active drug (Ab) have similar intestinal permeabilities, and any absorbed AbA is quickly transformed in enterocytes or the liver into Ab, before entering the systemic circulation . Note that AbA solubilization is a prerequisite for the subsequent hydrolysis of AbA to Ab.…”

Section: Resultsmentioning

confidence: 99%

“…27,31,48 Both the prodrug (AbA) and active drug (Ab) have similar intestinal permeabilities, and any absorbed AbA is quickly transformed in enterocytes or the liver into Ab, before entering the systemic circulation. 48 Note that AbA solubilization is a prerequisite for the subsequent hydrolysis of AbA to Ab. Therefore, both AbA and Ab aqueous concentration−time profiles were measured during in vitro lipolysis studies (displayed in Figure 4).…”

Section: Molecularmentioning

confidence: 99%

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Role of Silica Intrawall Microporosity on Abiraterone Acetate Solubilization and In Vivo Oral Absorption

et al. 2022

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SBA-15 mesoporous silica (MPS) has been widely used in oral drug delivery; however, it has not been utilized for solidifying lipid-based formulations, and the impact of their characteristic intrawall microporosity remains largely unexplored. Here, we derive the impact of the MPS microporosity on the in vitro solubilization and in vivo oral pharmacokinetics of the prostate cancer drug abiraterone acetate (AbA) when coencapsulated along with medium chain lipids into the pores. AbA in lipid (at 80% equilibrium solubility) was imbibed within a range of MPS particles (with comparable morphology and mesoporous structure but contrasting microporosity ranging from 0−247 m 2 /g), and their solid-state properties were characterized. Drug solubilization studies during in vitro lipolysis revealed that microporosity was the key factor in facilitating AbA solubilization by increasing the surface area available for drug−lipid diffusion. Interestingly, microporosity hindered hydrolysis of AbA to its active metabolite, abiraterone (Ab), under simulated intestinal conditions. This unique relationship between microporosity and AbA/Ab aqueous solubilization behavior was hypothesized to have significant implications on the subsequent bioavailability of the active metabolite. In vivo oral pharmacokinetics studies in male Sprague−Dawley rats revealed that MPS with moderate microporosity attained the highest relative bioavailability, while poor in vitro−in vivo correlations (IVIVC) existed between in vitro drug solubilization during lipolysis and in vivo AUC. Despite this, a reasonable IVIVC was established between the in vitro solubilization and in vivo C max , providing evidence for an association between silica microporosity and oral drug absorption.

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Section: Resultsmentioning

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Molecularmentioning

confidence: 99%

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Role of Silica Intrawall Microporosity on Abiraterone Acetate Solubilization and In Vivo Oral Absorption

et al. 2022

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“…Absorption of TOS in the fasted state was also substantially improved, with 4.7-times higher relative bioavailability when compared to R-AA fasted (on a mg to mg basis). The potential mechanism behind the rapid absorption of the drug from the formulation was discussed by the authors in another article [18]. The substantial food effect seen with R-AA was not observed with TOS-administration of TOS is likely to be far more reliable than that of R-AA, whether given with or without food.…”

Section: Discussionmentioning

confidence: 99%

Dose Finding and Food Effect Studies of a Novel Abiraterone Acetate Formulation for Oral Suspension in Comparison to a Reference Formulation in Healthy Male Subjects

Jordán¹,

Basa-Dénes²,

Angi³

et al. 2021

Pharmaceutics

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Currently approved formulations of the androgen synthesis inhibitor abiraterone acetate (AA) consist of multiple tablets administered daily in a fasted state. Removing the food effect and switching to a suspension formulation is expected to improve the pharmacokinetic profile and facilitate drug administration for patients with late-stage prostate cancer. Two four-sequence, four-period randomized crossover investigations were undertaken to establish the pharmacokinetic profiles of single doses of commercially available Zytiga®, as the reference AA (R-AA), and a novel tablet for oral suspension (TOS). Four single doses of TOS (from 62.5 to 250 mg) were compared in study C01, and two single doses each of TOS (250 mg) and R-AA (1000 mg) were compared under fasted and fed (modified fasted for R-AA) conditions in C02. Plasma concentrations of abiraterone over time were measured, and pharmacokinetic parameters were calculated. Each doubling of the dose of TOS was associated with a greater than 3-fold increase in exposure. A single dose of TOS (250 mg) exhibited similar exposure over 24 h, whether given fasted (625 ng × h/mL) or fed (485 ng × h/mL). A single dose of TOS (250 mg) was associated with higher (fasted, p = 0.028) or equivalent exposure (fed) compared to 1000 mg R-AA fasted (532 ng × h/mL). Substantially higher exposures were seen with 1000 mg R-AA under modified fasted conditions compared to TOS, irrespective of prandial status (p < 0.001). TOS was generally safe and well tolerated in the study. A 250 mg dose of a novel AA formulation for oral suspension demonstrated bioequivalence to 1000 mg R-AA under fasted conditions. This novel TOS formulation also addresses some of the limitations of current AA treatment, including low bioavailability, high variability in systemic exposure and a large food effect. It may offer an alternative for patients with dysphagia or discomfort with swallowing large pills.

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“…As per the literature analysis, the published reports have focused primarily on the stabilization of polymorphic forms of the drug. 11 A few reports have been published about the solid dispersions and silica lipid hybrid nanoparticles of abiraterone acetate. 12 Although these studies have addressed some of the drug delivery challenges of abiraterone, the manufacturing methods are difficult to reproduce.…”

Section: Introductionmentioning

confidence: 99%

Systematic Development of Solid Lipid Nanoparticles of Abiraterone Acetate with Improved Oral Bioavailability and Anticancer Activity for Prostate Carcinoma Treatment

et al. 2022

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In the present work, an attempt was undertaken to improve the oral bioavailability and anticancer activity of abiraterone acetate. Solid lipid nanoparticles (SLNs) were developed using the quality by design (QbD) principles and evaluated through in vitro , ex vivo , and in vivo studies. Solid lipid suitability was evaluated by equilibrium solubility study, while surfactant and cosurfactant were screened based on the ability to form microemulsion with the selected lipid. SLNs were prepared by emulsion/solvent evaporation method using glyceryl monostearate, Tween 80, and Poloxamer 407 as the solid lipid, surfactant, and cosurfactant, respectively. Box-Behnken design was applied for optimization of material attributes and evaluating their impact on particle size, polydispersity index, zeta potential, and entrapment efficiency of the SLNs. In vitro drug release study was evaluated in simulated gastric and intestinal fluids. Cell culture studies on PC-3 cells were performed to evaluate the cytotoxicity of the drug-loaded SLNs in comparison to the free drug suspension. Qualitative uptake was evaluated for Rhodamine B-loaded SLNs and compared with free dye solution. Ex vivo permeability was evaluated on Wistar rat intestine and in vivo pharmacokinetic evaluation on Wistar rats for SLNs and free drug suspension. Concisely, the SLNs showed potential for significant improvement in the biopharmaceutical performance of the selected drug candidate over the existing formulations of abiraterone acetate.

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Investigations of the mechanism behind the rapid absorption of nano-amorphous abiraterone acetate

Cited by 19 publications

References 22 publications

Role of Silica Intrawall Microporosity on Abiraterone Acetate Solubilization and In Vivo Oral Absorption

Role of Silica Intrawall Microporosity on Abiraterone Acetate Solubilization and In Vivo Oral Absorption

Dose Finding and Food Effect Studies of a Novel Abiraterone Acetate Formulation for Oral Suspension in Comparison to a Reference Formulation in Healthy Male Subjects

Systematic Development of Solid Lipid Nanoparticles of Abiraterone Acetate with Improved Oral Bioavailability and Anticancer Activity for Prostate Carcinoma Treatment

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