Novel formulation of abiraterone acetate might allow significant dose reduction and eliminates substantial positive food effect

Solymosi, Tamás; Ötvös, Zsolt; Angi, Réka; Ordasi, Betti; Jordán, Tamás; Molnár, László; McDermott, John; Zann, Vanessa; Church, Ann; Mair, Stuart; Filipcsei, Genovéva; Heltovics, Gábor; Glavinas, Hristos

doi:10.1007/s00280-017-3406-6

Cited by 26 publications

(16 citation statements)

References 8 publications

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“…To keep the focus of the editorial, clinical pharmacokinetics comparison is only drawn between 200 mg DIB formulation versus 1000 mg Zytiga. In the two important parameters namely, peak concentration (C max ) and area under the concentration vs. time curve extrapolated to time infinity (AUC inf ), the values obtained for 200 mg DIB were 206 ng/mL and 408 ng.h/mL, respectively; relative to the values of 93 ng/mL and 513 ng.h/ mL, respectively, for the 1000 mg Zytiga tablets [5]. This clearly indicated that despite a 5-fold reduced oral dose of abiraterone acetate in DIB, the C max was almost 2-fold higher and AUC inf was 0.9-fold as compared to the respective values for the 1000 mg Zytiga reference product.…”

Section: Abirateronementioning

confidence: 97%

“…In order to address the issue of low solubility and large oral dose which impeded oral absorption of abiraterone acetate in clinical pharmacology studies, Solymosi et al [5] created amorphous nanoparticles using continuous flow precipitation technology used frequently for such difficult drug substances [6,7]. This creative adaptation of published technologies enabled novel abiraterone acetate formulation that improved dissolution rate along with enhanced solubility [5].…”

Section: Abirateronementioning

confidence: 99%

“…This creative adaptation of published technologies enabled novel abiraterone acetate formulation that improved dissolution rate along with enhanced solubility [5].…”

Section: Abirateronementioning

confidence: 99%

“…A 3-way crossover clinical study was performed using the drug in bottle (DIB) containing the novel formulated abiraterone at doses of 100 and 200 mg relative to a single dose of 1000 mg of Zytiga tablets [5]. To keep the focus of the editorial, clinical pharmacokinetics comparison is only drawn between 200 mg DIB formulation versus 1000 mg Zytiga.…”

Section: Abirateronementioning

confidence: 99%

“…While the DIB formulated abiraterone acetate showed promising results including little impact of the food effect, there is still the need to develop a commercially viable product of the reduced dose which can show bioequivalence with respect to both rate and extent of absorption of abiraterone to enable the switch. In this regard, it was recommended that strength of 250 mg of the newly formulated product would yield bioavailability matching to that of 1000 mg Zytiga tablets [5]. In this regard, another novel formulation of abiraterone acetate fine particle (AAFP) at a 500 mg dose was deemed bioequivalent to the 1000 mg dose of Zytiga when co-administered with steroids (mean ratio of test: reference was 93, 96, and 112% for AUC inf , AUC0-t, and C max , respectively) with considerably lower pharmacokinetic variability [8].…”

Section: Abirateronementioning

confidence: 99%

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Improved Oral Bioavailability and Variability Control in Pharmacokinetic Data – Role of Formulations

Srinivas¹

2018

J Bioequiv Availab

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Section: Abirateronementioning

confidence: 97%

Section: Abirateronementioning

confidence: 99%

“…This creative adaptation of published technologies enabled novel abiraterone acetate formulation that improved dissolution rate along with enhanced solubility [5].…”

Section: Abirateronementioning

confidence: 99%

Section: Abirateronementioning

confidence: 99%

Section: Abirateronementioning

confidence: 99%

See 3 more Smart Citations

Improved Oral Bioavailability and Variability Control in Pharmacokinetic Data – Role of Formulations

Srinivas¹

2018

J Bioequiv Availab

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A prospective phase I multicentre randomized cross-over pharmacokinetic study to determine the effect of food on abiraterone pharmacokinetics

Lubberman¹,

Benoist²,

Gerritsen

et al. 2019

Cancer Chemother Pharmacol

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PurposeAbiraterone acetate is used at a fixed oral dose of 1000 mg once daily (OD) taken fasted. By administering abiraterone acetate with food, a reduced dose can potentially be given while maintaining equivalent abiraterone exposure. Moreover, administering abiraterone acetate with a breakfast is considered more patient friendly. The aim of this study was to establish the bio-equivalent lower dose of abiraterone when taken with a continental breakfast (CB) compared to the standard intake of 1000 mg OD fasted.MethodsIn this phase I, randomized cross-over, multi-center study, abiraterone pharmacokinetics (PK) were evaluated in patients with metastatic castration-resistant prostate cancer who were treated for 14 days with 1000 mg abiraterone acetate taken fasted, followed by 14 days of treatment with 500 mg taken with a CB.Results14 patients were enrolled into the study, of whom 12 were eligible for PK analysis. The geometric mean ratio (GMR) (fed/fasted) was 0.88 (90% CI 0.73–1.07) for area-under-the-curve (AUC0–24h), 1.03 (90% CI 0.79–1.34) for Cmax and 0.81 (90% CI 0.60–1.10) for Ctrough, respectively. High inter-patient variability (> 50%) was found for all PK parameters under both intake conditions. Patients seemed to be slightly more satisfied about the intake of 500 mg abiraterone acetate when taken with a CB compared to 1000 mg fasted.ConclusionIn conclusion, a bioequivalent lower dose of abiraterone taken with food could not be established in our study. Although based on the absence of a exposure–toxicity relationship, the strict bioequivalence margins as defined by the FDA guidelines could be applied more flexible for abiraterone. Information on the effect of food on abiraterone pharmacokinetics as presented in our study can be used for patients with difficulties taken their medication fasted.Electronic supplementary materialThe online version of this article (10.1007/s00280-019-03952-w) contains supplementary material, which is available to authorized users.

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Effect of food on the pharmacokinetics of the WEE1 inhibitor adavosertib (AZD1775) in patients with advanced solid tumors

Någård

Ah-See

et al. 2020

Cancer Chemother Pharmacol

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Purpose To support future dosing recommendations, the effect of food on the pharmacokinetics of adavosertib, a first-inclass, small-molecule reversible inhibitor of WEE1 kinase, was assessed in patients with advanced solid tumors. Methods In this Phase I, open-label, randomized, two-period, two-sequence crossover study, the pharmacokinetics of a single 300 mg adavosertib dose were investigated in fed versus fasted states. Results Compared with the fasted state, a high-fat, high-calorie meal (fed state) decreased adavosertib maximum plasma concentration (C max) by 16% and systemic exposure (area under the plasma concentration-time curve [AUC]) by 6%; AUC 0-t decreased by 7% and time to maximum plasma concentration was delayed by 1.97 h (P = 0.0009). The 90% confidence interval of the geometric least-squares mean treatment ratio for AUC and AUC 0-t was contained within the no-effect limits (0.8-1.25), while that of C max crossed the lower bound of the no-effect limits. Adverse events (AEs) related to adavosertib treatment were reported by 20 (64.5%) of the 31 patients treated in this study. Grade ≥ 3 AEs were reported by four (12.9%) patients (one in the fed state, three in the fasted state); two of these AEs were considered treatment-related by the investigator. Three serious AEs were reported in three (9.7%) patients; these were not considered treatment-related. No patients discontinued because of treatment-related AEs, and no new safety signals were reported. Conclusion A high-fat meal did not have a clinically relevant effect on the systemic exposure of adavosertib, suggesting that adavosertib can be administered without regard to meals.

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Novel formulation of abiraterone acetate might allow significant dose reduction and eliminates substantial positive food effect

Cited by 26 publications

References 8 publications

Improved Oral Bioavailability and Variability Control in Pharmacokinetic Data – Role of Formulations

Improved Oral Bioavailability and Variability Control in Pharmacokinetic Data – Role of Formulations

A prospective phase I multicentre randomized cross-over pharmacokinetic study to determine the effect of food on abiraterone pharmacokinetics

Effect of food on the pharmacokinetics of the WEE1 inhibitor adavosertib (AZD1775) in patients with advanced solid tumors

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