Pharmacokinetics of Abiraterone Acetate Released from a Tablet Based on Lipid Matrix in Beagle Dogs

Home , Abiraterone acetate, CYP17A1 inhibitor

ORIGINAL ARTICLES

Department of Pharmaceutics1, School of Pharmacy, Qingdao University; Department of Thoracic Surgery2, Qingdao Central Hospital, Qingdao, China

Pharmacokinetics of abiraterone acetate released from a tablet based on lipid matrix in beagle dogs

H. ZHOU1, P. XU2, Y. SUN1,*

Received November 23, 2020, accepted April 17, 2021 *Corresponding author: Yong Sun, Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266071, China [email protected] Pharmazie 76: 308-312 (2021) doi: 10.1691/ph.2021.0171

Objective: To compare the pharmacokinetic behavior of abiraterone acetate after oral administration of a lipid- based formulation tablet and a reference preparation, and to study the relative bioavailability of abiraterone acetate released from the lipid matrix-based tablet. Methods: Beagle dogs received a single dose orally. The experimental dosage was 75 mg/tablet, and the reference dosage was 250 mg/tablet. Six beagle dogs in each group were investigated with the method of 3 × 3 cross-administration. Blood plasma was collected and centrifuged before administration and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 h after administration, and the plasma samples were analyzed by liquid chromatography–tandem mass spectrometry (LC–MS/MS). Results:

The half-life (T1/2) values of lipid-based formulation (LBF) abiraterone acetate tablet samples (75 mg/tablet) and reference tablets (250 mg/tablet) after oral administration were 3.42 and 4.27 h, respectively, while the area under the concentration time curve (AUC0-t) (h·ng/mL) values were 107.71 and 52.83, respectively. The F value of the relative bioavailability was 704.80%. Conclusion: The preparation method based on lipid matrix can significantly improve the bioavailability of abiraterone acetate tablets, which is a feasible method to improve the bioavailability of biopharmaceutical classification system (BCS) class IV drugs.

1. Introduction In this study, we prepared a lipid-based formulation (LBF), which Prostate cancer, with strong pathological heterogeneity and only dissolved and dispersed the insoluble drug in the lipid matrix 28% 5-year survival rate, is the second deadliest cancer in men in a molecular state, followed by the addition of an appropriate (Desborough et al. 2008). Abiraterone acetate inhibits key enzymes surfactant, dispersion of the insoluble drugs in the unano-pore size in androgen synthesis and has an inhibitory effect on androgen absorbents, and preparation of the oral solid formulation (Becker production in testes and other parts of the body. Therefore, it is et al. 2015; Shukla et al. 2011). After oral administration, LBF used in the treatment of advanced prostate cancer (Malikova et al. reduces the particle size of abiraterone as much as possible under 2017; Schweizer and Antonarakis 2012). the action of surfactants; thus, insoluble abiraterone and molecular The concept of the biopharmaceutical classification system was intestinal juice form a small particle size microemulsion that is first proposed in 1995. The drugs are classified into four cate- easily absorbed by intestinal epithelial cells, which increases the gories depending on their solubility and intestinal membrane bioavailability of oral preparations and improves their efficacy permeability. Among them, the biopharmaceutical classification (Kyatanwar et al. 2010; Pouton 2000; Taylor and Zhang 2016; system (BCS) class IV drug include drugs with low solubility and Williams et al. 2013). poor ability to cross the small-intestine epithelial cell membrane The Lipid Formula Classification System (LFCS) was proposed (Amidon et al. 1995; Schultz et al. 2020a,b), resulting in low and by Pouton. LFCS divides LBF into four main types depending on variable bioavailability. Abiraterone belongs to the BCS class IV the ratios of surfactants and co-surfactants (Pouton 2000, 2006). category (Benoist et al. 2016; Schultz et al. 2020a,b). Owing to its A self-microemulsifying drug delivery system (SMEDDS) is a low intrinsic solubility, the absolute bioavailability of abiraterone type III lipid preparation, which is composed of lipids, surfactants, has not been successfully determined due to the inability to and co-surfactants. SMEDDS can effectively solve the problem of develop an acceptable intravenous formulation. The bioavail- formulating poorly soluble drugs with low solubility in the gastro- ability of abiraterone is 5% (Thakur 2015); however, since 92% intestinal fluids. Although the potential use of SMEDDS has been of abiraterone is metabolized to inactive metabolites in vivo, the known for some time, it has only been widely developed and used actual utilization rate is only 0.4% (Schultz et al. 2020a,b). in recent years. Many BCS class IV drug developments based on The traditional method to improve the solubility of insoluble drugs SMEDDS have been successful. mainly relies on improving their dispersion in aqueous solution To compare the bioavailability between abiraterone acetate LBF through the action of surfactants, which reduces the particle size and ordinary abiraterone acetate tablets, in this study we made of the drugs (Dokania and Joshi 2015; Larsen et al. 2008; Singh et abiraterone acetate LBF as tablet formulation, established the al. 2009). However, since the insoluble drugs and water belong to determination method of abiraterone acetate in beagles’ plasma by two-phase system, it is difficult to disperse the insoluble drugs in high performance liquid chromatography–tandem mass spectrom- the aqueous phase in the form of a single molecule, which results etry (HPLC–MS/MS), analyzed the pharmacokinetic parameters in large aggregate particle sizes of the insoluble drug, thereby of abiraterone acetate LBF and reference tablets after oral admin- limiting the effectiveness of this method in improving the insoluble istration, and provided references for the solid oral preparations of drugs’ bioavailability. abiraterone acetate (Benoist et al. 2016; Kim et al. 2017; Schultz 308 Pharmazie 76 (2021) ORIGINAL ARTICLES et al. 2020a,b; Solymosi et al. 2017a; Solymosi et al. 2017b; Xiao Table 1: Interday and intraday accuracy and precision of abiraterone et al. 2012). acetate in dog plasma

Adding Interday Intraday 2. Investigations, results and discussion concentration Accuracy Precision Accuracy Precision (ng/mL) (RR, %, n = 18) (RSD, %, n = 18) (RR, %, n = 6) (RSD, %, n = 6) 2.1. Standard curve 1 4.52 4.50 3.68 12.89 The linear range was set wider and optimized through the determination of the samples’ measured concentration in the later stage. 50 6.36 9.96 5.16 1.66 Specifically, it was 0.5–1000 ng/mL in the beginning, and it was 800 2.69 6.89 8.86 2.96 adjusted to 0.5–500 ng/mL in the end. The obtained standard curve equation was Abbreviations: RR - recall rate; RSD - relative standard deviation y = 0.01284x + 6.34261e−4, r2 = 0.99535 (weight coefficient 1/x2, n = 6), (1) indicating that a fine linear range was presented within the range of 0.5–1000 μg/mL. The deviations between the measured concentration and theoretical concentration of all standard curved samples with different concentrations did not exceed 15% (the lower limit of quantitation [LLQQ] was not more than 20%).

2.2. Method specifi city Under the abovementioned chromatographic conditions, basically no endogenous characteristic peak of the blank plasma samples was observed within the range of 0–4 min. The retention time of abiraterone was 1.9 min (Fig. 1-A-II) and that of internal standard (carbamazepine) was 1.73 min (Fig. 1-B-II). Both abiraterone and carbamazepine achieved complete separation, which showed that the endogenous substances in the plasma did not interfere with the determination of abiraterone, indicating that this method had good specificity. Typical multi-response monitoring (MRM) chromatograms of determination of abiraterone and carbamazepine in dog plasma are shown in Fig. 1.

2.3. Accuracy and precision The results of interday and intraday accuracy and precision of Fig. 2: The plasma concentration–time curve of abiraterone acetate after oral admin- abiraterone in dog plasma are shown in Table 1. Accuracy (recall istration of lipid-based formulation (LBF) abiraterone acetate tablet samples rate [RR], %) was between 2.69% and 8.86%, while precision (75 mg/tablet) in dogs (n = 6). (relative standard deviation [RSD], %) was not more than 12.89%, indicating that this method could be used for the determination of abiraterone in dog plasma. oral administration of LBF abiraterone acetate tablet samples (75 mg/tablet) are shown in Fig. 2, while the data for reference tablets (250 mg/tablet) are shown in Fig. 3. The average plasma 2.4. Plasma concentration data concentration–time data after oral administration of LBF abiraterone Nos. 1–5 were samples for test, and Nos. 6–10 were reference acetate tablet samples (75 mg/tablet) and those of reference tablets tablets. The plasma concentration–time data of abiraterone after (250 mg/tablet) are shown in Fig. 4.

Fig. 1: Typical multi-response monitoring (MRM) chromatograms of abiraterone acetate and internal standard carbamazepine in dog plasma: (A) abiraterone acetate; (B) carbamazepine; (I) chromatogram of blank plasma; (II) chromatogram of blank plasma with abiraterone acetate or carbamazepine. Pharmazie 76 (2021) 309 ORIGINAL ARTICLES

Table 3: Pharmacokinetics parameters of abiraterone acetate after oral administration of reference tablets (250 mg/tablet) in dogs (n = 6)

Dog No. 7 9 10 11 12 Mean SD Cmax 63.13 19.08 11.35 39.52 17.56 30.13 21.27 (ng/mL) Tmax (h) 1 0.5 0.75 1.5 0.75 0.9 0.38 AUC(0-t) 131.26 23.36 12.71 69.94 26.9 52.83 48.98 (h·ng/mL)

T1/2 (h) 6.63 3.79 1.77 3.25 5.93 4.27 1.99

Abbreviations: AUC - area under the cure; Cmax - peak concentration; LBF - lipid-based formula-

tion; SD - standard deviation; T1/2 - half-life; Tmax - peak time

The half-life (T1/2) of the reference preparation group was 4.27±1.99 h. After oral administration, the maximum concentration (30.13±21.27 ng/mL) was reached 0.9±0.38 h after adminis-

tration. The T1/2 of the LBF abiraterone acetate tablet group was 3.42±0.62 h. After oral administration, LBF abiraterone acetate tablets showed rapid absorption and reached the maximum concentration (62.94±41.99 ng/mL) 1±0.35 h after administration.

Fig. 3: The plasma concentration–time curve of abiraterone acetate after oral administration of reference preparations (250 mg/tablet) in dogs (n = 6). 2.6. Relative bioavailability The AUCt of the LBF abiraterone acetate administration group was 107.71 h·ng/mL and the average dose was 5.69 mg/kg of dog weight, while the AUCt of the reference preparation administration group was 52.83 h·ng/mL and the average dose was 19.67 mg/kg of dog weight. The detailed pharmacokinetic parameters are shown in Tables 2 and 3, and the relative bioavailability was calculated as follows: F = AUCt · Dr / AUCr · Dt × 100% = (107.71 × 19.67) / (52.83 × 5.69) × 100% = 704.80%. The results showed that after oral administration of either homemade LBF abiraterone acetate tablets or commercially available abiraterone acetate tablets, abiraterone reached the maximum plasma concentration around 0.9–1, which then gradually decreased into the distribution and elimination phases, indicating that the carrier did not affect the metabolism of abiraterone acetate in the body. However, after oral administration of LBF abiraterone acetate tablets, the blood peak concentration

(Cmax) and the area under the drug–time curve AUC were far greater than those of the commercially available abiraterone acetate tablets, indicating that LBF abiraterone acetate tablets had good gastroin- testinal absorption and lower first-pass metabolism. The difference between LBF abiraterone acetate tablets and reference tablets is mainly reflected in the process of drug dispersion Fig. 4: Comparison of average plasma concentration–time curve between lipid-based formulation (LBF) abiraterone acetate tablets and reference tablets and absorption. However, as human body is a complex organism, (n = 6). the differences in absorption would also affect the corresponding distribution, metabolism, and excretion, thus showing different 2.5. Pharmacokinetic parameters analysis pharmacokinetics (Alskär et al. 2018; Feeney et al. 2016; Both the LBF abiraterone acetate group and the reference prepara- Kyatanwar et al. 2010). tion group showed abnormal data in one of the dogs, which led to high standard deviations. After discarding the abnormal data, the 2.7. Conclusion pharmacokinetics parameters of abiraterone after oral administra- We established a sensitive, accurate, stable, and universal LC-MS/ tion of LBF abiraterone acetate tablets (75 mg/tablet) are shown MS method for the determination of abiraterone in beagle dog in Table 2, while those for reference tablets (250 mg/tablet) are plasma so that abiraterone and other components in beagle dog shown in Table 3. plasma can be well separated and high recovery rate is achieved. Table 2: Pharmacokinetics parameters of abiraterone acetate after The RSD (%) was small, and its detection limit was 0.1 ng/mL. oral administration of LBF abiraterone acetate tablets (75 mg/tablet) This method is considered feasible and the detection results are in dogs (n = 6) reliable. After oral administration of LBF abiraterone acetate

tablets in beagle dogs, the blood concentration Cmax and the area Dog No. 1 2 3 4 5 Mean SD under the drug–time curve AUC were much greater than those of Cmax 47.69 18.99 54.92 60.72 132.37 62.94 41.99 the commercially available abiraterone acetate tablets (trade name: (ng/mL) ZYTIGA). LBF abiraterone acetate tablets had 7.04 times higher bioavailability than the reference tablets. Tmax (h) 0.5 1 1.5 1 1 1 0.35 AUC(0-t) 46.72 38.36 87.44 90.26 275.78 107.71 96.81 (h·ng/mL) 3. Experimental 3.1. Experimental materials T1/2 (h) 2.96 3.58 3.17 4.44 2.96 3.42 0.62 Test sample included LBF of abiraterone acetate tablet, self-made, 75 mg in specifi- Abbreviations: AUC - area under the cure; Cmax - peak concentration; LBF - lipid-based formula- cation. Namely, the optimized liquid SMEDDS loaded with abiraterone acetate was tion; SD - standard deviation; T1/2 - half-life; Tmax - peak time composed of medium-chain triglycerides, castor oil polyoxyethylene ether 40, and 310 Pharmazie 76 (2021) ORIGINAL ARTICLES isopropanol. S-SMEDDS was prepared by spray drying with mesoporous silica as 3.3.4. Administration route and dosage the carrier. LBF abiraterone acetate tablets were prepared by granulation and direct Oral administration was adopted in the same manner of clinical administration with compression method. Reference tablet was abiraterone acetate tablet, Zytiga, 250 mg/ a single dose. After 12 hours of fasting, the drugs were placed in the beagle dogs’ tablet, batch no. ZTZP. Methanol, acetonitrile, and formic acid were all chromato- throats and were washed down with 10 mL purified water. Normal diet and drinking graphically pure; the blank plasma of dogs was produced by Shandong New Times were resumed after blood collection, 2 h after the administration. The dosage of refer- Pharmaceutical Co., LTD. ence preparation was one tablet with the specification of 250 mg/tablet, and the total dosage per animal was 250 mg/tablet. The dosage of LBF abiraterone acetate tablet 3.2. Experimental animals was one tablet with the specification of 75 mg/tablet, and the total dosage was 75 mg/ tablet. The method of 3 × 3 cross-administration was adopted, and the washout period We included six 12-month-old beagle dogs, ordinary grade, with a body weight lasted one week. between 9 and 18 kg. The animals were obtained from Qingdao Bolong Experimental Animals Co., LTD. (experimental animal production license no. SCXK 20170006). The animal experiments complied with the Animal Research: Reporting of In Vivo 3.3.5. Sample collection Experiments (ARRIVE) guidelines. Blood samples (0.6 mL) were collected from the forelimb or hindlimb vein before administration and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 h after administration 3.2.1. Animal quarantine and identifi cation of the drug. Blood collection points were rotated among the venous blood collection locations of the extremities without repeating any location. The plasma was collected After receiving the animals, each animal’s number was determined according to by centrifugation with heparin sodium as anticoagulant, and it was stored at -20 °C the earmark of each animal, and the cage card indicated the subject number, animal for further testing. number, sex, date of receiving the animal, and the person in charge of the project. After arrival of all of the animals, the adaptation period was at least one week, and quarantine observation was conducted to observe the animals’ activities, diet, and 3.3.6. Biological sample treatment and analysis other performance. The animals were checked and qualified before the test, and only qualified animals were used for the test. Before the formal experimental administra- Internal standard solution (500 μL) was added to 50 L medicated plasma; the mixture tion, the animals were often trained to complete the simulated administration and was agitated for 1 min with TARGIN VX-II multifunctional vortex agitator (Beijing blood collection, so that they could fully adapt to and cooperate with the experimental Tajin Technology Co., LTD.) and centrifuged for 5 min (12000 rpm) with TGL-20M operation. table-top & high-speed refrigerated centrifuge (Changsha Xiangyi Centrifuge Instru- ment Co., LTD.), and 2 mL of supernatant was taken for LC-MS/MS analysis.

3.2.2. Experimental site Conventional animal room of Shandong New Times Pharmaceutical Co., LTD. 3.3.7. Standard curves and quality control samples The selected internal standard was carbamazepine (Bhatnagar et al. 2018). By adjusting the diluent (from 80:20 of methanol and water to pure methanol) and 3.2.3. Environmental conditions for feeding and management of experi- probe wash solution (from 50:50 of methanol and water to 80:20 of methanol and water in order to dissolve the residual) in an earlier stage, while optimizing liquid mental animals phase method (such as gradient elution conditions and injection volume) and sample Room temperature was kept between 16°C and 22°C, with daily temperature differ- pretreatment method (adjusting protein precipitant volume), the final method was ences ≤ 4°C, relative humidity 40–70%, and 12 h light/12 h night. The animals were determined as shown in 2.3.1. Blank plasma of dogs was used to dilute the plasma fed separately in 90 cm × 80 cm × 85 cm stainless steel cages, one animal per cage. samples to 10, 20, 50, 100, 500, and 1000 ng/mL stock solution. The samples of abiraterone were prepared in high, medium, and low concentrations (800, 50, and 1.0 ng/mL, respectively; n = 6), and a linear regression was conducted with the peak 3.2.4. Animal feed and drinking water area ratio y between abiraterone and internal standard as ordinate against plasma The experimental dogs’ feed of 400 g per day was provided by Jiangsu Synergic Phar- concentration C as abscissa. maceutical Biological Engineering Co., LTD. Drinking water that had been previously boiled and cooled was provided. 3.3.8. Accuracy and precision Accuracy and precision were assessed both interday and intraday. Blank plasma 3.3. Instruments and analytical conditions samples (50 μL) were taken from beagle dogs and placed in Eppendorf tubes. Next, 50 μL of each of the three concentrations (low, medium, and high) of abiraterone solution 3.3.1. Chromatographic conditions was added to prepare the corresponding plasma concentrations of 1, 50, and 800 ng/ The liquid chromatograph (LC) system used was the Thermo Dionex Ultimate 3000 mL, respectively. Each concentration was prepared in three samples in parallel in UHPLC system (Thermo Fisher Scientific Inc., USA), equipped with a solvent three successive days. Liquid phase was measured and plugged in following standard degasser, a quaternary pump, an automatic sampler, and a column temperature curve to calculate the measured concentration of the samples. Accuracy and precision compartment. Chromatographic separation was performed on YMC Trait C18 (50 × were expressed as relative error (RE) and RSD. RE was within 15%, while RSD did 20 mm, 5 μm); the mobile phase was 1 mM aqueous solution containing 0.1% formic not exceed 15%. acid (a) and acetonitrile (B); the flow rate was 0.4 mL/min; 80% B-phase isocratic elution was adopted with the flow rate of 0.4 mL/min, injection volume of 2 μL, and column temperature of 40 °C. 3.3.9. Data processing The main pharmacokinetic parameters of the tested animals were obtained from the plasma concentration–time data in the test, including C , peak time (T ), AUC(0-t), 3.3.2. Verifi cation of abiraterone’s LC-MS/MS determination method max max and elimination T1/2. The relative bioavailability obtained after oral administration was The methodological verification of the abiraterone quantitative analysis method in calculated from the AUC(0-t) of LBF abiraterone acetate tablet and reference tablet. this study was carried out with reference to the guidelines formulated by the U.S. Food and Drug Administration (FDA) (Holt and Ju 2006) and the Chinese Pharmaco- Acknowledgements: We thank LetPub (www.letpub.com) for its linguistic assistance poeia Commission (Xu et al. 2012). during the preparation of this manuscript.

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