Pharmaceutical composition

Abstract

The present disclosure relates to a pharmaceutical composition. Specifically, a pharmaceutical composition of abiraterone acetate is provided, wherein a 300 mg dose of abiraterone acetate is bioequivalent to a 1000 mg dose of Zytiga® in healthy male subjects in a fasting state.

Claims

1. A pharmaceutical composition, comprising abiraterone acetate and an absorption enhancer, wherein the absorption enhancer is at least one selected from the group consisting of capric acid, sodium caprate, potassium caprate, N-(10-[2-hydroxybenzoyl]amino)capric acid, caprylic acid, sodium caprylate, potassium caprylate, N-(5-chlorosalicyloyl)-8-aminocaprylic acid, 8-(salicylamido)caprylic acid and sodium 8-(salicylamido)caprylate, wherein: a) the D90 value of abiraterone acetate is 400 to 600 nm, or b) the D50 value of abiraterone acetate is 150 to 300 nm.

2. The pharmaceutical composition according to claim 1, wherein a mean blood plasma C.sub.max of 209±142 ng/ml is provided upon orally administering 300 mg dose of abiraterone acetate to a group of healthy male subjects in a fasting state.

3. The pharmaceutical composition according to claim 1, wherein a median T.sub.max of 1 hour is provided upon orally administering 300 mg dose of abiraterone acetate to a group of healthy male subjects in a fasting state.

4. The pharmaceutical composition according to claim 1, wherein a mean blood plasma AUC.sub.0-t of 620.08±370.19 n.Math.gh/ml is provided upon orally administering 300 mg dose of abiraterone acetate to a group of healthy male subjects in a fasting state.

5. The pharmaceutical composition according to claim 1, wherein a mean blood plasma AUC.sub.0-∞ of 627.60±370.44 n.Math.gh/ml is provided upon orally administering 300 mg dose of abiraterone acetate to a group of healthy male subjects in a fasting state.

6. The pharmaceutical composition according to claim 1, further comprising lactose.

7. The pharmaceutical composition according to claim 6, wherein the lactose is present in an amount of 15 to 80%, relative to the total weight of the pharmaceutical composition.

8. The pharmaceutical composition according to claim 1, wherein the absorption enhancer is at least one of 8-(salicylamido)caprylic acid and sodium 8-(salicylamido)caprylate.

9. The pharmaceutical composition according to claim 1, wherein the weight ratio of the absorption enhancer to abiraterone acetate is 1:10 to 20:1.

10. The pharmaceutical composition according to claim 1, further comprising a disintegrant, wherein the disintegrant is at least one selected from the group consisting of croscarmellose sodium, crospovidone, sodium carboxymethyl starch, calcium carboxymethylcellulose, low-substituted hydroxypropyl cellulose, starch, pregelatinized starch and alginic acid.

11. The pharmaceutical composition according to claim 1, further comprising at least one stabilizer selected from the group consisting of cellulose derivatives and surfactants.

12. The pharmaceutical composition according to claim 1, wherein 80 to 125% of the mean blood plasma AUC.sub.0-∞ of 627.60 n.Math.gh/mL is provided upon orally administering 300 mg dose of the abiraterone acetate pharmaceutical composition to a group of healthy male subjects in a fasting state.

13. The pharmaceutical composition according to claim 1, wherein 80 to 125% of the mean blood plasma C.sub.max of 209 ng/ml is provided upon orally administering 300 mg dose of the abiraterone acetate pharmaceutical composition to a group of healthy male subjects in a fasting state.

14. The pharmaceutical composition according to claim 1, wherein the mean blood plasma C.sub.max is up to 3 times that of the fasting state upon orally administering 300 mg dose of the abiraterone acetate pharmaceutical composition to a group of healthy male subjects in a high-fat statetimes.

15. The pharmaceutical composition according to claim 1, wherein the mean blood plasma AUC.sub.0-t is up to 3 times that of the fasting state upon orally administering 300 mg dose of the abiraterone acetate pharmaceutical composition to a group of healthy male subjects in a high-fat statetimes.

16. The pharmaceutical composition according to claim 1, comprising: a) 150 mg of abiraterone acetate, b) 10 to 40% by weight of an absorption enhancer, c) 0.5 to 20% by weight of a stabilizer, d) 25 to 75% by weight of lactose, and e) 0.5 to 20% by weight of a disintegrant, the pharmaceutical composition further comprises 0.1 to 2.0% by weight of a lubricant.

17. A method for preparing the pharmaceutical composition according to claim 1, comprising the steps of mixing abiraterone acetate with an absorption enhancer and optionally at least one excipient, and granulating through a fluidized bed, wherein the excipient is at least one selected from the group consisting of lactose and disintegrants.

18. A method for treating prostate cancer, comprising administering the pharmaceutical composition according to claim 1 at a daily dose of 300 mg.

19. The pharmaceutical composition according to claim 11, wherein the cellulose derivative is hydroxypropyl methyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose or sodium carboxymethyl cellulose; the surfactant is polyoxyethylene ether, poloxamer, polyethylene glycol glyceride, polyoxyethylenated castor oil or polyethoxylated hydrogenated castor oil, sodium lauryl sulfate or sodium cholate.

20. The pharmaceutical composition according to claim 16, wherein the absorption enhancer is at least one of 8-(salicylamido)caprylic acid and sodium 8-(salicylamido)caprylate, and the stabilizer is at least one of hydroxypropyl methyl cellulose and sodium lauryl sulfate.

21. A pharmaceutical composition comprising a 300 mg dose of abiraterone acetate, an absorption enhancer and optionally at least one excipient, wherein the excipient is at least one selected from the group consisting of lactose and disintegrants.

Description

DETAIL DESCRIPTION OF THE INVENTION

(1) The present disclosure will be further described in detail with reference to the following examples. These examples are only for the purpose of illustration and should not be considered as limiting the scope of the present disclosure.

Example 1

(2) TABLE-US-00002 Contents Formulation 1 (mg) Nanosuspension Abiraterone acetate 150 Hydroxypropyl methylcellulose E5 LV 38.6 Sodium dodecyl sulfate 3.85 water 1479.3 Preparation Lactose 240.00 Crosslinked povidone XL 48.00 Sodium 8-(salicylamido)caprylate 150.00 Magnesium stearate 12.736

(3) 1) Preparation of Nanosuspension

(4) 19.2 g of HPMC E5 LV was dispersed and dissolved in 739.6 g of water, and then 1.92 g of SDS was dissolved in it. 75 g of abiraterone acetate was then added to the above solution followed by stirring and dispersion.

(5) The sand mill (the volume of grinding chamber is 160 ml and filled with 112 ml of 0.3 mm grinding beads, the feeding speed is 160 rpm, and the grinding speed is 3000 rpm) was equipped. The dispersed suspension was added into the formulation tank of the sand mill, and grinded under stirring to obtain the nanosuspension of abiraterone acetate with D90 about 500 nm.

(6) 2) Fluid-Bed Granulation

(7) 105 g of absorption enhancer SNAC was added into 1170.2 g of the nanosuspension above, and then stirred for dispersion. 168 g of lactose and 33.6 g of cross-linked povidone XL were added into the fluidized bed for fluidized bed top spray granulation. After granulation, the granules were dried untile the moisture content of the particles was less than 2%.

(8) 3) Tabletting

(9) The granules prepared by fluid-bed were mixed with magnesium stearate and then tableted to obtain 150 mg of big tablet.

(10) In Vitro Dissolution Test

(11) The dissolution test was carried out with the reference preparation (250 mg) and ½ tablet of the reference preparation (containing 125 mg of abiraterone acetate) according to the second method of dissolution determination (paddle method) in Chinese Pharmacopoeia (2015 Edition). 900 ml of phosphate buffer solution with pH6.8 containing 0.25% SDS was used as the dissolution medium. The specific dissolution rate data are shown in table 1 below.

(12) TABLE-US-00003 TABLE 1 Complete tablet of 1/2 tablet of Time reference preparation reference preparation Formulation 1 (min) (%) (%) (%) 5  4.6 7 11 10 10.1 17 24 15 17.7 30 37 20 24.3 41 48 25 30.1 50 58 30 / 56 68 45 44.8 68 90 60 51.1 74 98 Note: Reference preparation R (commercial name Zytiga ®) 250 mg tablet.

Example 2

(13) The formulations of table 2 were prepared according to the method described in Example 1.

(14) TABLE-US-00004 TABLE 2 Formulation 2 Formulation 3 Formulation 4 mg/ Ratio mg/ ratio mg/ ratio tablet (%) tablet (%) tablet (%) Abiraterone 150.000 23.56 150.000 23.56 150.000 19.79 Acetate Hydroxypropyl 38.462 6.04 38.462 6.04 38.462 5.07 methylcellulose E5 LV Sodium 3.846 0.60 3.846 0.60 3.846 0.51 dodecyl sulfate sodium 8- 150.000 23.56 150.000 23.56 150.000 19.79 (salicylamido) caprylate lactose 240.000 37.69 160.000 25.13 240.000 31.66 Microcrystal- N/A N/A 80.000 12.56 120.000 15.83 line cellulose 102 Crosslinked 48.000 7.54 48.000 7.54 48.000 6.33 povidone XL Magnesium 6.495 1.02 6.495 1.02 7.732 1.02 stearate Total weight 636.803 100.01 636.803 100.01 758.040 100.00

(15) In Vitro Dissolution Test

(16) The dissolution test was carried out with Formulation 2, 3 and 4 according to the second method of dissolution determination (paddle method) in Chinese Pharmacopoeia (2015 Edition). 900 ml of phosphate buffer solution with pH6.8 containing 0.25% SDS was used as the dissolution medium. The specific dissolution rate data are shown in table below.

(17) TABLE-US-00005 TABLE 3 Dissolution (%) Formulation 2 Formulation 3 Formulation 4 Time (min) API SNAC API SNAC API SNAC  5 min 10 11 7 8 11 12 10 min 22 23 14 16 22 24 15 min 34 35 23 25 34 36 20 min 46 46 32 33 45 47 25 min 56 56 39 41 55 57 30 min 65 65 46 48 64 66 45 min 84 85 62 64 83 85 60 min 95 95 74 76 92 94 Note: API is the active ingredient abiraterone acetate, and the SNAC is sodium 8 - (salicylamido).

(18) Results: the dissolution of the composition comprising lactose is better when comparing formulation 2 with formulation 3, and the dissolution of the composition comprising microcrystalline cellulose is slower. Moreover, compared with formulation 2, the amount of lactose for formulation 4 is unchanged, but the amount of microcrystalline cellulose is increased and the tablet weight is also increased. However, the dissolution of the two has no significant difference. The above results show that the addition of microcrystalline cellulose has no effect on dissolution, but the addition of microcrystalline cellulose leads to the increase of tablet weight and tablet size, which affects the swallowing of patients.

Test Example 1

Pharmacokinetics Study of Formulation 2

(19) Eight male cynomolgus monkeys were administered by single oral gavage, including 4 cycles, 5 days per cycle, 20 days in total (see Table 4 for the protocol).

(20) TABLE-US-00006 TABLE 4 Pharmacokinetic protocol Administration Number of Dose Number animals Test (mg/ of Administration Group Male samples* animal) tablets route Cycle I (Fasting before administration) 1 8 T  300 2 PO Cycle II (Fasting before administration) 1 8 R 1000 4 PO Cycle III (High fat diet before administration, HFD) 1 8 T  300 2 PO Cycle IV (High fat diet before administration, HFD) 1 8 R 1000 4 PO *T refers to the Formulation 2, R referes to the reference preparation R(commercially available, trade name Zytiga ®), t = 24 h.

(21) The animals in cycle I and II were fasted before administration, while the animals in cycle III and IV were given high-fat food before administration. Animals in cycle I and III were given 300 mg of Formulation 2 (2 tablets of abiraterone acetate, T, comprising 300 mg of abiraterone), while animals in cycle II and IV were given 1000 mg of reference preparation (4 tablets of abiraterone acetate Zytiga®, R). Blood samples were collected before administration or at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 8, 12 and 24 hours after administration. The validated LC-MS/MS method was used to determine the concentrations of abiraterone and SNAC in plasma samples. Only abiraterone was detected for those given reference preparation, while abiraterone and SNAC were both detected for those given test formulations. The main pharmacokinetic parameters were calculated according to the concentrations of abiraterone and SNAC in plasma using Phoenix WinNonlin® 7.0 software. The main pharmacokinetic data of abiraterone in plasma in cycles I-IV are shown in Table 5, and the main pharmacokinetic data of SNAC in plasma in cycles I and III are shown in Table 6.

(22) TABLE-US-00007 TABLE 5 Main pharmacokinetic parameters of abiraterone in plasma after administration for cycles I-IV (Mean ± SD, n = 8) Cycle I Cycle II Cycle III Cycle IV T.sub.1/2 (h) 5.16 ± 1.43 6.98 ± 2.55 2.73 ± 0.45 4.18 ± 1.85 T.sub.max (h) 2.63 ± 1.09 5.31 ± 2.28 3.88 ± 0.35 4.38 ± 1.51 C.sub.max (ng/ml) 638.72 ± 446.43 279.24 ± 278.84 1318.03 ± 1222.55 2194.92 ± 1834.66 C.sub.max/Dose 2.13 ± 1.49 0.28 ± 0.28 4.39 ± 4.08 2.19 ± 1.83 (ng/ml/mg) AUC.sub.(0-t) 2878.79 ± 1887.91 2237.37 ± 2149.95 6693.37 ± 4588.85 17896.14 ± 17519.8  (h*ng/ml) AUC.sub.(0-∞) 2936.88 ± 1891.39 2061.49 ± 1272.36  6713.8 ± 4589.14  19638.3 ± 18392.73 (h*ng/ml) AUC.sub.(0-t)/Dose  9.6 ± 6.29 2.24 ± 2.15 22.31 ± 15.3   17.9 ± 17.52 (h*ng/ml/mg)

(23) By fasting administration (cycles I and II), the pharmacokinetic parameters of 300 mg of Formulation 2 are 638.72±446.43 ng/ml for C.sub.max, 2878.79±1887.91 h*ng/ml for AUC.sub.(0-t), 2.63 h for T.sub.max and 5.16 h for T.sub.1/2, which are 1.29 times, 2.29 times, 0.50 times and 0.74 times of those of 1000 mg reference preparation, respectively. By high fat diet before administration (cycles III and IV), the pharmacokinetic parameters of 300 mg of Formulation 2 are 1318.03±1222.55 ng/ml for C.sub.max and 6693.37±4588.85 h*ng/ml for AUC.sub.(0-t), which are 0.60 times and 0.37 times of those of 1000 mg of reference preparation, respectively. Comparing the reference preparations under fasting and high fat diet before administration (cycles II and IV), the C.sub.max and AUC.sub.(0-t) of the abiraterone in the plasma of the male cynomolgus monkeys under high-fat diet are 7.86 and 8.00 times respectively of those under fasting state, showing significant food effect. Comparing the Formulation 2 under fasting and high fat diet before administration (cycles I and III), the C.sub.max and AUC.sub.(0-t) of the abiraterone in the plasma of the male cynomolgus monkeys under high-fat diet were 2.07 and 2.33 times respectively of those under fasting state, showing a certain food effect which is lower than that of the reference preparation.

(24) TABLE-US-00008 TABLE 6 Main pharmacokinetic parameters of SNAC in plasma after administration for Cycles I and III (mean ± SD, n = 8) T.sub.1/2 T.sub.max C.sub.max AUC.sub.(0-t) AUC.sub.(0-∞) Cycles h h ng/ml h*ng/ml h*ng/ml Cycle 1 (Fasting) 3.16 ± 0.93 0.72 ± 0.49 34165.76 ± 18040.59 40349.03 ± 10430.88 40945.21 ± 10605.42 Cycle 3 (High Fat Diet) 2.71 ± 0.74 2.88 ± 0.74 4656.97 ± 2395.17 18374.08 ± 5740.25  18727.86 ± 5619.06 

(25) The peak time of SNAC in the plasma of cynomolgus monkeys under fasting state is faster, and T.sub.max is 0.72±0.49 h, C.sub.max is 34165.76±18040.59 ng/ml, AUC.sub.(0-24 h) is 40349.03±10430.88 h*ng/ml, while T.sub.max is 2.88±0.74 h, C.sub.max is 4656.97±2395.17 ng/ml and AUC.sub.(0-24 h) is 18374.08±5740.25 h*ng/ml under high-fat state. T.sub.max of SNAC in cynomolgus monkeys after high-fat diet is prolonged, and C.sub.max and AUC.sub.(0-24 h) are decreased. Considering SNAC as an acidic drug (PKA 5.0), it may be related to the increased PH value in gastrointestinal tract under high-fat state.

(26) Conclusion: in male cynomolgus monkeys under fasting state in Cycles I and II, the unit dose exposure (AUC (0-t)/dose) of abiraterone in the plasma of Formulation 2 is 4.29 times that of reference preparation, which improves the bioavailability of abiraterone significantly. The effect of high-fat diet on the exposure (AUC (0-t)) and C.sub.max of 300 mg of test formulations is less than that of 1000 mg reference preparation.

Example 2

(27) TABLE-US-00009 Formulation 5 mg/tablet ratio (%) Abiraterone Acetate 150.000 23.56 Hydroxy propyl 38.462 6.04 methylcellulose E5 LV Sodium dodecyl sulfate 3.846 0.60 sodium 8 - (salicylamido) 150.000 23.56 caprylate lactose 240.000 37.69 Crosslinked povidone XL 48.000 7.54 Magnesium stearate 6.495 1.02 Total weight 636.803 100.01

(28) 1) Preparation of Nanosuspension

(29) Hydroxypropyl methylcellulose LV (0.212 kg) and sodium dodecyl sulfate (0.021 kg) were added into purified water (8.1 kg) and dissolved in it. Abiterone acetate (0.825 kg) was then added and stirred to dispersion. Two batches of above suspension were prepared for use.

(30) The above three batches of dispersed suspension were added into the formulation tank of MULTI LAB grinding machine (0.3 mm zirconia grinding beads) and grinded under stirring to obtain the nano suspension of abiraterone acetate which has D90 of 455 nm, D50 of 227 nm, D10 of 99.3 nm, average particle size of 211.3 nm, and particle size distribution index PDI of 0.169.

(31) 2) Granulation

(32) 2.250 kg of sodium 8-(salicylamido) caprylate was added into the above nanosuspention and stirred, which was then added into the prescription amount of lactose and crosslinked povidone XL for MP3 Advanced fluidized bed granulation. After granulation, the granules are dried and pelleted.

(33) 3) Tabletting

(34) The granules obtained above were mixed with magnesium stearate, and then pressed according to the theoretical tablet weight of 636.803 mg in the range of 95.0%-105.0%.

(35) In Vitro Dissolution Test

(36) According to the second method (paddle method) for dissolution determination in Chinese Pharmacopoeia (2015 Edition), 900 ml phosphate solution containing 0.25% SDS at pH 6.8 was used as dissolution medium for dissolution test. The specific dissolution rate data were shown in table 7 below. The dissolution test was carried out according to the second method of dissolution determination (paddle method) in Chinese Pharmacopoeia (2015 Edition) with 900 ml of phosphate buffer solution with pH 6.8 containing 0.25% SDS as the dissolution medium. The specific dissolution rate are shown in table 7 below.

(37) TABLE-US-00010 TABLE 7 Dissolution rate Formulation 5 Time (min) API RSD SNAC RSD  5 min 9 8.1 10 5.9 10 min 20 6.6 22 5.5 15 min 32 5.7 33 5.1 20 min 43 5.5 44 5.2 25 min 52 4.9 53 4.8 30 min 61 4.5 62 4.3 45 min 81 3.6 81 3.4 60 min 93 2.5 94 2.4

Test Example 2

In Vivo Pharmacokinetics Study in Healthy Subjects

(38) 2.1 Study Objectives

(39) To study the pharmacokinetic characteristics of 75 mg, 150 mg, 300 mg and 450 mg doses of abiraterone acetate tablets in healthy subjects after a single oral administration under fasting state.

(40) 2.2 Study Plan

(41) A single-center, open-label, sequential trial design was applied. A total of 16 healthy male subjects were planned to be enrolled in the study, who entered the four dose groups sequentially and the washout period of each dose group was seven days. Blood samples were collected at a series of time points, and safety test was performed. The blood concentration of abiraterone at different time points after dosing was determined by HPLC-MS/MS. Pharmacokinetic parameters were calculated using non-compartmental model and statistically analyzed.

(42) 2.3 Dosing Regimen

(43) The subjects were admitted to the ward before dinner on the day before the administration of each studied dose. They had a standardized light diet in the evening, and then were fasting for solids and liquids overnight. They were fasting for at least 10 hours before dosing. According to the trial protocol, subjects were given a single oral administration of the investigational drug, abiraterone acetate tablets, 75 mg (split 150 mg tablet along the score line into half a tablet), 150 mg (150 mg×1 tablet), 300 mg (150 mg×2 tablets) and 450 mg (150 mg×3 tablets) with 240 mL water under fasting state in the morning on the day of trial of each dose group. Liquid was prohibited before administration and within 1 h after administration, and standard lunch and dinner (a standardized light diet) were taken about 4 and 10 h after administration.

(44) 2.4 Investigational Drug

(45) Test Formulation (T): Abiraterone acetate tablets (Formulation 5), specification: 150 mg.

(46) 2.5 Pharmacokinetic Results

(47) PKPS (PKPS, all enrolled in the group and receiving the study drug, at least one subject with analyzable PK parameters during the trial) was used for the statistical analysis of pharmacokinetic parameters.

(48) In this study, 16 healthy subjects were enrolled, and a total of 16 subjects were included in the PKPS. One subject was withdrawn from this trial before dosing in group B due to increased uric acid.

(49) The main pharmacokinetic parameters of abiraterone and SNAC of four dose groups A/B/C/D after single oral administration of abiraterone acetate tablet are shown in Tables 8 and 9 below.

(50) TABLE-US-00011 TABLE 8 Main Pharmacokinetic Parameters of Abiraterone of Different Dose Groups after A Single Oral administration Mean ± SD (% CV) PK Dose group A Dose group B Dose group C Dose group D Parameters 75 mg 150 mg 300 mg 450 mg (Unit) (N = 16) (N = 15) (N = 15) (N = 15) C.sub.max 33.9 ± 12.9 (38.1) 81.4 ± 45.0 (55.3) 209 ± 142 (67.8) 405 ± 428 (106) (ng/mL) AUC.sub.0-t 98.96 ± 46.29 (46.77) 246.11 ± 97.19 (39.49) 620.08 ± 370.19 (59.70) 1041.37 ± 903.24 (86.74) (ng .Math. h/mL) AUC.sub.0-∞ 101.27 ± 46.61 (46.02) 250.27 ± 97.95 (39.14) 627.60 ± 370.44 (59.02) 1054.58 ± 904.86 (85.80) (ng .Math. h/mL) T.sub.max * (h) 1.13 (0.5-2.5) 1.0 (0.5-1.25) 1.0 (0.5-2.00) 1.0 (0.75-3.00) t.sub.1/2z (h) 10.15 ± 3.1 (30.52) 10.71 ± 2.03 (18.96) 10.62 ± 1.80 (16.94) 10.85 ± 1.51 (13.95) λ.sub.z (h.sup.−1) 0.08 ± 0.04 (45.65) 0.07 ± 0.02 (24.09) 0.07 ± 0.01 (17.06) 0.07 ± 0.01 (14.69) AUC.sub.—% Extrap 2.74 ± 1.52 (55.45) 1.77 ± 0.85 (48.03) 1.39 ± 0.72 (51.56) 1.60 ± 0.76 (47.31) (%) V.sub.z/F 12.31 ± 5.1 (41.23) 10.7 ± 4.7 (43.86) 9.1 ± 4.1 (45.59) 9.2 ± 3.95 (43.17) (×10.sup.3 L) CL.sub.z/F 9.26 ± 4.67 (50.44) 6.82 ± 2.41 (35.52) 5.79 ± 2.2 (38.69) 5.79 ± 2.43 (42.04) (×10.sup.2 L .Math. h.sup.−1) MRT.sub.0-t(h) 5.36 ± 1.64 (30.49) 5.79 ± 1.06 (18.26) 5.7 ± 0.96 (16.83) 5.68 ± 1.34 (23.58) MRT.sub.0-∞(h) 6.56 ± 1.88 (28.73) 6.82 ± 1.47 (21.49) 6.51 ± 1.34 (20.6) 6.6 ± 1.72 (26.01) * T.sub.max is expressed using median (minimum-maximum).

(51) TABLE-US-00012 TABLE 9 Main Pharmacokinetic Parameters of SNAC of Different Dose Groups after A Single Oral administration Mean ± SD (% CV) PK Dose group A Dose group B Dose group C Dose group D Parameters 75 mg 150 mg 300 mg 450 mg (Unit) (N = 16) (N = 15) (N = 15) (N = 15) C.sub.max 407 ± 140 (34.4) 977 ± 385 (39.4) 1870 ± 484 (25.9) 2460 ± 963 (39.2) (ng/mL) AUC.sub.0-t 291.34 ± 61.44 (21.09) 668.36 ± 153.26 (22.93) 1396.58 ± 284.15 (20.35) 2121.8 ± 491.85 (23.18) (ng .Math. h/mL) AUC.sub.0-∞ 294.82 ± 61.4 (20.83) 672.15 ± 152.2 (22.64) 1409.79 ± 285.05 (20.22) 2131.49 ± 490.78 (23.03) (ng .Math. h/mL) T.sub.max * (h) 0.38 (0.25-1.25) 0.5 (0.25-0.75) 0.5 (0.25-1.75) 0.5 (0.25-0.75) t.sub.1/2z (h) 3.53 ± 2.54 (71.79) 2.94 ± 1.39 (47.26) 5.35 ± 3.92 (73.26) 4.88 ± 2.37 (48.47) λ.sub.z (h.sup.−1) 0.28 ± 0.14 (49.45) 0.29 ± 0.14 (46.65) 0.19 ± 0.11 (58.63) 0.18 ± 0.09 (48.95) AUC.sub.—% Extrap 1.23 ± 1.12 (91.06) 0.63 ± 0.62 (97.47) 0.95 ± 0.91 (95.91) 0.50 ± 0.44 (87.05) (%) V.sub.z/F 1.28 ± 0.88 (68.58) 1.01 ± t0.63 (62.71) 1.74 ± 1.28 (73.48) 1.52 ± 0.66 (43.62) (×10.sup.3 L) CL.sub.z/F 2.66 ± 0.64 (23.96) 2.36 ± 0.62 (26.11) 2.22 ± 0.51 (23.04) 2.22 ± 0.51 (23.3) (×10.sup.2 L .Math. h.sup.−1) MRT.sub.0-t(h) 1.32 ± 0.52 (39.31) 1.21 ± 0.48 (39.74) 1.28 ± 0.36 (28.37) 1.40 ± 0.53 (37.74) MRT.sub.0-∞(h) 1.58 ± 0.76 (48.31) 1.32 ± 0.5 (38.27) 1.55 ± 0.54 (35.01) 1.53 ± 0.51 (33.51) * T.sub.max is expressed using median (minimum-maximum)

(52) 2.6 Analysis of Statistical Results

(53) 1) Dose Linearity Analysis

(54) The linearity between AUC and C.sub.max and the administration dose was analyzed by confidence interval method, and linear regression analysis was performed on the AUC and C.sub.max after natural logarithmic transformation respectively and the administration dose, to observe the slope of the linear regression equation and 90% confidence interval. The analysis results are shown in Table 10 below.

(55) The results show that: within the dose range of 75-450 mg of test Formulation(T), the β values of C.sub.max, AUC.sub.0-t and AUC.sub.0-∞ of abiraterone are 1.27, 1.29, and 1.29, respectively, which are all within the range of 0.5-2.0, indicating that test Formulation(T) has the tendency of linear dynamic characteristics within the dose range of 75-450 mg. Moreover, the 90% confidence intervals of the β values of C.sub.max, AUC.sub.0-t and AUC.sub.0-∞ of abiraterone are 1.15-1.38, 1.22-1.37, and 1.21-1.36, respectively, which basically fall within the judgment range of 0.61-1.39, indicating that test Formulation(T) has linear dynamic characteristics.

(56) Within the dose range of 75-450 mg of test Formulation(T) (the content of SNAC was equivalent to that of the main active pharmaceutical ingredient), the β values of C.sub.max, AUC.sub.0-t and AUC.sub.0-∞ of SNAC are 1.00, 1.10, and 1.10, respectively, which are all within the range of 0.8-1.25, indicating that SNAC has the tendency of linear dynamic characteristics within the dose range of 75-450 mg. Moreover, the 90% confidence intervals of the β values of C.sub.max, AUC.sub.0-t and AUC.sub.0-∞ of SNAC are 0.90-1.10, 1.07-1.14, and 1.06-1.14, respectively, which basically fall within the judgment range of 0.88-1.12, indicating that the SNAC has linear dynamic characteristics.

(57) TABLE-US-00013 TABLE 10 Results of Linear Pharmacokinetic Characteristics of Pharmacokinetic Parameters by the Confidence Interval Method (N = 16) Slope of the linear 90% confidence Analyte PK parameter regression equation (β) interval of β Judgment range Abiraterone LnC.sub.max 1.27 1.15-1.38 0.61-1.39 LnAUC.sub.0-t 1.29 1.22-1.37 0.61-1.39 LnAUC.sub.0-∞ 1.29 1.21-1.36 0.61-1.39 SNAC LnC.sub.max 1.00 0.90-1.10 0.88-1.12 LnAUC.sub.0-t 1.10 1.07-1.14 0.88-1.12 LnAUC.sub.0-∞ 1.10 1.06-1.14 0.88-1.12 Note: As abiraterone acetate is a highly variable drug under fasting conditions, the judgment range can be relaxed to 0.5-2.0 according to the literatrue “Hummel J, McKendrick S, Brindley C, et al. Exploratory assessment of dose proportionality: review of current approaches and proposal for a practical criterion. Pharm Stat, 2009, 8: 38-49.

(58) 2) Pharmacokinetic Conclusion

(59) After oral administration of test Formulation(T), the mean peak concentration (C.sub.max) of abiraterone in groups A-D is 33.9, 81.4, 209 and 405 ng/mL, respectively. The mean exposure (AUC.sub.0-t) is 98.96, 246.11, 620.08 and 1,041.37 ng.Math.h/mL, respectively. The median time to peak plasma concentration (T.sub.max) is 1.13 h, 1.0 h, 1.0 h and 1.0 h, respectively. The mean volume of distribution (Vz/F) is 12.31, 10.7, 9.1 and 9.2×10.sup.3 L, respectively. The mean elimination half-life (t.sub.1/2) is 10.15, 10.71, 10.62 and 10.85 h, respectively. The mean plasma clearance (CLz/F) is 9.26, 6.82, 5.79 and 5.79×10.sup.2 L/h, respectively. There are basically no statistically significant differences among the various dose groups for the drug distribution and elimination related parameters, Vz, t½z and C.sub.Lz. Compared with the previously reported data (analysis results are shown in Table 11), the exposure (C.sub.max and AUC) of 300 mg test Formulation(T) is in line with expectations, i.e. the exposure dose is not lower than that of 1,000 mg branded drug.

(60) TABLE-US-00014 TABLE 11 Main Pharmacokinetic Parameters of Oral Administration of Two Types of Abiraterone Acetate Tablets PK Parameter Abiraterone acetate tablets Test Formulation (Unit) (Zytiga ®) .sup.[1] (T) Dose (mg) 1000 300 N 433 (POOLED)  16 T.sub.max * (h) 2 (1-8) 1 (0.5-2) C.sub.max(ng/mL) 93.5 (58.6) 209.5 (142.1) AUC.sub.0-C(ng .Math. h/mL) 503 (299) 627.6 (370.4) t.sub.1/2z (h) 15.2 (4.0) 10.6 (1.80) Note: .sup.[1] Excerpt from FDA.ZYTIGA ®, CENTER FOR DRUG EVALUATION AND RESEARCH, APPLICATION NUMBER: 202379Orig1s000, PHARMACOLOGY REVIEW(S)

(61) After oral administration of test Formulation (T), the mean peak concentration (C.sub.max) of SNAC in groups A-D is 407, 977, 1,870 and 2,460 ng/mL, respectively. The mean exposure (AUC.sub.0-t) is 291.34, 668.36, 1,396.58 and 2,121.8 ng.Math.h/mL, respectively. The median time to peak plasma concentration (T.sub.max) is 0.38 h, 0.5 h, 0.5 h and 0.5 h, respectively. The mean volume of distribution (V.sub.z/F) is 1.28, 1.01, 1.74 and 1.52×10.sup.3 L, respectively. The mean elimination half-life (t.sub.1/2) is 3.53, 2.94, 5.35 and 4.88 h, respectively. The mean plasma clearance (CL.sub.z/F) is 2.66, 2.36, 2.22 and 2.22×10.sup.2 L/h, respectively. There are no statistical differences among the various dose groups for the drug distribution and elimination related parameters, V.sub.z, t.sub.1/2z and CL.sub.z.

Test Example 3

In Vivo Food Effects Study in Healthy Subjects

(62) 3.1 Study Objectives

(63) To study the effect of food on the pharmacokinetic characteristics of abiraterone acetate tablets through a single oral administration of abiraterone acetate tablets under fasting state or after meal, or a single oral administration of abiraterone acetate tablets (Zytiga®) produced by Patheon Inc. under modified fasting state, in healthy subjects.

(64) 3.2 Study Plan

(65) A single-center, randomized, open-label, three-period, self-controlled crossover trial design was applied. A total of 24 healthy male subjects were planned to be enrolled in the study. The washout period between each dose group was seven days. Blood samples were collected at a series of time points, and safety test was performed. The HPLC-MS/MS method was used to determine the plasma concentration of abiraterone and SNAC at different time points after drug administration. The non-compartmental model was used to calculate the pharmacokinetic parameters, and statistical analysis was performed.

(66) 3.3 Dosing Regimen

(67) The subjects were orally administered a single dose of the test formulation (T) under fasting state at a dose of 300 mg (150 mg×2 tablets), a single dose of the test formulation (T) of 300 mg abiraterone acetate tablets (I) (150 mg×2 tablets) after a high-fat meal (the total calories were approximately 800˜1,000 kcal, wherein approximately 50% of the calories were derived from fat; the test meal of each test cycle for the postprandial administration should be consistent; a high-fat meal was given 30 minutes before drug administration and should be finished within 30 minutes), or a single dose of the reference preparation of 1,000 mg abiraterone acetate tablets (Zytiga®) (250 mg×4 tablets) under modified fasting state (a medium-fat meal was given two hours before drug administration and one hour after drug administration; the total calories were approximately 450 kcal wherein 30% of the calories were derived from fat; the meal should be finished within 30 minutes), with 240 mL of warm water, in the morning on the day of drug administration for each cycle. Liquid was prohibited before administration and one hour after drug administration, and a standard lunch and dinner (a standardized light diet) were given approximately 4 and 10 hours after drug administration. The drug was swallowed whole instead of being sucked or chewed.

(68) 3.4 Investigational Drug

(69) Test Formulation (T): Abiraterone acetate tablets (Formulation 5), specification: 150 mg;

(70) Reference Preparation (R): Abiraterone Acetate Tablets; produced by Patheon Inc.; trade name: Zytiga®; specification: 250 mg.

(71) 3.5 Pharmacokinetic Results

(72) The PKPS was used for the statistical analysis of pharmacokinetic parameters.

(73) Twenty-four healthy subjects were enrolled in this study, and a total of 24 subjects were included in the PKPS. One subject was withdrawn from this trial after completing Cycle 1 due to increased blood bilirubin. The main PK parameters of abiraterone in each dose groups after single oral administration of abiraterone acetate tablet under fasting state are shown in Table 12 and 13 below.

(74) TABLE-US-00015 TABLE 12 Main Pharmacokinetic Parameters After Oral Administration of abiraterone acetate tablets (Fasting), abiraterone acetate tablets (After a High-Fat Meal), and Reference Preparation (R) (Modified Fasting), Mean ± SD (% CV) Grouping Information (Mean ± SD) Test Formulation Under Test Formulation After a Reference Preparation Under Pharmacokinetic Fasting State High-Fat Meal Modified Fasting State Parameters (Unit) (N = 23) (N = 24) (N = 23.sup.#) C.sub.max (ng/mL) 177 ± 102 (57.7) 393 ± 193 (49.2) 2160 ± 858 (39.8) AUC.sub.0-t (ng .Math. h/mL) 513.45 ± 207.46 (40.40) 992.75 ± 325.77 (32.81) 4226.25 ± 1269.37 (30.04) AUC.sub.0-∞ (ng .Math. h/mL) 521.63 ± 208.06 (39.89) 1007.84 ± 335.75 (33.31) 4271.93 ± 1292.73 (30.26) T.sub.max * (h) 1.00 (0.50, 5.00) 1.50 (1.00, 5.00) 1.50 (1.25, 3.00) t.sub.1/2 (h) 9.78 ± 2.8 (28.63) 10.83 ± 2.82 (26.06) 9.93 ± 2.54 (25.62) V.sub.z/F (mL) 9404.17 ± 4619.55 (49.12) 4980.33 ± 1531.55 (30.75) 3735.25 ± 1844.13 (49.37) CL.sub.z/F (mL .Math. h.sup.−1) 664.24 ± 256.15 (38.56) 335.86 ± 130.6 (38.89) 262.45 ± 103.28 (39.35) λ.sub.z (h.sup.−1) 0.08 ± 0.02 (29.19) 0.07 ± 0.02 (33.02) 0.07 ± 0.02 (24.20) MRT.sub.0-t (h) 6.13 ± 2.16 (35.27) 5.64 ± 1.56 (27.60) 4.93 ± 1.24 (25.23) MRT.sub.0-∞ (h) 7.09 ± 3.06 (43.11) 6.43 ± 2.04 (31.78) 5.53 ± 1.79 (32.48) AUC.sub.—% Extrap (%) 1.69 ± 1.68 (99.42) 1.34 ± 1.06 (78.72) 1.02 ± l.01 (99.39) * T.sub.max is expressed by median (minimum-maximum).

(75) TABLE-US-00016 TABLE 13 Main Pharmacokinetic Parameters of SNAC After a Single Oral Administration of abiraterone acetate tablets (Fasting), abiraterone acetate tablets (After a High-Fat Meal), Mean ± SD (% CV) Grouping Information (Mean ± SD) Test Formulation Test Formulation Pharmacokinetic Under Fasting State After a High-Fat Meal Parameters (Unit) (N = 23)  (N = 24) C.sub.max (ng/mL) 1580 ± 697 (44.1) 1120 ± 574 (51.4) AUC.sub.0-t (ng .Math. h/mL) 1246.29 ± 304.53 (24.43) 1541.7 ± 246.83 (16.01) AUC.sub.0-∞ (ng .Math. h/mL) 1254.58 ± 306.16 (24.4) 1548.48 ± 245.02 (15.82) T.sub.max * (h) 0.50 (0.25, 5.00) 1.13 (0.50, 5.00) t.sub.1/2 (h) 4.22 ± 1.71 (40.60) 3.06 ± 1.19 (38.98) V.sub.z/F (mL) 1617.33 ± 948.82 (58.67) 869.66 ± 362.41 (41.67) CL.sub.z/F (mL .Math. h.sup.−1) 255.02 ± 72.16 (28.3) 198.03 ± 28.78 (14.53) λ.sub.z (h.sup.−1) 0.19 ± 0.08 (42.75) 0.27 ± 0.12 (45.94) MRT.sub.0-t (h) 1.59 ± 1.35 (84.59) 2.28 ± 0.99 (43.45) MRT.sub.0-∞ (h) 1.74 ± 1.38 (79.42) 2.36 ± 1 (42.2) AUC.sub.—% Extrap (%) 0.66 ± 0.54 (81.44) 0.46 ± 0.63 (134.49)

(76) With the dosing order, dosing cycle and dosing regimen as fixed effects, the subjects were included as random effects in the linear mixed model as random effects. The least-squares mean ratio of C.sub.max, AUC.sub.0-t and AUC.sub.0-∞ of abiraterone in plasma after oral administration of the test formulation T under a high-fat meal or fasting states, and its 90% confidence interval were calculated. The analysis results are shown in Table 14.

(77) According to literature reports (See Table 15), the C.sub.max and AUC.sub.0-t of abiraterone after oral administration of 1,000 mg ZYTIGA® under high-fat meal conditions are approximately 16.8 times and 9.92 times of that in a fasting state, respectively, and the C.sub.max and AUC.sub.0-t of abiraterone after oral administration of 1,000 mg ZYTIGA® under modified fasting state are 11.7 times and 7.49 times of that in a fasting state, respectively. The C.sub.max and AUC.sub.0-t of abiraterone after oral administration of 500 mg YONSA® after a high-fat meal are 6.50 times and 4.59 times of that in a fasting state, respectively.

(78) The test results show that: after oral administration of the test formulation, abiraterone acetate tablets after a high-fat meal, the C.sub.max of abiraterone is approximately 2.19 times of that in the fasting state, AUC.sub.0-t is approximately 1.97 times of that in the fasting state, and AUC.sub.0-∞ is approximately 1.96 times of that in the fasting state. Abiraterone acetate tablet has certain food effect. However, comparing with the food effects of ZYTIGA® and YONSA® as reported in the literature, the effect of food on the modified formulation of abiraterone acetate tablet is significantly lower.

(79) Abiraterone acetate tablet, ZYTIGA®, developed by Johnson & Johnson, is largely affected by food. Furthermore, considering the diversity and variability of food, taking them with food may lead to increased exposure and abnormal changes. Therefore, the package insert of ZYTIGA® clearly requires patients to abstain from food two hours before drug administration and one hour after drug administration. Based on the present test results, abiraterone acetate tablet (T) shows a relatively low food effect, so the use of abiraterone acetate tablet (T) without eating restrictions can be considered in the later stage, improving compliance of patient and convenience of drug administration.

(80) TABLE-US-00017 TABLE 14 Ratio of AUC to C.sub.max of Abiraterone in Subjects After Oral Administration of the Test Formulation T Under High-Fat Meal/Fasting State and Its 90% Confidence Interval Geometric Mean and Ratio T After a High- T Under Fasting State (T After a High-Fat Fat Meal After a High-Fat Meal Meal/T Under 90% Confidence Parameters (N = 24) (N = 23) Fasting Satate) % Interval C.sub.max (ng/mL) 339.77 155.49 218.52 170.02%~280.85% AUC.sub.0-t (ng .Math. h/mL) 938.97 477.76 196.53 168.60%~229.10% AUC.sub.0-∞ (ng .Math. h/mL) 951.78 486.15 195.78 168.12%~227.99%

(81) TABLE-US-00018 TABLE 15 Relative Bioavailability of Abiraterone After Oral Administration of ZYTIGA ® and YONSA ® in Different Dietary States ZYTIGA ® 1000 mg ZYTIGA ® 1000 mg YONSA ® 500 mg Parameter GMR (After a High-Fat (Modified (After a High-Fat (Fed/Fasted %) Meal/Fasting) % Fasting/Fasting) % Meal/Fasting) % C.sub.max (ng/mL) 1683 1169.5 649.5 AUC.sub.0-t (hr* ng/mL) 992 773.6 458.6 AUC.sub.0-∞ (hr* ng/mL) 969 749.2 442.4 Note: * C.sub.max, N = 41; AUC.sub.0-t, N = 41; AUC.sub.0-∞, N = 37; [1] Excerpt from FDA.ZYTIGA ®, CENTER FOR DRUG EVALUATION AND RESEARCH, APPLICATION NUMBER: 202379Orig1s000, PHARMACOLOGY REVIEW(S); [2] Excerpt from FDA.YONSA ®, CENTER FOR DRUG EVALUATION AND RESEARCH, APPLICATION NUMBER: 210308Orig1s000, PHARMACOLOGY REVIEW(S) and [J]. Cancer chemotherapy and pharmacology, 2015, 75(1): 49-58.

(82) With the dosing orders, dosing cycle and dosing regimen as fixed effects, the subjects were included as random effects in the linear mixed model. The least-squares mean ratio of C.sub.max, AUC.sub.0-t and AUC.sub.0-∞ of abiraterone in plasma after oral administration of the test formulation T under a high-fat meal and oral administration of the reference formulation R under modified fasting states, and its 90% confidence interval were calculated. The analysis results are shown in Table 16.

(83) The results show that: the C.sub.max, AUC.sub.0-t and AUC.sub.0-∞ of the test formulation (T) under the effect of a high-fat meal are 339.77 ng/mL, 938.97 ng.Math.h/mL and 951.78 ng.Math.h/mL, respectively. The C.sub.max, AUC.sub.0-t and AUC.sub.0-∞ of the reference formulation under modified fasting states are 2,000.25 ng/mL, 4,037.82 ng.Math.h/mL and 4,079.87 ng.Math.h/mL, respectively. The exposure of 300 mg the test formulation T orally administered under high-fat meal is far lower than that of the reference formulation, 1,000 mg ZYTIGA®, under modified fasting conditions. Comparing with the exposure to the reference formulation under modified fasting conditions, the C.sub.max of the test formulation, orally administered after a high-fat meal is approximately 16.99%, AUC.sub.0-t is approximately 23.25%, and AUC.sub.0-∞ is approximately 23.33%. This shows that the maximum exposure to the test formulation T under the effect of a high-fat meal is under the upper limit of exposure of ZYTIGA® under the package insert conditions.

(84) TABLE-US-00019 TABLE 16 Ratio of AUC to C.sub.max of Abiraterone in Subjects After Oral Administration of Test Formulation T After a High-Fat Meal and Oral Administration of Reference Formulation R Under Modified Fasting States and Its 90% Confidence Interval Geometric Mean and Ratio (T Under High-Fat T After a R Under Modified Meal Conditions/ High-Fat Meal Fasting States R Under Modified 90% Confidence Parameter (N = 24) (N = 23) Fasting States) % Interval C.sub.max (ng/mL) 339.77 2000.25 16.99 13.22%~21.83% AUC.sub.0-t (ng .Math. h/mL) 938.97 4037.82 23.25 19.95%~27.11% AUC.sub.0-∞ (ng .Math. h/mL) 951.78 4079.87 23.33 20.03%~27.17%

Test Example 4

The Comparative PK Study of Abiraterone Acetate Tablets in Human after Single Dose

(85) 4.1 Study Objectives

(86) To study the pharmacokinetic characteristics of abiraterone acetate tablets after oral administration of a single dose in healthy subjects under fasting state, using the marketed abiraterone acetate tablets (Zytiga®) as reference preparation. The main pharmacokinetic parameters of the two formulations are compared and the relative bioavailability of the two formulations are evaluated. The effect of SNAC in the test formulations on pharmacokinetics of the combined prednisone and active metabolite prednisolone is observed.

(87) 4.2 Study Plan

(88) A single-center, randomized, open-label, 4-cycle repeation, crossover trial design was applied. The bioavailability under fasting state is studied. A total of 36 healthy male subjects were planned to be enrolled in the study. The washout period between cycles was 7 days. Blood samples were collected at a serial of time points, and safety test was performed. HPLC-MS/MS was used to measure blood concentration of abiraterone, SNAC, prednisone, and prednisolone at different time points after administration of the drug. Pharmacokinetic parameters were calculated using non-compartmental model and statistically analyzed.

(89) 4.3 Dosing Regimen

(90) The subjects were admitted to ward before dinner on the day before the administration in each cycle. They had a standardized light diet in the evening, and then were fasting for solids and liquids overnight. They were fasting for at least 10 hours before dosing. The subjects were given a single oral administration of 300 mg of the test abiraterone acetate tablets (I) (150 mg×2 tablets) and 5 mg of prednisone tablets, or 1000 mg of the reference preparation of abiraterone acetate tablets (Zytiga®) (250 mg×4 tablets) and 5 mg of prednisone tablets with 240 mL of water under fasting state in the morning on the day of the trial. Liquid was prohibited before administration and within 1 h after administration, and standard lunch and dinner (a standardized light diet) were taken about 4 and 10 h after administration.

(91) 4.4 Investigational Drug

(92) Test Formulation (T): Abiraterone acetate tablets (Formulation 5), specification: 150 mg.

(93) Reference Preparation (R): Abiraterone Acetate Tablets; produced by Patheon Inc.; trade name: Zytiga®; specification: 250 mg.

(94) Concurrent drugs: Prednisone Acetate Tablets: Manufacturer: Shanghai Sine Pharmaceutical Laboratories Co., Ltd.

(95) 4.5 Result

(96) 1) Pharmacokinetic Parameters

(97) Analysis of blood concentrations was conducted based on PKCS.

(98) After a single oral administration of abiraterone acetate 300 mg+prednisone 5 mg or Zytiga® 1000 mg+prednisone 5 mg under fasting state, the main pharmacokinetic parameters of abiraterone are shown in Table 17, and the main pharmacokinetic parameters of prednisone and active metabolite prednisolone are shown in Table 18 and Table 19.

(99) TABLE-US-00020 TABLE 17 The main pharmacokinetic parameters of abiraterone after a single oral administration of abiraterone acetate tablets 300 mg/Zytiga ® 1000 mg + prednisone tablets 5 mg in healthy subjects Mean ± SD (% CV) Arithmetic Mean ± SD (% CV) Test Preparations Reference Preparations Parameter (Units) (N = 36) (N = 35) T.sub.max * (h) 1.25 (0.75, 4.50) 1.50 (0.75, 4.50) C.sub.max (ng/mL) 171 ± 84.3 (49.4) 161 ± 76.5 (47.4) AUC.sub.0-t (ng .Math. h/mL) 500.09 ± 209.34 (41.86) 560.86 ± 307.79 (54.88) AUC.sub.0-∞ (ng .Math. h/mL) 509.00 ± 214.35 (42.11) 579.58 ± 315.43 (54.42) λz (h.sup.−1) 0.07 ± 0.02 (33.54) 0.06 ± 0.03 (39.55) t.sub.1/2 (h) 10.30 ± 2.80 (27.23) 12.45 ± 5.24 (42.09) V.sub.z/F (L) 10237.30 ± 5111.45 (49.93) 39711.20 ± 25733.45 (64.80) CL.sub.z/F (L .Math. h.sup.−1) 719.67 ± 390.55 (54.27) 2386.19 ± 1971.83 (82.64) MRT.sub.0-t (h) 6.06 ± l.52 (25.05) 7.35 ± 1.53 (20.88) MRT.sub.0-∞ (h) 7.05 ± 2.23 (31.60) 9.52 ± 3.77 (39.64) * Median (min-max) for T.sub.max.

(100) TABLE-US-00021 TABLE 18 The main pharmacokinetic parameters of prednisone after a single oral administration of abiraterone acetate tablets 300 mg/Zytiga ® 1000 mg + prednisone tablets 5 mg in healthy subjects Mean ± SD (% CV) Arithmetic Mean ± SD (% CV) Test Preparatopms Reference Preparations Parameter (Units) (N = 36) (N = 35) T.sub.max * (h) 2.50 (1.25, 5.00) 2.50 (1.50, 4.00) C.sub.max (ng/mL) 22.7 ± 2.82 (12.4) 23.5 ± 3.39 (14.4) AUC.sub.0-t (ng .Math. h/mL) 123.12 ± 16.72 (13.58) 122.8 ± 17.75 (14.45) AUC.sub.0-∞ (ng .Math. h/mL) 129.99 ± 18.54 (14.26) 128.88 ± 19.53 (15.16) λ.sub.z (h.sup.−1) 0.28 ± 0.03 (11.87) 0.29 ± 0.03 (10.52) t.sub.1/2 (h) 2.47 ± 0.30 (12.21) 2.41 ± 0.24 (10.18) V.sub.z/F (L) 139 ± 19.96 (14.36) 136.83 ± 19.02 (13.9) CL.sub.z/F (L .Math. h.sup.−1) 39.25 ± 5.72 (14.57) 39.65 ± 5.81 (14.66) MRT.sub.0-t (h) 4.25 ± 0.36 (8.37) 4.16 ± 0.36 (8.57) MRT.sub.0-∞ (h) 4.84 ± 0.55 (11.47) 4.69 ± 0.49 (10.46) * Median (min-max) for T.sub.max.

(101) TABLE-US-00022 TABLE 19 The main pharmacokinetic parameters of prednisolone after a single oral administration of abiraterone acetate tablets 300 mg/Zytiga ® 1000 mg + prednisone tablets 5 mg in healthy subjects Mean ± SD (% CV) Arithmetic Mean ± SD (% CV) TestPreparations Reference Preparations Parameter (Units) (N = 36) (N = 35) T.sub.max * (h) 1.25 (0.50, 4.50) 1.00 (0.50, 4.00) C.sub.max (ng/mL) 127 ± 20.8 (16.4) 143 ± 21.1 (14.8) AUC.sub.0-t (ng .Math. h/mL) 589.34 ± 95.47 (16.20) 590.12 ± 96.88 (16.42) AUC.sub.0-∞ (ng .Math. h/mL) 620.09 ± 105.59 (17.03) 617.98 ± 105.89 (17.13) λ.sub.z (h.sup.−1) 0.28 ± 0.02 (8.49) 0.28 ± 0.02 (7.60) t.sub.1/2 (h) 2.53 ± 0.22 (8.58) 2.49 ± 0.19 (7.74) V.sub.z/F (h) 29.94 ± 3.79 (12.66) 29.69 ± 4.37 (14.72) CL.sub.z/F (L .Math. h.sup.−1) 8.29 ± 1.38 (16.69) 8.32 ± 1.41 (16.93) MRT.sub.0-t (h) 3.89 ± 0.38 (9.88) 3.74 ± 0.37 (9.86) MRT.sub.0-∞ (h) 4.45 ± 0.50 (11.33) 4.26 ± 0.45 (10.61) * Median (min-max) for T.sub.max.

(102) 2) Relative Bioavailability of Abiraterone

(103) The dosing order, preparations and cycles were considered as fixed effects. The preparation factors of different subjects were considered as random effects. The repeated measurements of preparations in individual subjects were also considered. The mixed-effect model was used to perform an analysis of variance for log-transformed values of C.sub.max, AUC.sub.0-t, and AUC.sub.0-∞, and ABE or RSABE method was used to evaluate relative bioavailability of abiraterone of the test preparations and the reference preparations. The relative bioavailability of abiraterone for the test preparation and the reference preparation is shown in Table 20. The results show that: after a single oral administration of the test abiraterone acetate tablets 300 mg+prednisone tablets 5 mg or the reference preparations Zytiga®1000 mg+prednisone tablets 5 mg in 36 healthy subjects under fasting state, C.sub.max, AUC.sub.0-t, and AUC.sub.0-∞ of abiraterone in the test preparation and the reference preparation are bioequivalent, i.e., under fasting atate, the exposure of the test preparation abiraterone acetate tablets 300 mg is equivalent to that of Zytiga® 1000 mg, providing preliminary support for efficacy of abiraterone acetate tablets 300 mg.

(104) Comparing the intra-individual variations of abiraterone between the test preparation and the reference preparation, the intra-individual variations of C.sub.max are basically equivalent; however, the intra-individual variation of AUC.sub.0-t and AUC.sub.0-∞ of the test preparation are reduced by 10.58% and 11.34% respectively, compared with the reference preparation, and there were statistically significant of differences (p<0.01), suggesting that the exposure of abiraterone acetate tablets to human body is more stable than that of Zytiga®.

(105) Non-parametric Kruskal-Wallis rank sum test was conducted for T.sub.max of abiraterone after oral administration of the test preparations and the reference preparations under fasting state, and there were statistically significant differences of T.sub.max of abiraterone (p<0.05), however the differences are not clinically significant, and would not influence safety and efficacy for clinical applications.

(106) TABLE-US-00023 TABLE 20 Statistical results of relative bioavailability of abiraterone after oral administration of abiraterone acetate tablets 300 mg/Zytiga ® 1000 mg + prednisone tablets 5 mg under fasting state (PKPS, N = 36) Geometric mean and ratio Intra-individual Intra-individual Test Reference 90% CVWR % of CVWT % Preparations Preparations GMR Confidence the reference of the test Parameters (T) (N = 36) (R) (N = 35) (%) interval preparations preparations C.sub.max 151.67 142.25 106.62 95.73~118.76 31.66 32.65 (ng/mL) AUC.sub.0-t 456.50 485.58 94.01 87.42~101.10 25.62 15.04 (ng*h/mL) AUG.sub.0-∞ 464.43 502.74 92.38 86.00~99.23  26.30 14.96 (ng*h/mL)