Article Figures & Data
Figures
- Fig. 1.
Arithmetic mean plasma concentration-time profiles: apalutamide and dose-normalized 14C-apalutamide in plasma [linear; part A bioavailability (BA) study] (A); apalutamide metabolites M3 and M4 in plasma (logarithmic-linear; BA study) (B); apalutamide in plasma, and 14C-apalutamide in plasma and whole blood (linear; part B AME study) (C).
- Fig. 2.
Cumulative recovery of 14C in urine, feces, and total excretion.
- Fig. 3.
Radiochromatograms for human urine [0–240 hours (A); 240–1680 hours (B)] and human feces ([0–240 hours (C); 240–1680 hours (D)] after a single oral dose of 240 mg of apalutamide.
- Fig. 4.
Proposed scheme of apalutamide metabolism in human plasma, urine, and feces. The 14C label, marked with an *, is at the 8 position of the 8-oxo-6-thiooxo-5,7-diazaspiro[3,4]octan-5-yl ring.
- Fig. 5.
Effect of specific esterase and cytochrome P450 inhibitors on the formation of M3 (A) or M4 (B) from apalutamide in human hepatocytes. GEM, gemfibrozil + gemfibrozil glucuronide; ITRA, itraconazole; TOA, troleandomycin.
- Fig. 6.
Accurate mass full scan (A) and product ion mass spectra (B) of apalutamide.
- Fig. 7.
Product ion mass spectra of M3 (A) and M4 (B).
Tables
- TABLE 1
Summary statistics of pharmacokinetic parameters for apalutamide, M3, M4, and 14C-apalutamide in plasma and blood. Geometric mean (% CV) data are presented, except for Tmax for which median (minimum–maximum) data are presented
Analyte Cmax Tmaxa AUC0-t AUC0-inf t1/2 F CL Vd µg/ml h h/µg per milliliter h l/h l Part A—bioavailability study, N = 6 Apalutamide 3.25 (12.2) 1.01 (1.00–1.50) 185 (16.2) 200 (14.5) 175 (19.0) 1.11 (2.1) N.D. N.D. M3 0.302 (20.0) 265.84 (144.00–313.70) 183 (10.6) 199 (12.0) 248 (23.7) N.D. N.D. N.D. M4b 0.0662 (33.2) 3.00 (2.00–6.00) 8.83 (52.0) N.D. N.D. N.D. N.D. N.D. 14C-apalutamide 0.00235 (25.3) 0.23 (0.08–0.42) 0.0699 (19.7) 0.0719 (19.7) 170 (23.3) N.D. 1.33 (15.0) 326 (17.0) DN 14C-apalutamide 5.64 (25.3) N.D. 168 (19.7) 173 (19.7) N.D. N.D. N.D. N.D. Part B—AME study, N = 6 Apalutamide 3.18 (14.5) 1.50 (1.00–2.02) 175 (23.5) 185 (22.1) 148 (22.0) N.D. N.D. N.D. M3 0.322 (21.9) 204.00 (120.00–240.00) 169 (14.0) 186 (12.2) 225 (23.4) N.D. N.D. N.D. M4b 0.0717 (19.4) 3.00 (2.00–6.00) 11.1 (39.0) N.D. N.D. N.D. N.D. N.D. Total 14Cc 2.82 (25.9) 1.25 (0.50–2.00) 413 (10.2) 418 (10.5) 257 (11.6) N.D. N.D. N.D. Total 14C (blood)c,d 2.34 (19.1) 1.00 (1.00–1.00) 133 (11.1) N.D. N.D. N.D. N.D. N.D. CL, clearance; DN, dose normalized to 240 mg; F, absolute bioavailability; N, number of subjects; N.D., not determined; t1/2, terminal half-life; Vd, volume of distribution.
↵a For 14C-apalutamide, Tmax was measured relative to the start of the intravenous infusion at 2 h after oral dosing.
↵b Geometric mean AUC0–inf and t1/2 could not be reliably determined.
↵c For total 14C in plasma and blood, the units for Cmax (µg Eq/ml), AUC0–t (h/µg Eq per milliliter), and AUC0–inf (h/µg Eq per milliliter) differed from the units shown above.
↵d For total 14C in blood, AUC0–t was calculated up to time t = 168 h.
- TABLE 2
Mass balance of unchanged 14C-apalutamide and its metabolites expressed as a percentage of the administered dose and found in urine and feces after oral administration of 240 mg of apalutamide
Component Urine Feces 0–240 h 240–1680 h 0–1680 h 0–240 h 240–1680 h 0–1680 h % Inj % Dose % Inj % Dose % Dose % Inj % Dose % Inj % Dose % Dose M2 0.6 0.17 0.2 0.07 0.23 M3 3.5 0.98 4.8 1.75 2.73 7.9 0.62 8.3 1.35 1.97 M4 44.6 12.53 51.5 18.59 31.12 8.8 0.69 10.4 1.69 2.38 M8 2.2 0.61 0.8 0.29 0.90 2.5 0.20 1.2 0.19 0.39 M9 1.0 0.29 0.6 0.21 0.50 20.5 1.61 11.6 1.88 3.49 M10 Trace Trace Trace Trace Trace M11 2.4 0.66 1.2 0.45 1.11 M12 + M13 + M14 8.4 2.35 6.6 2.38 4.73 11.1a 0.87a 23.4a 3.79a 4.67a M15 3.0 0.84 2.0 0.71 1.54 Trace Trace Trace Trace Trace M17 Trace Trace Trace Trace Trace Trace Trace Trace Trace Trace M18 0.5 0.14 0.4 0.13 0.27 4.2 0.33 3.5 0.57 0.90 M19 11.7 3.29 5.6 2.02 5.31 2.5 0.20 1.3 0.21 0.41 M20 7.7 2.17 13.0 4.68 6.85 1.4 0.11 1.1 0.17 0.29 M21 + M22 3.2 0.91 4.2 1.53 2.44 Unchanged drug 3.3 0.92 0.8 0.28 1.20 11.5 0.91 3.9 0.64 1.54 Sum of reported entities 92.0 25.9 91.2 33.0 58.8 70.5 5.5 64.8 10.5 16.0 Sum of observed metabolites (dose %) 28.1 36.1 64.2 7.9 16.2 24.1 % Dose, percentage of oral dose; % Inj, percentage of 14C injected onto the HPLC column.
↵a Includes M13 + M14 only.
- TABLE 3
Identification of in vivo metabolites of apalutamide after a single oral dose of 240 mg in healthy men
Component Identity Retention Time LC-AMS (min) Urine Retention Time LC-AMS (min) Feces Retention Time LC-MS (min) m/z Typical MS Fragments Matrix M2 −16 (−S+O) 18.7–18.9 23.0 462.1189 162, 193, 214, 403, 434 U M3 −14 (N-demethylation) 19.7–19.9 18.7–18.9 24.1 464.0804 162, 179, 190, 207, 419, 436, 447 F, U, P M4 −13 (oxidative deamination) 16.3–16.9 15.7 21.1 465.0644 162, 180, 208, 230, 437 F, U, P M8 +16 (+O) 17.3–17.5 16.3 21.7 494.091 162, 193, 206, 211, 219, 230, 381, 419, 450 F, U M9 +104 (cysteine condensation) 13.3–13.5 12.5 17.7 582.0893 105, 249, 334, 478, 508 F, U M10 +161 (cysteine-glycine condensation) 17.9 639.1107 116, 162, 249, 391, 478, 508, 536 U M11 +192 (+O+gluc) 12.9–13.1 17.4 670.1231 162, 193, 219, 381, 419, 450, 494 U M12 +147 (cysteine-glycine addition+N- demethylation) 12.3 16.8 625.0951 116, 162, 235 U M13 +18 (water addition) 12.3 11.3 16.5 496.1066 231, 248, 249, 479 F, U M14 +90 (cysteine addition+N-demethylation) 12.1 11.3 16.5 568.0736 105, 235, 334 F, U M15 +4 (water addition+N-demethylation) 10.9 15.1 482.091 218, 235, 248, 249, 409, 454, 465 F, U M17 +91 (cysteine addition+oxidative deamination) 14.6 569.0576 105, 208, 236, 334 F, U M18 +5 (water addition+oxidative deamination) 8.3 7.5 12.7 483.075 236, 466 F, U M19 −211 (ring opening+hydrolysis) 5.5 4.7 9.7 267.1145 58, 99, 138, 162, 190, 193, 208, 236, 239 F, U M20 −225 (ring opening+hydrolysis+ demethylation) 4.7 4.1–4.3 8.9 253.0988 138, 162, 179, 190, 208, 225 F, U M21 −35 (ring opening+hydrolysis+gluc) 3.1–4.1 8.4 443.1466 162, 208, 221, 236, 239, 267 U M22 −49 (ring opening+hydrolysis+ demethylation+gluc) 3.1–4.1 8.1 429.1309 162, 208, 225, 236, 253 U UD Parent 20.7–20.9 19.7–19.9 25.1 478.0961 162, 164, 190, 193, 221, 230, 419, 447, 450 F, U, P UD, unchanged drug.
Data Supplement
- Supplemental Data -
4 supplemental figures, 1 table.
- Supplemental Data -
In this issue
Apalutamide Human Absorption, Metabolism, and Excretion
