Article Figures & Data
Figures
- Fig. 1.
Equations used to determine CL/F and Vd/F for sunitinib (A) and SU12662 (B).
- Fig. 2.
Diagnostic goodness-of-fit plots for sunitinib (A) and metabolite (B) final models, showing population and individual predicted versus observed concentrations, weighted residuals versus time, and weighted residuals versus population predicted concentrations. Lines represent the unity (population and individual predicted plots) or null value (weighted residual plots).
- Fig. 3.
Simulation predictions of sunitinib (A) and total drug (B) exposures in covariate subpopulations compared with baseline [a 77-kg Caucasian male with metastatic renal cell carcinoma and ECOG score ≤1; gastrointestinal stromal tumor and solid tumor patients were expected to display similar changes]. Wide bars represent Cavg (Cavg × 24 h = AUC) and thinner bars represent Cmax. Each bar indicates the 5th, 50th, and 95th percentiles for the subpopulation.
Tables
- Table 1.
Summary of design of single-agent studies from which data were analyzed
Design (study number) Population (n) Dosing schedule* Study day for full PK sampling Full PK sampling time points post-dose (h) Single-dose studies R, DB, PC (001) Healthy volunteers (6) 50 mg† 1 Pre-dose (0), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 9, 10, 11, 12, 16, 24, 30, 36, 48 R, OL, three-way CO of sunitinib free base, l-malate salt, and the effect of food (004) Healthy volunteers (15) 50 mg‡ 1 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 9, 10, 11, 12, 16, 24, 30, 36, 48, 72, 216 3 single doses (free base fasted; l-malate salt fasted; l-malate salt fed) R, OL, two-way CO study with/without concomitant ketoconazole (009) Healthy volunteers (27) 10 mg§ 1 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 24, 30, 36, 48, 72, 120, 168, 216, 312, 408, 504 Ketoconazole: 400 mg p.o. qd ×7 d OL, CO study with/without concomitant rifampin (1001) Healthy volunteers (25) 50 mg 1 0, 2, 4, 7, 8, 9, 12, 16, 24, 36, 48, 72, 144, 240, 288, 336, 408 Rifampin: 400 mg p.o. qd ×7 d OL, dose escalation (006) AML (29) 50-350 mg‡ 1 0, 4, 6, 8, 10, 12, 24, 48 Multiple-dose studies OL, single-arm, NR, dose-escalating study of three treatment schedules (013) GIST (68, of which 18 with full PK) 25, 50 or 75 mg qd (2/2, 4/2 or 2/1) Schedule 2/2∥ Cycle 1: 1, 14 0, 1, 4, 6, 8, 10, 12, 24, 48 Cycle 2: 14 Schedule 4/2∥ Cycle 1: 1 and 28 As above Cycle 2: 28 Schedule 2/1∥ Cycle 1: 1, 14 As above Cycle 2: 14 DB, PC, R (1004) GIST (154) 50 mg qd (4/2) Schedule 4/2 Cycle 1: 1, 14, 28 Trough sampling only Additional cycles: 1, 28 OL, NR (1045) GIST (12) 25, 50, 75 mg qd (4/2) Schedule 4/2∥ Cycle 1: 1 0, 1, 2, 4, 6, 8, 10 Cycle 1: 2, 7, 14, 21 0 Cycle 1: 28 0, 1, 2, 4, 6, 8, 10, 24, 48 OL, NR (014) mRCC (56) 50 mg qd (4/2) Schedule 4/2 Cycles 1-4: 1, 14, 28 Trough sampling only Additional cycles: 1 OL, NR (1006) mRCC (92) 50 mg qd (4/2) Schedule 4/2 Cycle 1: 1, 14, 28Cycles 2-4: 1, 28 Trough sampling only Additional cycles: 1 OL, NR, dose escalation (002) Solid tumor (27) 25, 50, 75 or 100 mg‡ qd or qod (4/2) Schedule 4/2∥ Cycle 1: 1 and 27 or 28 0, 1, 2, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 8, 10, 12, 14, 16, 24 OL, NR, dose escalation (005) Solid tumor (41) 50, 75 mg‡ qd or qod (2/2 or 4/2) Schedule 2/2∥ Cycle 1: 1 and 13 or 14 0, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 20, 24, 48 Cycles 2 and 3: 13 or 14 Schedule 4/2∥ Cycle 1: 1 and 28 As above Cycles 2 and 3: 28 Schedule 4/2∥ Cycle 1: 14 0, 4, 6, 8, 10, 12, 24 OL, NR (016) Solid tumor (12) 50 mg qd (2/1) Schedule 2/1∥ Cycle 1: 1 and 14 0, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 20, 24 Cycle 2: 14 Cycle 3: 14 OL, dose escalation (018) Solid tumor (26) 50-175 mg loading dose on day 1; 50 mg qd (2/1) Schedule 2/1∥ Cycle 1: 1 0, 4, 6, 8, 10, 12, 24 Cycle 2: 1 and 14 Cycle 3: 14 (for >50 mg) Cycle 1: 14 0, 4, 6, 8, 10, 12, 24, 72, 120 Abbreviations: CO, crossover; DB, double-blind; MD, multiple dose; mRCC, metastatic renal cell carcinoma; GIST, gastrointestinal stromal tumor; n, number of subjects evaluable for PK; NR, nonrandomized; OL, open-label; PC, placebo-controlled; p.o., oral; PK, pharmacokinetics; qd, everyday; qod, every other day; R, randomized; SD, single dose.
↵* Information provided: dose of sunitinib (in all studies sunitinib was administered in the form of l-malate salt capsules unless stated); frequency of dosing and dosing schedule (weeks on treatment/weeks off treatment).
↵† Free base powder in bottle.
↵‡ Free base and l-malate salt capsule.
↵§ l-Malate salt powder in bottle.
↵∥ Trough PK sampling was also done.
- Table 2.
Summary of patient physiologic and demographic characteristics
(A) Summary values at screening (or first available measurement) of continuous covariates Variable Age (y) Weight (kg) CrCL (mL/min)* Minimum 18 34.0 32.2 1st quartile 44 64.0 74.1 Mean 53 77.6 98.2 Median 55 76.9 93.5 3rd quartile 64 88.0 118 Maximum 87 168 347 Total N 590 590 587 SD 15 18.8 36.7 (B) No. of subjects within a range at screening (or first available measurement) Demographic(range at screening) Subgroup Healthy volunteers Patients All Age, y (18-87) <40 63 36 99 40-60 10 275 285 60-75 0 180 180 >75 0 26 26 Weight, kg (34-168) ≥135 0 6 6 76-<135 36 271 307 41-75 37 237 274 ≤40 0 3 3 CrCL, mL/min (32-347)* >80 72 318 390 50-80 1 168 169 30-49 0 28 28 <30 0 3 3 ↵* Excludes three subjects with low CrCL values (<1 mL/min; these are thought to be an artifact of the Cockroft-Gault estimation).
- Table 3.
Values of final parameter estimates for the base models for sunitinib and SU12662
Parameter Estimate (SE/estimate) Interindividual variability (SE/estimate) Interindividual variability (variance)* Sunitinib CL/F, L/h 37.7 (1.8%) 37.9% (8.8%) 0.14 Vd/Fcentral, liters 1,940 (3.8%) 44.7% (13%) 0.20 Ka, 1/h 0.195 (6.8%) 81.2% (13%) 0.66 Intercompartmental flow (Q/F), L/h 6.37 (18%) NA NA Vd/Fperipheral, liters 588 (8.7%) NA NA Proportional error 0.147 (9.6%) NA NA SU12662 CL/F, L/h 20.2 (2.3%) 52.2% (8.5%) 0.27 Vd/Fcentral, liters 2,710 (3.9%) 65.1% (8.7%) 0.42 Ka, 1/h 0.287 (6.6%) 89.1% (13%) 0.79 Intercompartmental flow (Q/F), L/h 27.7 (26%) NA NA Vd/Fperipheral, liters 345 (22%) NA NA Proportional error 0.0913 (7.3%) NA NA Abbreviation: NA, not applicable.
↵* Calculated as [%CV/100]2.
- Table 4.
Values of final parameter estimates for the final models for sunitinib and SU12662
Parameter Sunitinib SU12662 Estimate (SE/estimate) Interindividual variability (%CV) Interindividual variability (variance)* 95% CI Estimate (SE/estimate) Interindividual variability (%CV) Interindividual variability (variance)* 95% CI CL/F, L/h 51.8 (4%) 38% 0.14 47.9-55.7 29.6 (3%) 47% 0.22 27.2-32.0 Vd/Fcentral, liters 2,030 (4%) 43% 0.18 1,877-2,183 3,080 (4%) 59% 0.35 2,815-3,345 Ka, 1/h 0.195 (7%) 80% 0.64 0.170-0.220 0.290 (7%) 86% 0.74 0.252-0.328 Q/F, L/h 7.22 (20%) NA NA 4.44-10.00 23.3 (30%) NA NA 9.64-37.0 Vd/Fperipheral, liters 583 (9%) NA NA 485-681 289 (27%) NA NA 138-440 Weight on CL/F NA NA NA NA 0.296 (64%) NA NA −0.074 to 0.666 Weight on Vd/F 0.459 (16%) NA NA 0.318-0.600 0.510 (49%) NA NA 0.024-0.996 Gender on CL/F −0.0876 (34%) NA NA −0.145 to −0.030 −0.274 (15%) NA NA −0.354 to −0.294 Gender on Vd/F NA NA NA NA −0.241 (23%) NA NA −0.339 to −0.133 Asian race on CL/F −0.130 (30%) NA NA −0.206 to −0.054 −0.123 (31%) NA NA −0.198 to −0.048 ECOG on CL/F NA NA NA NA −0.0652 (96%) NA NA −0.188 to 0.058 GIST on CL/F −0.285 (14%) NA NA −0.361 to −0.209 −0.224 (15%) NA NA −0.289 to −0.159 Solid tumor on CL/F −0.269 (15%) NA NA −0.349 to −0.189 −0.287 (14%) NA NA −0.366 to −0.208 mRCC on CL/F −0.258 (13%) NA NA −0.323 to −0.193 −0.257 (12%) NA NA −0.316 to −0.198 Proportional error 0.146 (10%) NA NA 0.118-0.174 0.0914 (7%) NA NA 0.0782-0.105 Abbreviations: 95% CI, 95% confidence interval; NA, not available (covariates not found to have a significant effect when the full model was subjected to stepwise backward elimination were omitted from the final model).
↵* Calculated as [%CV/100]2.
Volume 15, Issue 7
