Article Figures & Data
Figures
- Fig. 1.
Hybrid pharmacokinetic model containing a 2-compartment plasma disposition model and 1-compartment tumor model. This model configuration was the best-fit model describing either the carboplatin or topotecan preclinical plasma and tumor concentration data. The forcing function, describing the plasma drug concentration-time profile, is directly generated from the 2-compartment structure and then is input into the tumor compartment. The notation used for the rate constants, K12 and K21, is consistent with the SAAM II conventions.
- Fig. 2.
Model-predicted (—) and observed ○ carboplatin plasma (A) and tumor (B) concentrations in rats bearing intraperitoneal NuTu19 tumors, a preclinical model of ovarian cancer. The best-fit model is illustrated in Fig. 1<$REFLINK> , and resulted in the following parameter values (mean ± SD) for carboplatin: K01 = 0.0394 ± 0.0036, K12 = 0.0041 ± 0.0013, K21 = 0.0174 ± 0.0026, K34 = 0.0269 ± 0.0035, K43 = 0.0107 ± 0.0020, V1 = 36.2 ± 3.9. The units for all rate constants (K values) are minutes−1 and milliliters for the volume of distribution of the central compartment (V1).
- Fig. 3.
Model-predicted (—) and observed • topotecan plasma (A) and tumor (B) concentrations in rats bearing intraperitoneal NuTu19 tumors, a preclinical model of ovarian cancer. The best-fit model is illustrated in Fig. 1<$REFLINK> , and resulted in the following parameter values (mean ± SD) for topotecan K01 = 0.0811 ± 0.2278, K12 = 0.0825 ± 0.1238, K21 = 0.3989 ± 1.540, K34 = 0.0132 ± 0.0096, K43 = 0.0424 ± 0.0138, V1 = 108.6 ± 262.6. The units for all rate constants (K values) are minutes−1, and milliliters for the volume of distribution of the central compartment (V1).
- Fig. 4.
Hybrid pharmacokinetic model containing a 2-compartment plasma disposition model and 3-compartment tumor model. This model configuration was the best-fit model describing temozolomide preclinical plasma and tumor concentration data in the absence (control) and presence (TNP-470) of an angiogenesis inhibitor. The model was obtained in a sequential manner; first defining the forcing function based on the plasma drug concentration-time profile and then fitting the parameters for the tumor compartment. See Table 1<$REFLINK> for the parameter values.
- Fig. 5.
Model-predicted (—) and observed • temozolomide plasma (A) and tumor (B) concentrations under control treatment conditions in rats bearing subcutaneous gliomas that overexpress VEGF. See Table 1<$REFLINK> for parameter values.
- Fig. 6.
Model-predicted (—) and observed • temozolomide plasma (A) and tumor (B) concentrations under TNP-470 treatment conditions in rats bearing subcutaneous gliomas that overexpress VEGF. See Table 1<$REFLINK> for parameter values.
- Fig. 7.
Distribution of predicted human tumor carboplatin AUC values determined from the hybrid pharmacokinetic model, N = 200.
- Fig. 8.
Histogram indicating the number of data sets (total N = 200) in which model-predicted topotecan tumor concentrations were ≥10 ng/mL, expressed as a fraction of time over a dosing interval of 12 hours.
- Fig. 9.
Distribution of predicted human temozolomide tumor AUCif values under control (A) and TNP-470 (B) treatment conditions, N = 100 for each condition. It can be seen that the AUCif values obtained following a therapeutic regimen of TNP-470 are shifted to smaller values compared with the control treatment.
- Fig. 10.
Human hybrid pharmacokinetic model for temozolomide that was applied to simulate concentrations for both control and TNP-470 treatments. The human-based parameters are indicated in boldface (i.e., A, K, Ka, Q, fu, Vv, Vif, Vic), whereas those assumed to be equivalent to the preclinical values are in regular font. Parameters that were common to both the control and TNP-470 models were tumor blood flow, Q = 30 mL/minute; fraction unbound in plasma, fu = 0.86; volume of the vascular compartment, Vv = 5 mL; volume of the interstitial fluid compartment, Vif = 20 mL; volume of the intracellular compartment, Vic = 25 mL; absorption rate constant, Ka = 0.0443 minute−1; and elimination rate constant, K = 0.0063 minute−1, K46 = 0.5 minute−1. Mean (SD) fitted parameters that differed between control and TNP-470 treatments were the following for control: A = 1.46 (0.0024) ug/mL, K34 = 0.0168 (0.042) minute−1, and K43 = 0.0638 (0.0147) minute−1. Mean (SD) fitted parameters that differed between control and TNP-470 treatments were the following and for the TNP-470 model: A = 1.42 (0.0054) μg/mL, K34 = 0.0470 (0.0098) minute−1, and K43 = 0.0156 (0.0443) minute−1.
Tables
- Table 1
Hybrid model parameters for temozolomide in rats
Parameters Control TNP-470 K01 (minutes−1) 0.0157 (7.6) * 0.0183 (10.1) K12 (minutes−1) 0.086 (25.6) 0.0803 (22.6) K21 (minutes−1) 0.0488 (43.7) 0.0737 (39.8) V1 (mL) 553.1 (7.5) 479.7 (10.0) K34 (minutes−1) 0.173 (13.9) 0.0475 (8.22) K43 (minutes−1) 0.740 (15.0) 0.164 (10.5) K46 (minutes−1) 0.5 0.5 Q (mL/minutes ) 0.93 0.93 f u 0.8 0.8 Vv (mL) 0.16 0.16 Vif (mL) 0.62 0.62 Vic (mL) 0.78 0.78 -
* Values in parenthesis indicate % coefficient of variation of parameter estimate obtained by weighted least-squares regression.
-
- Table 2
Model parameters for human hybrid pharmacokinetic models for carboplatin and topotecan
Parameters Carboplatin Topotecan K01 (minutes−1) 0.015 (7.9) * 0.022 (7.9) K12 (minutes−1) 0.011 (39.8) 0.010 (6.6) K21 (minutes−1) 0.018 (78.2) 0.025 (12) K34 (minutes−1) 0.027 (26.4) 0.013 (27) K43 (minutes−1) 0.011 (26.6) 0.043 (29) V1 (L) 9.59 (7.2) 42.0 (9.6) -
* Values represent mean (% coefficient of variation) of model-fitted estimates from simulated error datasets (N = 200) for each drug.
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Volume 10, Issue 23
