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Population pharmacokinetics of high-dose methotrexate after intravenous administration in Chinese osteosarcoma patients from a single institution.

Zhang W, Zhang Q, Tian X, Zhao H, Lu W, Zhen J, Niu X - Chin. Med. J. (2015)

Bottom Line: The effects of fixed-effect factors were evaluated, and the final regression model was obtained.A good fit was derived for the PPK.The model could be used to provide guidance for MTX treatment and reduce adverse effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Pharmacology, Beijing Jishuitan Hospital, Beijing 100035, China.

ABSTRACT

Background: High-dose methotrexate (HD-MTX) with folinic acid (leucovorin) rescue is the gold standard therapy in the treatment of osteosarcoma. The plasma concentration of MTX is closely related to efficacy and toxicity. There are large individual differences. Many authors have described the pharmacokinetic (PK) profile of MTX regarding osteosarcoma under a variety of circumstances. However, no data concerning Chinese osteosarcoma patient PKs using the nonlinear mixed effects models (NONMEM) have been previously reported. The goals of this study were to establish the population pharmacokinetics (PPK) of HD-MTX treatment in Chinese osteosarcoma patients, and to explore the influence of patient covariates and between-occasion variability on drug disposition.

Methods: An intravenous HD-MTX solution (10 g/m 2 ) was given 274 times to 148 osteosarcoma patients. MTX plasma concentrations were measured at 0, 6, 12, 24, 48 and 72 h after commencement of the infusion, and the fluorescence polarization immunoassay was used to determine MTX plasma concentrations. The PPK model and parameters were estimated using NONMEM software. The effects of fixed-effect factors were evaluated, and the final regression model was obtained.

Results: The following population parameters were obtained using a two-compartment model: CL1 (clearance of central compartment): (CL1 ) = CL1TV × [1 - θ CL1- MTXNUM × MTXNUM] × [1 - θ CL1- CrCl1 × (CrCl1 - 1.89)] × e ηCL1i (L/h). V1 (central volume): (V1)i = V1TV × e ηV1i (L). CL2 (clearance of peripheral compartment): (CL2)i = CL2TV × [1 - θCL2 - BODY AREA × (body area - 1.62)] × e ηCL2i (L/h). V2 (peripheral compartment): (V2 )i = V2TV × [1 - θ V2-bodyarea × (bodyarea-1.62)] × e ηV2i (L). The PPK parameters (RSD%) were CL1, V1, CL2 and V2 with values of 6.20 L/h (8.48%), 19.6 L (extremely small), 0.0172 L/h (50.9%) and 0.515 L (39.1%), respectively. Creatinine clearance and the number of methotrexate chemotherapy cycles before MTX infusion had a significant effect on the CL1, and body surface area had a significant effect on the CL2 and the V2 (P < 0. 01).

Conclusions: A good fit was derived for the PPK. The model could be used to provide guidance for MTX treatment and reduce adverse effects.

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Related in: MedlinePlus

Observed concentration (DV; semilog), individual predicted concentration (IPRED; semilog) and population predicted concentration (PRED; semilog) versus TIME in the base model (a) and the final model (b). The blue crosses represent the DV, the red blank circles represent the IPRED and the yellow triangles represent the PRED.
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Figure 4: Observed concentration (DV; semilog), individual predicted concentration (IPRED; semilog) and population predicted concentration (PRED; semilog) versus TIME in the base model (a) and the final model (b). The blue crosses represent the DV, the red blank circles represent the IPRED and the yellow triangles represent the PRED.

Mentions: The goodness of fit between the predicted and observed values of serum drug concentration could be evaluated overall by plotting these two values against time. The half-logarithm coordinate diagram of the observed value, population predicted value, individual predicted value and time is shown in Figure 4. Figure 4a shows the basic model while Figure 4b shows the final model; the population predicted values from final model were closer to the observed values than was the case for the basic model, indicating that final model was an improvement on the basic model.


Population pharmacokinetics of high-dose methotrexate after intravenous administration in Chinese osteosarcoma patients from a single institution.

Zhang W, Zhang Q, Tian X, Zhao H, Lu W, Zhen J, Niu X - Chin. Med. J. (2015)

Observed concentration (DV; semilog), individual predicted concentration (IPRED; semilog) and population predicted concentration (PRED; semilog) versus TIME in the base model (a) and the final model (b). The blue crosses represent the DV, the red blank circles represent the IPRED and the yellow triangles represent the PRED.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4837805&req=5

Figure 4: Observed concentration (DV; semilog), individual predicted concentration (IPRED; semilog) and population predicted concentration (PRED; semilog) versus TIME in the base model (a) and the final model (b). The blue crosses represent the DV, the red blank circles represent the IPRED and the yellow triangles represent the PRED.
Mentions: The goodness of fit between the predicted and observed values of serum drug concentration could be evaluated overall by plotting these two values against time. The half-logarithm coordinate diagram of the observed value, population predicted value, individual predicted value and time is shown in Figure 4. Figure 4a shows the basic model while Figure 4b shows the final model; the population predicted values from final model were closer to the observed values than was the case for the basic model, indicating that final model was an improvement on the basic model.

Bottom Line: The effects of fixed-effect factors were evaluated, and the final regression model was obtained.A good fit was derived for the PPK.The model could be used to provide guidance for MTX treatment and reduce adverse effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Pharmacology, Beijing Jishuitan Hospital, Beijing 100035, China.

ABSTRACT

Background: High-dose methotrexate (HD-MTX) with folinic acid (leucovorin) rescue is the gold standard therapy in the treatment of osteosarcoma. The plasma concentration of MTX is closely related to efficacy and toxicity. There are large individual differences. Many authors have described the pharmacokinetic (PK) profile of MTX regarding osteosarcoma under a variety of circumstances. However, no data concerning Chinese osteosarcoma patient PKs using the nonlinear mixed effects models (NONMEM) have been previously reported. The goals of this study were to establish the population pharmacokinetics (PPK) of HD-MTX treatment in Chinese osteosarcoma patients, and to explore the influence of patient covariates and between-occasion variability on drug disposition.

Methods: An intravenous HD-MTX solution (10 g/m 2 ) was given 274 times to 148 osteosarcoma patients. MTX plasma concentrations were measured at 0, 6, 12, 24, 48 and 72 h after commencement of the infusion, and the fluorescence polarization immunoassay was used to determine MTX plasma concentrations. The PPK model and parameters were estimated using NONMEM software. The effects of fixed-effect factors were evaluated, and the final regression model was obtained.

Results: The following population parameters were obtained using a two-compartment model: CL1 (clearance of central compartment): (CL1 ) = CL1TV × [1 - θ CL1- MTXNUM × MTXNUM] × [1 - θ CL1- CrCl1 × (CrCl1 - 1.89)] × e ηCL1i (L/h). V1 (central volume): (V1)i = V1TV × e ηV1i (L). CL2 (clearance of peripheral compartment): (CL2)i = CL2TV × [1 - θCL2 - BODY AREA × (body area - 1.62)] × e ηCL2i (L/h). V2 (peripheral compartment): (V2 )i = V2TV × [1 - θ V2-bodyarea × (bodyarea-1.62)] × e ηV2i (L). The PPK parameters (RSD%) were CL1, V1, CL2 and V2 with values of 6.20 L/h (8.48%), 19.6 L (extremely small), 0.0172 L/h (50.9%) and 0.515 L (39.1%), respectively. Creatinine clearance and the number of methotrexate chemotherapy cycles before MTX infusion had a significant effect on the CL1, and body surface area had a significant effect on the CL2 and the V2 (P < 0. 01).

Conclusions: A good fit was derived for the PPK. The model could be used to provide guidance for MTX treatment and reduce adverse effects.

Show MeSH
Related in: MedlinePlus