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Development of a physiologically based pharmacokinetic model of actinomycin D in children with cancer.

Walsh C, Bonner JJ, Johnson TN, Neuhoff S, Ghazaly EA, Gribben JG, Boddy AV, Veal GJ - Br J Clin Pharmacol (2016)

Bottom Line: Simulated values for actinomycin D AUC0-26h and clearance in infants aged 0-12 months ranged from 104 to 115 ng h ml(-1) and 3.5-3.8 l h(-1) , respectively.However, additional independent data from neonates and infants is needed for further validation.Physiological differences between paediatric cancer patients and healthy children also need to be further characterized and incorporated into PBPK models.

View Article: PubMed Central - PubMed

Affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.

No MeSH data available.


Related in: MedlinePlus

Visual predictive check showing the systemic concentration of Act D vs. time for clinical patients (circles) and mean (black line), 5th and 95th percentile (grey lines) of the simulated patient systemic Act D concentration. (A) Simulated and mean study patient Act D systemic concentration over time, 10–20 year old administered 1.29 mg m−2; (B) Simulated and mean study patient Act D systemic concentration over time, 1–6 year old administered 0.6 mg m−2
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bcp12878-fig-0003: Visual predictive check showing the systemic concentration of Act D vs. time for clinical patients (circles) and mean (black line), 5th and 95th percentile (grey lines) of the simulated patient systemic Act D concentration. (A) Simulated and mean study patient Act D systemic concentration over time, 10–20 year old administered 1.29 mg m−2; (B) Simulated and mean study patient Act D systemic concentration over time, 1–6 year old administered 0.6 mg m−2

Mentions: The final drug model incorporated clinical renal and biliary clearance values and an additional systemic clearance value to account for the differences observed in cumulative renal/biliary clearance and total observed systemic clearance (see Table 2 for values). Simulations using these clearance values were superimposed on the observed data (Figure 3A). Comparison of AUC0‐26h in observed and simulated patients within the 10–20‐year‐old group showed all mean predictions to be within two‐fold of the mean observed values. The fold variability compared to observed values ranged from 1.2‐fold to 1.6‐fold, depending on dose group (Figure 3B). The model prediction was compared to data obtained from an adult PK study dataset 6. The visual predictive check (Figure 4) showed that the simulated mean concentration–time profile fell within the observed results; however, the simulation failed to capture the full variability of the observed data (observed AUC0‐26h SD: 595.33 ng h ml−1, simulated AUC0‐26h SD: 9.04 ng h ml−1).


Development of a physiologically based pharmacokinetic model of actinomycin D in children with cancer.

Walsh C, Bonner JJ, Johnson TN, Neuhoff S, Ghazaly EA, Gribben JG, Boddy AV, Veal GJ - Br J Clin Pharmacol (2016)

Visual predictive check showing the systemic concentration of Act D vs. time for clinical patients (circles) and mean (black line), 5th and 95th percentile (grey lines) of the simulated patient systemic Act D concentration. (A) Simulated and mean study patient Act D systemic concentration over time, 10–20 year old administered 1.29 mg m−2; (B) Simulated and mean study patient Act D systemic concentration over time, 1–6 year old administered 0.6 mg m−2
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4834588&req=5

bcp12878-fig-0003: Visual predictive check showing the systemic concentration of Act D vs. time for clinical patients (circles) and mean (black line), 5th and 95th percentile (grey lines) of the simulated patient systemic Act D concentration. (A) Simulated and mean study patient Act D systemic concentration over time, 10–20 year old administered 1.29 mg m−2; (B) Simulated and mean study patient Act D systemic concentration over time, 1–6 year old administered 0.6 mg m−2
Mentions: The final drug model incorporated clinical renal and biliary clearance values and an additional systemic clearance value to account for the differences observed in cumulative renal/biliary clearance and total observed systemic clearance (see Table 2 for values). Simulations using these clearance values were superimposed on the observed data (Figure 3A). Comparison of AUC0‐26h in observed and simulated patients within the 10–20‐year‐old group showed all mean predictions to be within two‐fold of the mean observed values. The fold variability compared to observed values ranged from 1.2‐fold to 1.6‐fold, depending on dose group (Figure 3B). The model prediction was compared to data obtained from an adult PK study dataset 6. The visual predictive check (Figure 4) showed that the simulated mean concentration–time profile fell within the observed results; however, the simulation failed to capture the full variability of the observed data (observed AUC0‐26h SD: 595.33 ng h ml−1, simulated AUC0‐26h SD: 9.04 ng h ml−1).

Bottom Line: Simulated values for actinomycin D AUC0-26h and clearance in infants aged 0-12 months ranged from 104 to 115 ng h ml(-1) and 3.5-3.8 l h(-1) , respectively.However, additional independent data from neonates and infants is needed for further validation.Physiological differences between paediatric cancer patients and healthy children also need to be further characterized and incorporated into PBPK models.

View Article: PubMed Central - PubMed

Affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.

No MeSH data available.


Related in: MedlinePlus