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Factors affecting the pharmacokinetics and pharmacodynamics of PEGylated liposomal irinotecan (IHL-305) in patients with advanced solid tumors.

Wu H, Infante JR, Keedy VL, Jones SF, Chan E, Bendell JC, Lee W, Kirschbrown WP, Zamboni BA, Ikeda S, Kodaira H, Rothenberg ML, Burris HA, Zamboni WC - Int J Nanomedicine (2015)

Bottom Line: Patients aged <60 years had a 1.3-fold higher ratio of percent decrease in monocytes at nadir to percent decrease in absolute neutrophil count at nadir as compared with patients aged ≥60 years.Patients with a higher percent decrease in monocytes at nadir have a decreased plasma exposure of sum total CPT-11.Interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 was associated with age, body composition, and monocytes.

View Article: PubMed Central - PubMed

Affiliation: UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.

ABSTRACT
IHL-305 is a PEGylated liposomal formulation of irinotecan (CPT-11). The objective of this study was to evaluate the factors associated with interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 in patients with advanced solid tumors. IHL-305 was administered intravenously once every 4 weeks as part of a Phase I study. Pharmacokinetic studies of the liposomal sum total CPT-11, released CPT-11, SN-38, SN-38G, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin, and 7-ethyl-10-[4-amino-1-piperidino]-carbonyloxycamptothecin in plasma were performed. Noncompartmental and compartmental pharmacokinetic analyses were conducted using pharmacokinetic data for sum total CPT-11. The pharmacokinetic variability of IHL-305 is associated with linear and nonlinear clearance. Patients whose age and body composition (ratio of total body weight to ideal body weight [TBW/IBW]) were greater than the median age and TBW/IBW of the study had a 1.7-fold to 2.6-fold higher ratio of released CPT-11 area under the concentration versus time curve (AUC) to sum total CPT-11 AUC. Patients aged <60 years had a 1.3-fold higher ratio of percent decrease in monocytes at nadir to percent decrease in absolute neutrophil count at nadir as compared with patients aged ≥60 years. There was an inverse relationship between patient age and percent decrease in monocytes at nadir, ie, younger patients have a higher percent decrease in monocytes. Patients with a higher percent decrease in monocytes at nadir have a decreased plasma exposure of sum total CPT-11. The pharmacokinetics and pharmacodynamics of IHL-305 are consistent with those of other PEGylated liposomal carriers. Interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 was associated with age, body composition, and monocytes.

No MeSH data available.


Related in: MedlinePlus

Relationship between two factors, age, and the ratio of TBW/IBW, and ratio of released CPT-11 AUC to sum total CPT-11 AUC.Notes: Patients are divided into four groups according to the median value of age and TBW/IBW. The size of each circle correlates with ratio of released CPT-11 AUC to sum total CPT-11 AUC in a patient at the specific age and ratio of true body weight to ideal body weight. The mean ± standard deviation values for the ratio of released CPT-11 AUC to sum total CPT-11 AUC were 0.0042±0.0028, 0.0038±0.0038, 0.0066±0.0084, and 0.0025±0.0013 in patients aged <60 years and TBW/IBW <1.16, patients aged ≥60 years and TBW/IBW <1.16, patients aged ≥60 years and TBW/IBW ≥1.16, and patients aged <60 years and TBW/IBW ≥1.16, respectively; CPT-11 is irinotecan; IHL-305 is a PEGylated liposomal formulation of irinotecan.Abbreviations: AUC, area under the concentration versus time curve; TBW/IBW, total body weight to ideal body weight.
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f2-ijn-10-1201: Relationship between two factors, age, and the ratio of TBW/IBW, and ratio of released CPT-11 AUC to sum total CPT-11 AUC.Notes: Patients are divided into four groups according to the median value of age and TBW/IBW. The size of each circle correlates with ratio of released CPT-11 AUC to sum total CPT-11 AUC in a patient at the specific age and ratio of true body weight to ideal body weight. The mean ± standard deviation values for the ratio of released CPT-11 AUC to sum total CPT-11 AUC were 0.0042±0.0028, 0.0038±0.0038, 0.0066±0.0084, and 0.0025±0.0013 in patients aged <60 years and TBW/IBW <1.16, patients aged ≥60 years and TBW/IBW <1.16, patients aged ≥60 years and TBW/IBW ≥1.16, and patients aged <60 years and TBW/IBW ≥1.16, respectively; CPT-11 is irinotecan; IHL-305 is a PEGylated liposomal formulation of irinotecan.Abbreviations: AUC, area under the concentration versus time curve; TBW/IBW, total body weight to ideal body weight.

Mentions: Based on our previous studies reporting both age and TBW/IBW ratio affecting the pharmacokinetic disposition of S-CKD602, we evaluated the relationship between these two factors and the pharmacokinetic disposition of IHL-305. The relationship between TBW/IBW and dose-normalized CPT-11 AUC (AUC/dose) in all patients is presented in Figure 1. Controlling for age, there was an inverse relationship between TBW/IBW ratio and AUC/dose (R2=0.12, P=0.41), whereby low TBW/IBW was associated with high AUC/dose in patients aged <60 years. The effect of age and TBW/IBW together on the ratio of released CPT-11 AUC to sum total CPT-11 AUC in all patients was evaluated using a bubble chart and is presented in Figure 2. Patients whose age and TBW/IBW were greater than the median of the study had a 1.7-fold to 2.6-fold higher ratio of released CPT-11 AUC to sum total CPT-11 AUC.


Factors affecting the pharmacokinetics and pharmacodynamics of PEGylated liposomal irinotecan (IHL-305) in patients with advanced solid tumors.

Wu H, Infante JR, Keedy VL, Jones SF, Chan E, Bendell JC, Lee W, Kirschbrown WP, Zamboni BA, Ikeda S, Kodaira H, Rothenberg ML, Burris HA, Zamboni WC - Int J Nanomedicine (2015)

Relationship between two factors, age, and the ratio of TBW/IBW, and ratio of released CPT-11 AUC to sum total CPT-11 AUC.Notes: Patients are divided into four groups according to the median value of age and TBW/IBW. The size of each circle correlates with ratio of released CPT-11 AUC to sum total CPT-11 AUC in a patient at the specific age and ratio of true body weight to ideal body weight. The mean ± standard deviation values for the ratio of released CPT-11 AUC to sum total CPT-11 AUC were 0.0042±0.0028, 0.0038±0.0038, 0.0066±0.0084, and 0.0025±0.0013 in patients aged <60 years and TBW/IBW <1.16, patients aged ≥60 years and TBW/IBW <1.16, patients aged ≥60 years and TBW/IBW ≥1.16, and patients aged <60 years and TBW/IBW ≥1.16, respectively; CPT-11 is irinotecan; IHL-305 is a PEGylated liposomal formulation of irinotecan.Abbreviations: AUC, area under the concentration versus time curve; TBW/IBW, total body weight to ideal body weight.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4334335&req=5

f2-ijn-10-1201: Relationship between two factors, age, and the ratio of TBW/IBW, and ratio of released CPT-11 AUC to sum total CPT-11 AUC.Notes: Patients are divided into four groups according to the median value of age and TBW/IBW. The size of each circle correlates with ratio of released CPT-11 AUC to sum total CPT-11 AUC in a patient at the specific age and ratio of true body weight to ideal body weight. The mean ± standard deviation values for the ratio of released CPT-11 AUC to sum total CPT-11 AUC were 0.0042±0.0028, 0.0038±0.0038, 0.0066±0.0084, and 0.0025±0.0013 in patients aged <60 years and TBW/IBW <1.16, patients aged ≥60 years and TBW/IBW <1.16, patients aged ≥60 years and TBW/IBW ≥1.16, and patients aged <60 years and TBW/IBW ≥1.16, respectively; CPT-11 is irinotecan; IHL-305 is a PEGylated liposomal formulation of irinotecan.Abbreviations: AUC, area under the concentration versus time curve; TBW/IBW, total body weight to ideal body weight.
Mentions: Based on our previous studies reporting both age and TBW/IBW ratio affecting the pharmacokinetic disposition of S-CKD602, we evaluated the relationship between these two factors and the pharmacokinetic disposition of IHL-305. The relationship between TBW/IBW and dose-normalized CPT-11 AUC (AUC/dose) in all patients is presented in Figure 1. Controlling for age, there was an inverse relationship between TBW/IBW ratio and AUC/dose (R2=0.12, P=0.41), whereby low TBW/IBW was associated with high AUC/dose in patients aged <60 years. The effect of age and TBW/IBW together on the ratio of released CPT-11 AUC to sum total CPT-11 AUC in all patients was evaluated using a bubble chart and is presented in Figure 2. Patients whose age and TBW/IBW were greater than the median of the study had a 1.7-fold to 2.6-fold higher ratio of released CPT-11 AUC to sum total CPT-11 AUC.

Bottom Line: Patients aged <60 years had a 1.3-fold higher ratio of percent decrease in monocytes at nadir to percent decrease in absolute neutrophil count at nadir as compared with patients aged ≥60 years.Patients with a higher percent decrease in monocytes at nadir have a decreased plasma exposure of sum total CPT-11.Interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 was associated with age, body composition, and monocytes.

View Article: PubMed Central - PubMed

Affiliation: UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.

ABSTRACT
IHL-305 is a PEGylated liposomal formulation of irinotecan (CPT-11). The objective of this study was to evaluate the factors associated with interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 in patients with advanced solid tumors. IHL-305 was administered intravenously once every 4 weeks as part of a Phase I study. Pharmacokinetic studies of the liposomal sum total CPT-11, released CPT-11, SN-38, SN-38G, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin, and 7-ethyl-10-[4-amino-1-piperidino]-carbonyloxycamptothecin in plasma were performed. Noncompartmental and compartmental pharmacokinetic analyses were conducted using pharmacokinetic data for sum total CPT-11. The pharmacokinetic variability of IHL-305 is associated with linear and nonlinear clearance. Patients whose age and body composition (ratio of total body weight to ideal body weight [TBW/IBW]) were greater than the median age and TBW/IBW of the study had a 1.7-fold to 2.6-fold higher ratio of released CPT-11 area under the concentration versus time curve (AUC) to sum total CPT-11 AUC. Patients aged <60 years had a 1.3-fold higher ratio of percent decrease in monocytes at nadir to percent decrease in absolute neutrophil count at nadir as compared with patients aged ≥60 years. There was an inverse relationship between patient age and percent decrease in monocytes at nadir, ie, younger patients have a higher percent decrease in monocytes. Patients with a higher percent decrease in monocytes at nadir have a decreased plasma exposure of sum total CPT-11. The pharmacokinetics and pharmacodynamics of IHL-305 are consistent with those of other PEGylated liposomal carriers. Interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 was associated with age, body composition, and monocytes.

No MeSH data available.


Related in: MedlinePlus