Limits...
A Population Pharmacokinetic and Pharmacodynamic Analysis of Peginesatide in Patients with Chronic Kidney Disease on Dialysis.

Naik H, Tsai MC, Fiedler-Kelly J, Qiu P, Vakilynejad M - PLoS ONE (2013)

Bottom Line: The relationship between peginesatide and hemoglobin plasma concentrations was best characterized by a modified precursor-dependent lifespan indirect response model.The estimate of maximal stimulatory effect of peginesatide on the endogenous production rate of progenitor cells (Emax) was 0.54.Several significant (P<0.005) covariates affected simulated peginesatide exposure by ≤36%.

View Article: PubMed Central - PubMed

Affiliation: Pharmacometrics, Takeda Global Research and Development, Inc., Deerfield, Illinois, United States of America.

ABSTRACT
Peginesatide (OMONTYS®) is an erythropoiesis-stimulating agent that was indicated in the United States for the treatment of anemia due to chronic kidney disease in adult patients on dialysis prior to its recent marketing withdrawal by the manufacturer. The objective of this analysis was to develop a population pharmacokinetic and pharmacodynamic model to characterize the time-course of peginesatide plasma and hemoglobin concentrations following intravenous and subcutaneous administration. Plasma samples (n = 2,665) from 672 patients with chronic kidney disease (on or not on dialysis) and hemoglobin samples (n = 18,857) from 517 hemodialysis patients (subset of the 672 patients), were used for pharmacokinetic-pharmacodynamic model development in NONMEM VI. The pharmacokinetic profile of peginesatide was best described by a two-compartment model with first-order absorption and saturable elimination. The relationship between peginesatide and hemoglobin plasma concentrations was best characterized by a modified precursor-dependent lifespan indirect response model. The estimate of maximal stimulatory effect of peginesatide on the endogenous production rate of progenitor cells (Emax) was 0.54. The estimate of peginesatide drug concentration required for 50% of maximal response (EC50) estimates was 0.4 µg/mL. Several significant (P<0.005) covariates affected simulated peginesatide exposure by ≤36%. Based upon ≤0.2 g/dL effects on simulated hemoglobin levels, none were considered clinically relevant.

No MeSH data available.


Related in: MedlinePlus

Schematic of two-compartment, precursor-dependent, lifespan indirect response population PK/PD model for peginesatide following subcutaneous or intravenous administration.Abbreviations: SC = subcutaneous; Ka = Absorption rate constant (1/hr); IV = intravenous; Q = Apparent distribution clearance from the central to the peripheral compartment (mL/kg/hr); V3 =  Peripheral volume of distribution; V2 =  Central volume of distribution; Vmax = Maximum rate of elimination (ng/mL/hr); KM = Concentration needed to reach 50% of Vmax (ng/mL); C = Peginesatide serum concentration (ng/mL); Hgb = Hemoglobin (g/dL); Hgb1–7 =  Transit Compartment; Emax = Maximum stimulatory effect of peginesatide on progenitor cell production; EC50 =  Peginesatide serum concentration necessary to stimulate progenitor cell production rate at half of the maximum response (ng/mL); K0 =  Endogenous production rate constant of progenitor cells; PRC = Precursor cell compartment; K1 =  First-order transition rate constant from precursor cell to red blood cell; KT = First-order rate constant between the aging compartments; NRBC/MTT = Life span of red blood cells.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3686692&req=5

pone-0066422-g001: Schematic of two-compartment, precursor-dependent, lifespan indirect response population PK/PD model for peginesatide following subcutaneous or intravenous administration.Abbreviations: SC = subcutaneous; Ka = Absorption rate constant (1/hr); IV = intravenous; Q = Apparent distribution clearance from the central to the peripheral compartment (mL/kg/hr); V3 =  Peripheral volume of distribution; V2 =  Central volume of distribution; Vmax = Maximum rate of elimination (ng/mL/hr); KM = Concentration needed to reach 50% of Vmax (ng/mL); C = Peginesatide serum concentration (ng/mL); Hgb = Hemoglobin (g/dL); Hgb1–7 =  Transit Compartment; Emax = Maximum stimulatory effect of peginesatide on progenitor cell production; EC50 =  Peginesatide serum concentration necessary to stimulate progenitor cell production rate at half of the maximum response (ng/mL); K0 =  Endogenous production rate constant of progenitor cells; PRC = Precursor cell compartment; K1 =  First-order transition rate constant from precursor cell to red blood cell; KT = First-order rate constant between the aging compartments; NRBC/MTT = Life span of red blood cells.

Mentions: A sequential PK-PD modeling approach was used to characterize the time-course of peginesatide plasma concentrations (CP) and hemoglobin levels following IV and SC peginesatide administration to hemodialysis patients. A modified precursor-dependent LIDR model with stimulation of the production rate of precursor cells as described in Equation 1 and Figure 1 was used as the base PK-PD model:Where:


A Population Pharmacokinetic and Pharmacodynamic Analysis of Peginesatide in Patients with Chronic Kidney Disease on Dialysis.

Naik H, Tsai MC, Fiedler-Kelly J, Qiu P, Vakilynejad M - PLoS ONE (2013)

Schematic of two-compartment, precursor-dependent, lifespan indirect response population PK/PD model for peginesatide following subcutaneous or intravenous administration.Abbreviations: SC = subcutaneous; Ka = Absorption rate constant (1/hr); IV = intravenous; Q = Apparent distribution clearance from the central to the peripheral compartment (mL/kg/hr); V3 =  Peripheral volume of distribution; V2 =  Central volume of distribution; Vmax = Maximum rate of elimination (ng/mL/hr); KM = Concentration needed to reach 50% of Vmax (ng/mL); C = Peginesatide serum concentration (ng/mL); Hgb = Hemoglobin (g/dL); Hgb1–7 =  Transit Compartment; Emax = Maximum stimulatory effect of peginesatide on progenitor cell production; EC50 =  Peginesatide serum concentration necessary to stimulate progenitor cell production rate at half of the maximum response (ng/mL); K0 =  Endogenous production rate constant of progenitor cells; PRC = Precursor cell compartment; K1 =  First-order transition rate constant from precursor cell to red blood cell; KT = First-order rate constant between the aging compartments; NRBC/MTT = Life span of red blood cells.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3686692&req=5

pone-0066422-g001: Schematic of two-compartment, precursor-dependent, lifespan indirect response population PK/PD model for peginesatide following subcutaneous or intravenous administration.Abbreviations: SC = subcutaneous; Ka = Absorption rate constant (1/hr); IV = intravenous; Q = Apparent distribution clearance from the central to the peripheral compartment (mL/kg/hr); V3 =  Peripheral volume of distribution; V2 =  Central volume of distribution; Vmax = Maximum rate of elimination (ng/mL/hr); KM = Concentration needed to reach 50% of Vmax (ng/mL); C = Peginesatide serum concentration (ng/mL); Hgb = Hemoglobin (g/dL); Hgb1–7 =  Transit Compartment; Emax = Maximum stimulatory effect of peginesatide on progenitor cell production; EC50 =  Peginesatide serum concentration necessary to stimulate progenitor cell production rate at half of the maximum response (ng/mL); K0 =  Endogenous production rate constant of progenitor cells; PRC = Precursor cell compartment; K1 =  First-order transition rate constant from precursor cell to red blood cell; KT = First-order rate constant between the aging compartments; NRBC/MTT = Life span of red blood cells.
Mentions: A sequential PK-PD modeling approach was used to characterize the time-course of peginesatide plasma concentrations (CP) and hemoglobin levels following IV and SC peginesatide administration to hemodialysis patients. A modified precursor-dependent LIDR model with stimulation of the production rate of precursor cells as described in Equation 1 and Figure 1 was used as the base PK-PD model:Where:

Bottom Line: The relationship between peginesatide and hemoglobin plasma concentrations was best characterized by a modified precursor-dependent lifespan indirect response model.The estimate of maximal stimulatory effect of peginesatide on the endogenous production rate of progenitor cells (Emax) was 0.54.Several significant (P<0.005) covariates affected simulated peginesatide exposure by ≤36%.

View Article: PubMed Central - PubMed

Affiliation: Pharmacometrics, Takeda Global Research and Development, Inc., Deerfield, Illinois, United States of America.

ABSTRACT
Peginesatide (OMONTYS®) is an erythropoiesis-stimulating agent that was indicated in the United States for the treatment of anemia due to chronic kidney disease in adult patients on dialysis prior to its recent marketing withdrawal by the manufacturer. The objective of this analysis was to develop a population pharmacokinetic and pharmacodynamic model to characterize the time-course of peginesatide plasma and hemoglobin concentrations following intravenous and subcutaneous administration. Plasma samples (n = 2,665) from 672 patients with chronic kidney disease (on or not on dialysis) and hemoglobin samples (n = 18,857) from 517 hemodialysis patients (subset of the 672 patients), were used for pharmacokinetic-pharmacodynamic model development in NONMEM VI. The pharmacokinetic profile of peginesatide was best described by a two-compartment model with first-order absorption and saturable elimination. The relationship between peginesatide and hemoglobin plasma concentrations was best characterized by a modified precursor-dependent lifespan indirect response model. The estimate of maximal stimulatory effect of peginesatide on the endogenous production rate of progenitor cells (Emax) was 0.54. The estimate of peginesatide drug concentration required for 50% of maximal response (EC50) estimates was 0.4 µg/mL. Several significant (P<0.005) covariates affected simulated peginesatide exposure by ≤36%. Based upon ≤0.2 g/dL effects on simulated hemoglobin levels, none were considered clinically relevant.

No MeSH data available.


Related in: MedlinePlus