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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

Simulated concentration-time profile of peginesatide following administration of a single 5, 8, and 10 mg every 4 week IV (top panel) and SC (bottom panel) dose.EC50 values reflect the EC50 value estimated for the base PK-PD model.
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pone-0066422-g006: Simulated concentration-time profile of peginesatide following administration of a single 5, 8, and 10 mg every 4 week IV (top panel) and SC (bottom panel) dose.EC50 values reflect the EC50 value estimated for the base PK-PD model.

Mentions: Peginesatide administered SC has a model estimated bioavailability of 49.8%, which is similar to the range of 33% to 45% reported in studies conducted in healthy volunteers (unpublished data [AFX01_102, AFX01_103) as well as values reported for other ESAs [11]–[15]. Peginesatide, like other erythropoietins, appears to follow flip-flop pharmacokinetics [16] where the rate of absorption is slower than the rate of elimination. Following intravenous administration, peginesatide concentrations exceed the estimated EC50 (concentration required to obtain 50% of the maximum effect for hemoglobin) value, but subsequently decline, rapidly to values below the EC50 during the dosing interval. Following subcutaneous administration, the peak plasma concentrations of peginesatide are lower than those following intravenous administration; however, the plasma concentrations following subcutaneous administration remain sustained above the EC50 for a duration that is comparable to that of intravenous administration. Although the fraction of the dose absorbed from the extravascular compartment following subcutaneous dosing is approximately 50% that of intravenous dosing, subcutaneous dosing provides a similar hemoglobin response. This is further supported by the simulations performed using the final PK model as presented in Figure 6 where the time above EC50 was similar following IC and SQ every 4 weeks dosing of peginesatide.


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)

Simulated concentration-time profile of peginesatide following administration of a single 5, 8, and 10 mg every 4 week IV (top panel) and SC (bottom panel) dose.EC50 values reflect the EC50 value estimated for the base PK-PD model.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0066422-g006: Simulated concentration-time profile of peginesatide following administration of a single 5, 8, and 10 mg every 4 week IV (top panel) and SC (bottom panel) dose.EC50 values reflect the EC50 value estimated for the base PK-PD model.
Mentions: Peginesatide administered SC has a model estimated bioavailability of 49.8%, which is similar to the range of 33% to 45% reported in studies conducted in healthy volunteers (unpublished data [AFX01_102, AFX01_103) as well as values reported for other ESAs [11]–[15]. Peginesatide, like other erythropoietins, appears to follow flip-flop pharmacokinetics [16] where the rate of absorption is slower than the rate of elimination. Following intravenous administration, peginesatide concentrations exceed the estimated EC50 (concentration required to obtain 50% of the maximum effect for hemoglobin) value, but subsequently decline, rapidly to values below the EC50 during the dosing interval. Following subcutaneous administration, the peak plasma concentrations of peginesatide are lower than those following intravenous administration; however, the plasma concentrations following subcutaneous administration remain sustained above the EC50 for a duration that is comparable to that of intravenous administration. Although the fraction of the dose absorbed from the extravascular compartment following subcutaneous dosing is approximately 50% that of intravenous dosing, subcutaneous dosing provides a similar hemoglobin response. This is further supported by the simulations performed using the final PK model as presented in Figure 6 where the time above EC50 was similar following IC and SQ every 4 weeks dosing of peginesatide.

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