Table 1.
Review of peginesatide doses and pharmacokinetic sampling times, by study.
Figure 1.
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.
Table 2.
Summary of categorical covariates and concomitant medications, by population group.
Table 3.
Patient demographics and laboratory characteristics at baseline, by population group.
Table 4.
Covariates evaluated on the PK and PD parameters of peginesatide.
Table 5.
Covariates evaluated on the PK and PD parameters of peginesatide in NONMEM using forward selection and backward elimination approach.
Figure 2.
Diagnostic goodness-of-fit plots for the final population PK model of peginesatide (2A-C:upper panel set) and for the final population PK-PD model of peginesatide (2D-F: lower panel set).
Upper left (2A): measured concentration versus predicted concentration; Upper middle (2B): measured concentration versus individual predicted concentration; Upper right (2C): weighted residuals versus predicted concentration. Lower left (2D): measured hemoglobin versus predicted hemoglobin; Lower middle (2E): measured hemoglobin versus individual predicted hemoglobin; lower right (2F): weighted residual versus predicted hemoglobin concentration.
Table 6.
Peginesatide parameter estimates and their associated precision for the final PK model, including bootstrap evaluation results.
Table 7.
Peginesatide parameter estimates and their associated precision for the final PK-PD Model, including bootstrap evaluation results.
Figure 3.
Prediction-corrected visual predictive checks for the final PK model of peginesatide following intravenous and subcutaneous dosing and the final PK-PD model of predicted hemoglobin levels.
Upper left: visual predictive check for peginesatide PK model following intravenous administration; Upper right: visual predictive check for peginesatide PK model following subcutaneous administration; Lower panel: visual predictive check for hemoglobin based on final population PK-PD model for peginesatide.
Figure 4.
Visual predictive check for the PK-PD model of peginesatide using traditional visual predictive check.
Figure 5.
Effect of PK covariates on simulated peginesatide plasma concentrations and hemoglobin levels in patients with chronic kidney disease on dialysis following 10 mg SC dose every 4 weeks for 52 weeks.
Upper panel: effect of PK covariates on simulated peginesatide plasma concentrations; Middle and lower panels: effect of PK covariates on simulated peginesatide hemoglobin concentrations. Note that in the panel for hemoglobin levels by ESAD, the effect is very low and, as such, the profiles overlap. Abbreviations: BMI = body mass index, ALP = alkaline phosphatase, TBIL = total bilirubin, CR = serum creatinine, ETHN = ethnicity, and ESAD = erythropoiesis-stimulating agent dose.
Figure 6.
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.