Pharmacokinetic and Pharmacodynamic Modeling of Recombinant Human Erythropoietin After Single and Multiple Doses in Healthy Volunteers

Ramakrishnan, Rohini; Cheung, Wing K.; Wacholtz, Mary C.; Minton, Nigel P.; Jusko, William J.

doi:10.1177/0091270004268411

Cited by 123 publications

(137 citation statements)

References 25 publications

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“…In contrast to the previous analysis [23], this analysis also includes hemoglobin data in the estimation procedure. The determined 'a SS ' value (0.797 days or 19.1 h) is approximately the same as a similar physiological parameter determined in cynomolgus monkeys of 14.95 h and in humans of 10.76 h [19,20].…”

Section: Discussion Cellular Productionsupporting

confidence: 79%

“…Analogous terminology used by other authors includes "lifespan" and "maturation time" [16][17][18][19][20][21][22][23]. Previous Epo-reticulocyte pharmacokinetic/pharmacodynamic (PK/PD) models have commonly assumed that all cells have a time invariant and common lifespan or maturation time (i.e., "point distribution") [16][17][18][19][20][21]. Recently, Epo-reticulocyte PK/ PD models have been presented that allow for a fixed (time invariant) distribution of cell lifespans [22].…”

Section: Introductionmentioning

confidence: 99%

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Pharmacodynamic analysis of time-variant cellular disposition: reticulocyte disposition changes in phlebotomized sheep

Freise

Widness

Schmidt

et al. 2007

J Pharmacokinet Pharmacodyn

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Most pharmacodynamic (PD) models of cellular response assume a time-invariant (i.e., constant) cellular disposition despite known changes in the disposition with time, such as the reticulocyte residence time in the systemic circulation during stress erythropoiesis. To account for changes in cellular disposition, a comprehensive PD model that involves endogenous erythropoietin (Epo), reticulocytes, and hemoglobin responses was developed in phlebotomized sheep that considers a time-variant reticulocyte residence time and allows for the simultaneous determination of changes in the cellular disposition and cellular production. Five sheep were phlebotomized to hemoglobin concentrations of approximately 4 g/dl. Epo concentrations, reticulocytes, and hemoglobin concentrations were frequently sampled for 5-7 days prior to and 25-30 days following the phlebotomy. Initial steady-state conditions were assumed and the time-variant reticulocyte residence time in the systemic circulation was semiparametrically represented using a constrained spline function. Hemoglobin production was modeled using a Hill function via an effect site compartment. The initial steady state reticulocyte residence time in the systemic circulation was estimated as 0.477 (0.100) (mean (SD)) days, which maximally increased 2.01-to 2.64-fold higher than the initial steady-state residence time 5.95 (0.899) days post-phlebotomy (P < 0.01). On average, the residence time returned to steady-state values 15.4 (2.36) days post-phlebotomy, which was not significantly different from the initial steady-state value (P > 0.05). The baseline hemoglobin production rate was estimated at 0.0929 (0.0472) g/kg/day and the maximum production rate under stress phlebotomy was estimated at 0.504 (0.0422) g/kg/day. These data indicate that endogenously released Epo under acute anemic conditions can increase hemoglobin production approximately 5-fold. The determined increase in reticulocyte residence time produced under stress erythropoiesis is similar to the commonly reported 2-to 3-fold increase observed in human patients.

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Section: Discussion Cellular Productionsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Pharmacodynamic analysis of time-variant cellular disposition: reticulocyte disposition changes in phlebotomized sheep

Freise

Widness

Schmidt

et al. 2007

J Pharmacokinet Pharmacodyn

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“…For an average 70-kg human, the estimated mean s.c. relative bioavailability increased from ∼48% at 0.75 µg kg −1 to ∼78% at 8.0 µg kg −1 , similar to the trend reported for rHuEPO [28]. Saturable injection site loss, which has been observed for many proteins including rHuEPO [29,30], and/or saturable degradation by proteolytic enzymes in the lymph may contribute to this phenomenon [31].…”

Section: Discussionsupporting

confidence: 66%

Population pharmacokinetics of darbepoetin alfa in healthy subjects

Agoram

Sutjandra

Sullivan

2006

Brit J Clinical Pharma

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AimTo develop and evaluate a population pharmacokinetic (PK) model of the long-acting erythropoiesis-stimulating protein, darbepoetin alfa in healthy subjects. MethodsPK profiles were obtained from 140 healthy subjects receiving single intravenous and/or single or multiple subcutaneous doses of darbepoetin alfa (0.75-8.0 µ g kg − 1 , or either 80 or 500 µ g). Data were analysed by a nonlinear mixed-effects modelling approach using NONMEM software. Influential covariates were identified by covariate analysis emphasizing parameter estimates and their confidence intervals, rather than stepwise hypothesis testing. The model was evaluated by comparing simulated profiles (obtained using the covariate model) to the observed profiles in a test dataset. ResultsThe population PK model, including first-order absorption, two-compartment disposition and first-order elimination, provided a good description of data. Modelling indicated that for a 70-kg human, the observed nearly twofold disproportionate doseexposure relationship at the 8.0 µ g kg − 1 -dose relative to the 0.75 µ g kg − 1 -dose may reflect changing relative bioavailability, which increased from ∼ 48% at 0.75 µ g kg − 1 to 78% at 8.0 µ g kg − 1 . The covariate analysis showed that increasing body weight may be related to increasing clearance and central compar tment volume, and that the absorption rate constant decreased with increasing age. The full covariate model performed adequately in a fixed-effects prediction test against an external dataset. ConclusionThe developed population PK model describes the inter-and intraindividual variability in darbepoetin alfa PK. The model is a suitable tool for predicting the PK response of darbepoetin alfa using clinically untested dosing regimens.

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“…Thus, the BU approach can serve as an exploratory tool in PK/PD analysis. Linear as well as the E max and sigmoid E max models have been proposed for EPO stimulation in a number of complex PK/PD analyses [6][7][8][9]41]. The BU analysis lends support to the use of the parametric E max stimulatory transduction model.…”

Section: Pd Transduction Functionmentioning

confidence: 99%

“…Several PK/PD models for assessing EPO stimulation of erythropoiesis have been developed [4][5][6][7]. However, these studies utilized exogenous r-HuEPO and did not investigate the physiology of endogenous EPO produced in response to anemia.…”

Section: Introductionmentioning

confidence: 99%

A ‘bottom‐up’ approach for endo‐PK/PD analysis

Neelakantan

Widness

Schmidt

et al. 2006

Biopharm & Drug Disp

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A 'bottom-up' PK/PD analysis approach employing system analysis principles of convolution/ deconvolution and special nonparametric estimation procedures is presented to resolve the complex 'endo-PK/PD' of the endogenous form of recombinant drugs using erythropoietin (EPO) as an example. A novel cellular deconvolution algorithm is presented that facilitates the identification of the functional relationship between the variables involved in EPO's complex PK/PD. Five sheep each underwent two phlebotomies spaced 4-6 weeks apart when their hemoglobin levels were reduced from 12 g/dl to 3-4 g/dl. EPO levels and reticulocyte counts were frequently sampled. The data were analysed using end-constrained cubic splines. The rate of reticulocyte production was determined using the novel deconvolution methodology. The erythroid progenitor cells activation rate by EPO was estimated from the reticulocyte production rate using a lag-time parameter which determines the delay in the reticulocyte appearance in the blood relative to the activation of erythroid progenitors. Hysteresis minimization combined with cellular deconvolution was employed to determine the population PK/PD transduction function relating the progenitor activation rate to EPO concentrations in a nonparametric manner without assuming a specific structure. The proposed approach provides a rational informative starting point for developing parametric PK/PD models to resolve the complex endo-PK/PD of recombinant drugs.

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Pharmacokinetic and Pharmacodynamic Modeling of Recombinant Human Erythropoietin After Single and Multiple Doses in Healthy Volunteers

Cited by 123 publications

References 25 publications

Pharmacodynamic analysis of time-variant cellular disposition: reticulocyte disposition changes in phlebotomized sheep

Pharmacodynamic analysis of time-variant cellular disposition: reticulocyte disposition changes in phlebotomized sheep

Population pharmacokinetics of darbepoetin alfa in healthy subjects

A ‘bottom‐up’ approach for endo‐PK/PD analysis

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