Pharmacodynamic Age Structured Population Model For Cell Trafficking.

OBJECTIVES: Cell trafficking encompasses movement of the immune system cells (e.g., granulocytes, lymphocytes) between the blood and the extravascular tissues (e.g., lymph nodes). Corticosteroids are known to suppress cell trafficking. The age-structured cell population models introduce the transit time as a structure that allows one to quantify the distribution of times the immune cells spend in the blood and the extravascular tissues. The objective of this work is to develop an age-structured cell population model describing drug effects on cell trafficking and to implement the model in pharmacometric software to enable parameter estimation and simulations. METHODS: We adopted the well-known McKendrick age-structured population model to describe the age distributions in two cell populations: blood cells and cells in the extravascular space. The hazard of cell recirculation from the extravascular tissues was age dependent and described by the Weibull function with the shape ν and scale ß parameters. The drug effect on cell trafficking was modeled as the product of the Emax function of the drug plasma concentration and the Weibull hazard. The model was implemented in NONMEM 7.5.1. The model was applied to the basophil data in 34 healthy subjects who received a single intramuscular or oral dose of 6 mg dexamethasone (DEX). A recently published pharmacokinetic model was applied to describe DEX plasma concentration. Typical values of parameter estimates were further used to simulate the DEX effect of the basophil mean transit time in the extravascular tissues. RESULTS: Simulations of basophil time courses for varying ν demonstrated that the rebound in the blood count data following drug administration is only possible for ν >1. The estimates of model parameters were ν = 3.02, ß = 0.00863 1/h, and IC50 = 7.47 ng/mL. The calculated baseline mean transit times of basophils in the blood 7.2 h and extravascular tissues 104.9 h agree with the values reported in the literature. CONCLUSIONS: We introduced an age-structured population model to describe cell trafficking between the blood and extravascular tissues. The model was adopted to account for the inhibitory drug effect on the cell recirculation. We showed that the age structure is essential to explain the rebound observed in the blood count response to a single dose drug administration. The model was validated using the basophil responses to DEX treatment in healthy subjects.

Novel Combination of Erythropoietin and Romiplostim to Treat Chemotherapy-Induced Anemia and Thrombocytopenia via Pharmacodynamic Interaction on Hematopoietic Stem and Progenitor Cells.

Chemotherapy-induced anemia and thrombocytopenia (CIAT) in cancer patients are often caused by the damage of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow. We have previously shown that romiplostim, a thrombopoietin receptor agonist that could stimulate the expansion of HSPCs, could synergize with recombinant human erythropoietin (rHuEPO) to promote erythropoiesis in addition to stimulating platelet production, whereas rHuEPO could influence the platelet count through stem cell competition. Therefore, we hypothesize that a combination of romiplostim with rHuEPO can alleviate CIAT simultaneously, while minimizing the risk of thrombosis. In this study, we demonstrated that rHuEPO and romiplostim exhibit no stimulatory effects on the growth and invasion of LA-7 cancer cells both in vitro and in vivo. Using a rat model with carboplatin-induced anemia and thrombocytopenia, we showed that the red blood cells and hemoglobin concentration recovered faster, and the secondary thrombocytopenia was alleviated in the rHuEPO and romiplostim combination therapy groups compared with the corresponding rHuEPO monotherapy groups. The rebound phenomenon of platelets was inhibited compared with the romiplostim monotherapy group. In vitro study further demonstrated that romiplostim expands HSPCs and synergizes with rHuEPO to promote erythropoiesis, while rHuEPO inhibited megakaryopoiesis. Furthermore, we developed a mechanism-based pharmacokinetic-pharmacodynamic model to quantify the effects of the two drugs. This study suggests that rHuEPO and romiplostim combination therapy can treat CIAT simultaneously in rats while minimizing the risk of thrombosis, indicating that combination therapy might be superior to monotherapy in the supportive therapy of cancer patients undergoing chemotherapy.

A Population Model of Time-Dependent Changes in Serum Creatinine in (Near)term Neonates with Hypoxic-Ischemic Encephalopathy During and After Therapeutic Hypothermia.

The objective was to apply a population model to describe the time course and variability of serum creatinine (sCr) in (near)term neonates with moderate to severe encephalopathy during and after therapeutic hypothermia (TH). The data consisted of sCr observations up to 10 days of postnatal age in neonates who underwent TH during the first 3 days after birth. Available covariates were birth weight (BWT), gestational age (GA), survival, and acute kidney injury (AKI). A previously published population model of sCr kinetics in neonates served as the base model. This model predicted not only sCr but also the glomerular filtration rate normalized by its value at birth (GFR/GFR0). The model was used to compare the TH neonates with a reference full term non-asphyxiated population of neonates. The estimates of the model parameters had good precision and showed high between subject variability. AKI influenced most of the estimated parameters denoting a strong impact on sCr kinetics and GFR. BWT and GA were not significant covariates. TH transiently increased [Formula: see text] in TH neonates over the first days compared to the reference group. Asphyxia impacted not only GFR, but also the [Formula: see text] synthesis rate. We also observed that AKI neonates exhibit a delayed onset of postnatal GFR increase and have a higher [Formula: see text] synthesis rate compared to no-AKI patients. Our findings show that the use of [Formula: see text] as marker of renal function in asphyxiated neonates treated with TH to guide dose selection for renally cleared drugs is challenging, while we captured the postnatal sCr patterns in this specific population.

Minimal physiologically-based hybrid model of pharmacokinetics in pregnant women: Application to antenatal corticosteroids.

Minimal physiologically-based pharmacokinetic (mPBPK) models are an alternative to full physiologically-based pharmacokinetic (PBPK) models as they offer reduced complexity while maintaining the physiological interpretation of key model components. Full PBPK models have been developed for pregnancy, but a mPBPK model eases the ability to perform a "top-down" meta-analysis melding all available pharmacokinetic (PK) data in the mother and fetus. Our hybrid mPBPK model consists of mPBPK models for the mother and fetus with connection by the placenta. This model was applied to describe the rich PK data of antenatal corticosteroid betamethasone (BET) jointly with the limited data for dexamethasone (DEX) in the mother and fetus. Physiologic model parameters were obtained from the literature while drug-dependent parameters were estimated by the simultaneous fitting of all available data for DEX and BET. Maternal clearances of DEX and BET confirmed the literature values, and the expected fetal-to-maternal plasma ratios ranged from 0.3 to 0.4 for both drugs. Simulations of maternal plasma concentrations for the dosing regimens of BET and DEX recommended by the World Health Organization based on our findings revealed up to 60% lower exposures than found in nonpregnant women and offers a means of devising alternative dosing regimens. Our hybrid mPBPK model and meta-analysis approach could facilitate assessment of other classes of drugs indicated for the treatment of pregnant women.

Scaling Pharmacodynamics from Rats to Humans to Support Erythropoietin and Romiplostim Combination Therapy to Treat Erythropoietin-Resistant Anemia.

Recombinant human erythropoietin (rHuEPO) is one of the most effective drugs for the treatment of anemia in patients with chronic kidney disease. However, EPO-resistance is an important contributor to the increased risk of adverse effects. We previously showed that EPO treatment could induce precursor cell depletion, resulting in EPO-resistance. We further found that the combination of EPO with romiplostim, a thrombopoietin receptor agonist that can stimulate the expansion of hematopoietic stem cells, can treat EPO-resistance. In this study, we performed interspecies pharmacodynamic (PD) scaling of this combination therapy for human dose prediction. The pharmacokinetic parameters of both rHuEPO and romiplostim in humans were obtained from previous studies. The PD parameters obtained in rats were scaled to humans using allometric equations. The relationship between PD parameters of the megakaryocyte lineage from rats, monkeys, and humans was in agreement with those from the literature on allometric scaling. The PD response was translated to humans based on allometric scaling and agreed with the observed data. These parameters were used to simulate hemoglobin and platelet response in humans. RHuEPO 50 IU/kg thrice weekly and romiplostim 1 µg/kg once every 4 weeks from the second week is the recommended combination dosing regimen according to the model prediction. Our work successfully scaled the PD of rHuEPO and romiplostim monotherapy from rats to humans. The predicted dosing regimen of each drug in the combination therapy is less intensive than the approved starting dose of each drug, which supports additional evaluations of the combination therapy in humans.

Developmental pharmacokinetics of indomethacin in preterm neonates: Severely decreased drug clearance in the first week of life.

Indomethacin is used commonly in preterm neonates for the prevention of intracranial hemorrhage and closure of an abnormally open cardiac vessel. Due to biomedical advances, the infants who receive this drug in the neonatal intensive care unit setting have become younger, smaller, and less mature (more preterm) at the time of treatment. To develop a pharmacokinetics (PK) model to aid future dosing, we designed a prospective cohort study to characterize indomethacin PK in a dynamically changing patient population. A population PK base model was created using NONMEM, and a covariate model was developed in a primary development cohort and subsequently was tested for accuracy in a validation cohort. Postnatal age was a significant covariate for hepatic clearance (CLH ) and renal clearance (CLR ). The typical value of the total clearance (CL, the sum of CLR and CLH ) was 3.09 ml/h and expressed as CL/WTmedian  = 3.96 ml/h/kg, where WTmedian is the median body weight. The intersubject variability of CLR and CLH were 61% and 207%, respectively. The typical value of the volume of distribution Vp  = 366 ml (Vp /WTmedian  = 470 ml/kg), and its intersubject variability was 38.8%. Half-life was 82.1 h. Compared with more mature and older preterm populations studied previously, indomethacin CL is considerably lower in this contemporary population. Model-informed precision dosing incorporating important covariates other than weight alone offers an opportunity to individualize dosing in a susceptible patient undergoing rapid change.

Pharmacodynamic model of slow reversible binding and its applications in pharmacokinetic/pharmacodynamic modeling: review and tutorial.

Therapeutic responses of most drugs are initiated by the rate and degree of binding to their receptors or targets. The law of mass action describes the rate of drug-receptor complex association (kon) and dissociation (koff) where the ratio koff/kon is the equilibrium dissociation constant (Kd). Drugs with slow reversible binding (SRB) often demonstrate delayed onset and prolonged pharmacodynamic effects. This report reviews evidence for drugs with SRB features, describes previous pharmacokinetic/pharmacodynamic (PK/PD) modeling efforts of several such drugs, provides a tutorial on the mathematics and properties of SRB models, demonstrates applications of SRB models to additional compounds, and compares PK/PD fittings of SRB with other mechanistic models. We identified and summarized 52 drugs with in vitro-confirmed SRB from a PubMed literature search. Simulations with a SRB model and observed PK/PD profiles showed delayed and prolonged responses and that increasing doses/kon or decreasing koff led to greater expected maximum effects and a longer duration of effects. Recession slopes for return of responses to baseline after single doses were nearly linear with an inflection point that approaches a limiting value at larger doses. The SRB model newly captured literature data for the antihypertensive effects of candesartan and antiallergic effects of noberastine. Their PD profiles could also be fitted with indirect response and biophase models with minimal differences. The applicability of SRB models is probably commonplace, but underappreciated, owing to the need for in vitro confirmation of binding kinetics and the similarity of PK/PD profiles to models with other mechanistic determinants.

Dynamics of Erythroferrone Response to Erythropoietin in Rats.

Background: Erythroferrone (ERFE) is a hormone identified recently as a master regulator connecting iron homeostasis and erythropoiesis. Serum ERFE concentrations significantly increase in animals and humans with normal or impaired kidney function after receiving exogenous erythropoiesis-stimulating agents (ESAs), which suggests it might be a predictive factor for erythropoiesis. To evaluate whether ERFE is an early, sensitive biomarker for long-term erythropoietic effects of ESAs, we investigated the relationship between ERFE dynamics and time courses of major erythropoietic responses to ESA treatment. Methods: Healthy rats received single dose and multiple doses (thrice a week for 2 weeks) of recombinant human erythropoietin (rHuEPO) at three dose levels (100, 450, and 1350 IU/kg) intravenously. The rHuEPO and ERFE concentrations in plasma were determined at a series of time points after dosing. Erythropoietic effects including red blood cell count and hemoglobin concentrations were continuously monitored for 24 days (single dose) or 60 days (multiple doses). The expansion of erythroblasts in bone marrow was quantified by flow cytometry analysis. Results: ERFE significantly increased within a few hours and return to baseline at 24 h after rHuEPO treatment. The ERFE response was enhanced after repeated treatment, which was consistent with the observed expansion of erythroblasts in the bone marrow. In addition, the dynamics of ERFE showed double peaks at approximately 2 and 10 h after rHuEPO stimulation, and the ERFE baseline displayed a significant circadian rhythm. There was a strong positive correlation between peak values of short-term ERFE responses and the long-term hemoglobin responses. Conclusion: The stimulated release of ERFE is a rapid process within 24 h. The second peak in the ERFE response to rHuEPO suggests the presence of a feedback mechanism counterregulating the ESA stimulation. The early increase of ERFE at 2 h appears to be a predictor of the hemoglobin response at 14 days after single dose of rHuEPO. Under multiple-dose regimen, the enhanced ERFE responses still correlate with the peak hemoglobin responses. The ERFE baseline also exhibits a circadian rhythm.

Fate Determination Role of Erythropoietin and Romiplostim in the Lineage Commitment of Hematopoietic Progenitors.

Erythropoietin (EPO) and thrombopoietin (TPO) have long been known to promote erythropoiesis and megakaryopoiesis, respectively. However, the fate-changing role of EPO and TPO on megakaryocyte-erythroid progenitors (MEPs) to develop along the erythroid versus megakaryocyte lineage remains unclear. We have previously shown that EPO may have a fate-changing role because EPO treatment could induce progenitor cells depletion and result in EPO resistance. Therefore, we hypothesize that a combination of romiplostim, a TPO receptor agonist that could stimulate the expansion of progenitors, with EPO can treat EPO resistance. Using rats with anemia due to chronic kidney disease, we demonstrated that romiplostim synergized with EPO to promote red blood cells production whereas EPO inhibited platelet production in a dose-dependent manner to reduce the risk of thrombosis. Corroborating findings from in vivo, in vitro experiments demonstrated that romiplostim expanded hematopoietic stem cells and stimulated megakaryopoiesis whereas EPO drove the progenitors toward an erythroid fate. We further developed a novel pharmacokinetic-pharmacodynamic model to quantify the effects of EPO and romiplostim on megakaryopoiesis and erythropoiesis simultaneously. The modeling results demonstrated that EPO increased the differentiation rate of MEPs into burst-forming unit-erythroid cells up to 22-fold, indicating that the slight increase of MEPs induced by romiplostim could be further amplified and recruited by EPO to promote erythropoiesis. The data herein support that romiplostim in combination with EPO can treat EPO resistance. SIGNIFICANCE STATEMENT: This study clarified that erythropoietin (EPO) drives the fate of megakaryocyte-erythroid progenitors (MEPs) toward the erythroid lineage, thus reducing their megakaryocyte (MK) lineage commitment, whereas romiplostim, a thrombopoietin receptor agonist, stimulates megakaryopoiesis through the MK-committed progenitor and MEP bifurcation pathways simultaneously. These findings support an innovative combination of romiplostim and EPO to treat EPO-resistant anemia because the combination therapy further promotes erythropoiesis compared to EPO monotherapy and inhibits platelet production compared to romiplostim monotherapy.

Multiscale model of hepatitis C virus dynamics in plasma and liver following combination therapy.

This work explores the application of a physiologically structured population (PSP) framework in modeling hepatitis C virus (HCV) kinetics. To do so, a model was developed for the viral RNA load in plasma and liver as observed in 15 patients treated with a combination therapy of pegylated interferon, ribavirin, and telaprevir. By including both intracellular and extracellular processes of the HCV lifecycle, the model provided a description of the treatment effect on the intracellular HCV lifecycle. Combining PSP models with a nonlinear mixed effects approach in a single model permits a natural inclusion of the direct-acting antiviral effect on intracellular processes, which can then be integrated with the viral kinetics within the host while accounting for the interindividual variability between patients. This should allow an exploration of the treatment effect within the entire chronic HCV-infected population.

Delay differential equations based models in NONMEM.

Delay differential equations (DDEs) are commonly used in pharmacometric models to describe delays present in pharmacokinetic and pharmacodynamic data analysis. Several DDE solvers have been implemented in NONMEM 7.5 for the first time. Two of them are based on algorithms already applied elsewhere, while others are extensions of existing ordinary differential equations (ODEs) solvers. The purpose of this tutorial is to introduce basic concepts underlying DDE based models and to show how they can be developed using NONMEM. The examples include previously published DDE models such as logistic growth, tumor growth inhibition, indirect response with precursor pool, rheumatoid arthritis, and erythropoiesis-stimulating agents. We evaluated the accuracy of NONMEM DDE solvers, their ability to handle stiff problems, and their performance in parameter estimation using both first-order conditional estimation (FOCE) and the expectation-maximization (EM) method. NONMEM control streams and excerpts from datasets are provided for all discussed examples. All DDE solvers provide accurate and precise solutions with the number of significant digits controlled by the error tolerance parameters. For estimation of population parameters, the EM method is more stable than FOCE regardless of the DDE solver.

Population Model of Serum Creatinine as Time-Dependent Covariate in Neonates.

Serum creatinine (sCr) is a commonly measured biomarker to estimate glomerular filtration rate (GFR) and therefore widely used as a covariate in population pharmacokinetic models of renally excreted drugs. In neonates, sCr dynamically changes during the first few weeks after birth. Missing covariates are a common problem in pharmacokinetic modeling of neonates due to the limited availability of blood sampling in number and volume. The objective of this work is to develop a parsimonious population model describing time courses of sCr in neonates with the intent to be incorporated into pharmacokinetic models of various drugs where sCr values are sparse or missing. The data for model development consisted of sCr measurements in 1080 newborns with a gestational age of 24-42 weeks. The model is based on a pharmacokinetic model of sCr that involves GFR, backflow of creatinine from the renal tubules, and urinary flow. Gestational age is the only covariate explaining between-subject variability of sCr. The model adequately describes distinct features of the sCr time course such as a peak and decline to a plateau. For a neonate with a GA of 35 weeks, the typical value of sCr at birth was 0.584 mg/dL, the peak (0.794 mg/dL) occurred 2.3 days after birth, to reach a plateau of 0.255 mg/dL approximately after 24.7 days. Model simulations reveal that in neonates with a similar postnatal age, sCr decreases with increasing GA. In summary, our model is designed to be a part of full random effects pharmacokinetic models where sCr is a significant covariate.

A quantitative systems pharmacology model of hyporesponsiveness to erythropoietin in rats.

Recombinant human erythropoietin (rHuEPO) is effective in managing chronic kidney disease and chemotherapy-induced anemia. However, hyporesponsiveness to rHuEPO treatment was reported in about 10% of the patients. A decreased response in rats receiving a single or multiple doses of rHuEPO was also observed. In this study, we aimed to develop a quantitative systems pharmacology (QSP) model to examine hyporesponsiveness to rHuEPO in rats. Pharmacokinetic (PK) and pharmacodynamic (PD) data after a single intravenous dose of rHuEPO (100 IU/kg) was obtained from a previous study (Yan et al. in Pharm Res, 30:1026-1036, 2013) including rHuEPO plasma concentrations, erythroid precursors counts in femur bone marrow and spleen, reticulocytes (RETs), red blood cells (RBCs), and hemoglobin (HGB) in circulation. Parameter values were obtained from literature or calibrated with experimental data. Global sensitivity analysis and model-based simulations were performed to assess parameter sensitivity and hyporesponsiveness. The final QSP model adequately characterizes time courses of rHuEPO PK and nine PD endpoints in both control and treatment groups simultaneously. The model indicates that negative feedback regulation, neocytolysis, and depletion of erythroid precursors are major factors leading to hyporesponsiveness to rHuEPO treatment in rats.

Population pharmacodynamic modeling of intramuscular and oral dexamethasone and betamethasone effects on six biomarkers with circadian complexities in Indian women.

Population pharmacokinetic/pharmacodynamic (PK/PD) analysis was performed for extensive data for differing dosage forms and routes for dexamethasone (DEX) and betamethasone (BET) in 48 healthy nonpregnant Indian women in a partial and complex cross-over design. Single doses of 6 mg dexamethasone phosphate (DEX-P), betamethasone phosphate (BET-P), or 1:1 mixture of betamethasone phosphate and acetate (BET-PA) were administered orally (PO) or intramuscularly (IM) where each woman enrolled in a two-period cross-over study. Plasma concentrations collected over 96 h were described with a two-compartment model with differing PO and IM first-order absorption inputs. Overall, BET exhibited slower clearance, similar volume of distribution, faster absorption, and longer persistence than DEX with BET acetate producing extremely slow absorption but full bioavailability of BET. Six biomarkers were assessed over a 24-h baseline period with four showing circadian rhythms with complex baselines. These baselines and the strong responses seen after drug dosing were fitted with various indirect response models using the Laplace estimation methods in NONMEM 7.4. Both the PK and six biomarker responses were well-described with modest variability likely due to the homogeneous ages, weights, and ethnicities of the women. The drugs either inhibited or stimulated the influx processes with some models requiring joint inclusion of drug effects on circadian cortisol suppression. The biomarkers and order of sensitivity (lowest IC50/SC50 to highest) were: cortisol, T-helper cells, basophils, glucose, neutrophils, and T-cytotoxic cells. DEX sensitivities were generally greater than BET with corresponding mean ratios for these biomarkers of 2.86, 1.27, 1.72, 1.27, 2.69, and 1.06. Overall, the longer PK (e.g. half-life) of BET, but lesser PD activity (e.g. higher IC50), produces single-dose response profiles that appear quite similar, except for the extended effects from BET-PA. This comprehensive population modeling effort provides the first detailed comparison of the PK profiles and six biomarker responses of five commonly used dosage forms of DEX and BET in healthy women.

Population pharmacokinetic modeling of intramuscular and oral dexamethasone and betamethasone in Indian women.

Population analysis of pharmacokinetic data for five differing dosage forms and routes for dexamethasone and betamethasone in 48 healthy nonpregnant Indian women was performed that accounted for a partial and complex cross-over design. Single doses of 6 mg dexamethasone phosphate (DEX-P), betamethasone phosphate (BET-P), or 1:1 mixture of betamethasone phosphate and acetate (BET-PA) were administered orally (PO) or intramuscularly (IM). Plasma concentrations collected for two periods over 96 h were described with a two-compartment model with differing PO and IM first-order absorption inputs. Clearances and volumes were divided by the IM bioavailability [Formula: see text]. The homogeneous ages, body weights, and ethnicity of the women obviated covariate analysis. Parameter estimates were obtained by the Laplace estimation method implemented in NONMEM 7.4. Typical values for dexamethasone were clearance ([Formula: see text] of 9.29 L/h, steady-state volume ([Formula: see text] of 56.4 L, IM absorption constant [Formula: see text] of 0.460 1/h and oral absorption constant ([Formula: see text] of 0.936 1/h. Betamethasone parameters were CL/FIM of 5.95 L/h, [Formula: see text] of 72.4 L, [Formula: see text] of 0.971 1/h, and [Formula: see text] of 1.21 1/h. The PO to IM F values were close to 1.0 for both drugs. The terminal half-lives averaged about 7.5 h for DEX, 17 h for BET, and 78 h for BET from BET-PA with the latter reflecting very slow release of BET from the acetate ester. Overall, BET exhibited slower clearance, larger volume of distribution, faster absorption, and longer persistence than DEX. These data may be useful in considering exposures when substituting one form of corticosteroid for another.

Population Pharmacodynamic Modeling of Epoetin Alfa in End-Stage Renal Disease Patients Receiving Maintenance Treatment Using Bayesian Approach.

The ability to control dosage regimens of erythropoiesis-stimulating agents (ESAs) to maintain a desired hemoglobin (HGB) target is still elusive. We utilized a Bayesian approach and informative priors to characterize HGB profiles, using simulated drug concentrations, in patients with end-stage renal disease receiving maintenance doses of epoetin alfa. We also demonstrated an adaptive Bayesian method, applied to individual patients, to improve the accuracy of HGB predictions over time. The results showed that sparse HGB data from daily clinical practice were characterized successfully. The adaptive Bayesian method effectively improved the accuracy of HGB predictions by updating the individual model with new data accounting for within-subject changes over time. The Bayesian approach presented leverages existing knowledge of the model parameters and has a potential utility in clinical practice to individualize dosage regimens of epoetin alfa and ESAs to achieve target HGB. Further studies are warranted to develop an application for practical use.

Application of Reticulocyte-Based Estimation of Red Blood Cell Lifespan in Anemia Management of End-Stage Renal Disease Patients.

Shortened red blood cell (RBC) lifespan is one of the major factors contributing to anemia in end-stage renal disease (ESRD) patients and should be taken into account in anemia management protocols. In this study, we aimed to estimate RBC lifespan and the source of between-subject variability in ESRD patients. The resulting individual parameters (empirical Bayes estimates) were used to predict hemoglobin concentrations 2 weeks in advance. The reticulocyte-based estimation of RBC lifespan (REBEL) and the population modeling of RBC count data were used. A total of 120 blood samples collected biweekly over 10 weeks in 24 patients receiving maintenance doses of recombinant human erythropoietin (rHuEPO) subcutaneously were included in this analysis. Typical RBC lifespan was estimated to be 63.3 days. RBC lifespan was found to increase with erythroferrone, a recently identified hormone participating in iron metabolism. Approximately, a 10% increase in plasma erythroferrone was associated with a 5% increase in RBC lifespan. In addition, RBC lifespan was 18.7% shorter in females compared with males. Out of 24 subjects, 16 had hemoglobin concentrations predicted within 95% prediction intervals. The median absolute prediction error was 15.9% (interquartile range, 9.5 to 24.7%). We demonstrated that REBEL coupled with the population modeling technique can be used effectively to estimate RBC lifespan. Then, individual parameters can be used to predict future hemoglobin concentrations in ESRD patients.

Dose Correction for a Michaelis-Menten Approximation of a Target-Mediated Drug Disposition Model with a Multiple Intravenous Dosing Regimens.

This study aimed to develop a method for implementing dose correction in a Michaelis-Menten (M-M) approximation of a target-mediated drug disposition (TMDD) model with multiple intravenous (IV) bolus administrations. We derived the formula of a correction factor (Fcorr) for each dose in a multiple IV bolus dosing regimens for M-M model. Fcorr depends on the residual free drug amount prior IV bolus dosing event and dose amount. We conducted a stochastic simulation and estimation (SSE) exercise based on therapeutic antibody PK parameters to evaluate the effect of Fcorr on parameter estimation. Previously published clinical PK data of recombinant human erythropoietin (rHuEPO) from four clinical trials in healthy subjects receiving multiple IV bolus doses were analyzed by both M-M model with and without dose correction (MMC and MMNC) as well as the rapid-binding/quasi-steady-state (RB/QSS) TMDD models. Our results showed that MMNC introduced bias to fixed-effect parameter estimates and overestimated random-effect variables. Compared with MMC, MMNC was not able to adequately characterize the nonlinearity in the PK data of antibody and rHuEPO. The MMC-based simulation demonstrated that thricely weekly 10 IU/kg rHuEPO dosing regimen yielded Fcorr = 0.5. This result suggested that the lower-than-expected exposure for rHuEPO at low dose is due to target binding. An M-M approximation of the TMDD model should include a dose correction to avoid model misfitting and potential bias in the estimated PK parameters.

Population Pharmacokinetic Modeling in the Presence of Missing Time-Dependent Covariates: Impact of Body Weight on Pharmacokinetics of Paracetamol in Neonates.

Body weight is the primary covariate in pharmacokinetics of many drugs and dramatically changes during the first weeks of life of neonates. The objective of this study is to determine if missing body weights in preterm and term neonates affect estimates of model parameters and which methods can be used to improve performance of a population pharmacokinetic model of paracetamol. Data for our analysis were obtained from previously published studies on the pharmacokinetics of intravenous paracetamol in neonates. We adopted a population model of body weight change in neonates to implement three previously introduced methods of handling missing covariates based on data imputation, likelihood function modification, and full random effects modeling. All models were implemented in NONMEM 7.4, and population parameters were estimated using the FOCE method. Our major finding was that missing body weights minimally affect population estimates of pharmacokinetic parameters but do affect the covariate relationship parameters, particularly the one describing dependence of clearance on body weight. None of the tested methods changed estimates of between-subject variability nor impacted the predictive performance of the model. Our analysis shows that a modeling approach towards handling missing covariates allows borrowing information gathered in various studies as long as they target the same population. This approach is particularly useful for handling time-dependent missing covariates.