Influence of Dosing Schedule on Organ Exposure to Cyclosporin in Pediatric Hematopoietic Stem Cell Transplantation: Analysis with a PBPK Model

Gérard, Christophe; Bleyzac, Nathalie; Girard, Pascal; Bertrand, Yves; Tod, Michel

doi:10.1007/s11095-010-0252-1

Cited by 14 publications

(12 citation statements)

References 36 publications

(33 reference statements)

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“…As a consequence, administration of cyclosporin by II or CI may have equal efficacies, provided that the average blood concentration achieved is similar. The higher AUC of receptor occupancy in the interstitial fluid of aGVHD target organs yielded by CI, compared to II in our previous study (9), does not result in increased efficacy, probably because the difference in receptor occupancy is too small. As AUC is equal to the product of average concentration and dosing interval, AUC 0-24 h may also be used as a predictor of efficacy.…”

Section: Discussioncontrasting

confidence: 55%

“…The pediatric physiologically based pharmacokinetic (PBPK) model, including 11 organs validated in children (9), was fitted individually to the venous whole-blood cyclosporin concentrations of the 61 pediatric patients undergoing HSCT and receiving only cyclosporin as immunosuppressive treatment. For each patient, the data records included the dosing history, the first two concentration measurements, body weight, age, and hematocrit.…”

Section: Pbpk Model In Pediatric Patients and Predicted Exposurementioning

confidence: 99%

“…The estimated parameters were the hepatic intrinsic clearance and the plasma unbound fraction of cyclosporin. A Bayesian estimator (Maximum a Posteriori) was used to estimate these parameters, as described in our previous study (9). The areas under the concentration vs. time curves (AUC D1, from 0 to 24 h after the onset of treatment, and AUC SS, at steady state) were estimated by numerical integration in several compartments (venous blood and interstitial compartments of bone including bone marrow, skin, liver, thymus, and intestines), using the dosing history of each child.…”

Section: Pbpk Model In Pediatric Patients and Predicted Exposurementioning

confidence: 99%

“…Continuous infusion (CI) and 2-h intermittent infusions (II) are commonly used, but there is no consensus regarding the best mode of administration (8). Our previous study, using a physiologically based pharmacokinetic model, showed that the area under the receptor occupancy versus time curve in the interstitial fluid of aGVHD target organs was greater after CI than after II, suggesting that CI maybe more efficacious (9).…”

Section: Introductionmentioning

confidence: 99%

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Links Between Cyclosporin Exposure in Tissues and Graft-Versus-Host Disease in Pediatric Bone Marrow Transplantation: Analysis by a PBPK Model

et al. 2010

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Section: Discussioncontrasting

confidence: 55%

Section: Pbpk Model In Pediatric Patients and Predicted Exposurementioning

confidence: 99%

Section: Pbpk Model In Pediatric Patients and Predicted Exposurementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Links Between Cyclosporin Exposure in Tissues and Graft-Versus-Host Disease in Pediatric Bone Marrow Transplantation: Analysis by a PBPK Model

et al. 2010

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“…Gérard et al recently showed that intermittent infusions (i.e., a 2 h infusion administered every 12 h) had higher simulated cyclosporine concentrations in the GVHD target organs but lower simulated cyclosporine concentrations in the kidney, suggesting that intermittent infusions would be superior. 158 …”

Section: Calcineurin Inhibitorsmentioning

confidence: 99%

Pharmacokinetics, Pharmacodynamics and Pharmacogenomics of Immunosuppressants in Allogeneic Haematopoietic Cell Transplantation: Part I

2015

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Although immunosuppressive treatments and target concentration intervention (TCI) have significantly contributed to the success of allogeneic hematopoietic cell transplant (alloHCT), there is currently no consensus on the best immunosuppressive strategies. Compared to solid organ transplant, alloHCT is unique because of the potential for bi-directional reactions (i.e., host-versus-graft and graft-versus-host). Postgraft immunosuppression typically includes a calcineurin inhibitor (cyclosporine or tacrolimus) and a short course of methotrexate after high-dose myeloablative conditioning or a calcineurin inhibitor and mycophenolate mofetil after reduced-intensity conditioning. There are evolving roles for the antithymyocyte globulins (ATG) and sirolimus as postgraft immunosuppression. A review of the pharmacokinetics and TCI of the main postgraft immunosuppressants is presented in this two-part review. All immunosuppressants are characterized by large intra- and interindividual pharmacokinetic variability and by narrow therapeutic indices. It is essential to understand immunosuppressants’ pharmacokinetic properties and how to use them for individualized treatment incorporating TCI to improve outcomes. TCI, which is mandatory for the calcineurin inhibitors and sirolimus, has become an integral part of postgraft immunosuppression. TCI is usually based on trough concentration monitoring, but other approaches include measurement of the area under the concentration-time curve (AUC) over the dosing interval or limited sampling schedules with maximum a posteriori Bayesian personalization approaches. Interpretation of pharmacodynamic results is hindered by the prevalence of studies enrolling only a small number of patients, variability in the allogeneic graft source, and variability in postgraft immunosuppression. Given the curative potential of alloHCT, the pharmacodynamics of these immunosuppressives deserves to be explored in depth. The development of sophisticated systems pharmacology models and improved TCI tools are needed to accurately evaluate patients’ exposure to drugs in general and to immunosuppressants in particular. Sequential studies, first without and then with TCI, should be conducted to validate the clinical benefit of TCI in homogenous populations; randomized trials are not feasible due to higher priority research questions in alloHCT. In part I of this article, we review the alloHCT process to facilitate optimal design of pharmacokinetic and pharmacodynamics studies. We also review the pharmacokinetics and TCI of calcineurin inhibitors and methotrexate.

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Application of a physiologically‐based pharmacokinetic model for the prediction of bumetanide plasma and brain concentrations in the neonate

Donovan

Abduljalil

Cryan

et al. 2018

Biopharm & Drug Disp

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Bumetanide is a loop diuretic that is proposed to possess a beneficial effect on disorders of the central nervous system, including neonatal seizures. Therefore, prediction of unbound bumetanide concentrations in the brain is relevant from a pharmacological prospective. A physiologically-based pharmacokinetic (PBPK) model was developed for the prediction of bumetanide disposition in plasma and brain in adult and paediatric populations. A compound file was built for bumetanide integrating physicochemical data and in vitro data. Bumetanide concentration profiles were simulated in both plasma and brain using the Simcyp PBPK model. Simulations of plasma bumetanide concentrations were compared against plasma levels published in the literature. The model performance was verified with data from adult studies before predictions in the paediatric population were undertaken. The adult and paediatric intravenous models predicted pharmacokinetic factors, namely area under the concentration-time curve, maximum concentration in plasma and time to maximum plasma concentration, within two-fold of observed values. However, predictions of plasma concentrations within the neonatal intravenous model did not produce a good fit with the observed values. The PBPK approach used in this study produced reasonable predictions of plasma concentrations of bumetanide, except in the critically ill neonatal population. This PBPK model requires more information regarding metabolic intrinsic clearance and transport parameters prior to further validation of drug disposition predictions in the neonatal population. Given the lack of information surrounding certain parameters in this special population, the model is not appropriately robust to support the recommendation of a suitable dose of bumetanide for use as an adjunct antiepileptic in neonates.

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Influence of Dosing Schedule on Organ Exposure to Cyclosporin in Pediatric Hematopoietic Stem Cell Transplantation: Analysis with a PBPK Model

Abstract: CI may be slightly more favorable than II for aGVHD prevention.

Cited by 14 publications

References 36 publications

Links Between Cyclosporin Exposure in Tissues and Graft-Versus-Host Disease in Pediatric Bone Marrow Transplantation: Analysis by a PBPK Model

Links Between Cyclosporin Exposure in Tissues and Graft-Versus-Host Disease in Pediatric Bone Marrow Transplantation: Analysis by a PBPK Model

Pharmacokinetics, Pharmacodynamics and Pharmacogenomics of Immunosuppressants in Allogeneic Haematopoietic Cell Transplantation: Part I

Application of a physiologically‐based pharmacokinetic model for the prediction of bumetanide plasma and brain concentrations in the neonate

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