The pharmacokinetics of oral cyclosporin a (neoral) during the first month after bone marrow transplantation

Schultz, Kirk R.; Tj, Nevill; Toze, Cynthia L.; Corr, Traci R.; Cj, Currie; Strong, DK; Keown, Paul

doi:10.1016/s0041-1345(98)00385-6

Cited by 13 publications

(7 citation statements)

References 6 publications

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“…We present the first study in which the pharmacokinetics of CsA were evaluated with mixed effects modelling in allogeneic HSCT recipients after i.v. and oral dosing, Few pharmacokinetic studies on CsA have been performed in HSCT recipients and most have evaluated only very small numbers of patients [9, 24,42]. Hendriks et al measured CsA blood concentrations during 24 h to generate a pharmacokinetic profile in 21 haematopoietic AST recipients who were receiving i.v.…”

Section: Discussionmentioning

confidence: 99%

“…CsA 1.5 mg kg -1 by 2 h infusion [24].The dose normalized AUC(0,12 h) found compares well to the AUC(0,12 h) assessed in our study. Schultz et al studied the pharmacokinetics of oral CsA microemulsion (Neoral®) during the first month after bone marrow transplantation, by adding a single 3 mg kg -1 CsA oral dose to the CsA administered by continuous infusion [42]. The concentration-time curve was constructed by subtracting the concentration of i.v.…”

Section: Discussionmentioning

confidence: 99%

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Population pharmacokinetics of ciclosporin in haematopoietic allogeneic stem cell transplantation with emphasis on limited sampling strategy

Wilhelm¹,

Graaf²,

Veldkamp³

et al. 2012

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The population pharmacokinetics and limited sampling strategies for ciclosporin monitoring have been extensively studied in renal and liver transplant recipients. Little is known about the pharmacokinetics of ciclosporin in patients undergoing haematopoietic allogeneic stem cell transplantation (HSCT).• It is anticipated that there is a difference in pharmacokinetics in patients after kidney or liver transplantation compared with patients undergoing stem cell transplantation, because of mucositis and interacting drugs (e.g. fluconazole).• Data on the pharmacokinetics of ciclosporin and the relationship between its systemic exposure, as reflected by the area under the curve (AUC), and the biological effect as graft vs. host-disease (GVHD) prophylaxis and graft vs. tumour (GVT) response are scarce in patients after HSCT. WHAT THIS STUDY ADDS• A pharmacokinetic model was developed for orally and intravenously administered ciclosporin, enabling an adequate estimate of the systemic exposure of ciclosporin in patients after HSCT. A limited sampling strategy was tested that may serve as a tool to study the optimum systemic exposure (AUC) of ciclosporin in HSCT to prevent GVHD but establish adequate GVT response and to guide therapeutic drug monitoring. AIMTo develop a population pharmacokinetic model of ciclosporin (CsA) in haematopoietic allogeneic stem cell transplantation to facilitate a limited sampling strategy to determine systemic exposure (area under the curve [AUC]), in order to optimize CsA therapy in this patient population. METHODSThe pharmacokinetics of CsA were investigated prospectively in 20 patients following allogeneic haematopoietic stem cell transplantation (HSCT). CsA was given twice daily, as a 3 h i.v. infusion starting at day 1 of the conditioning scheme, and orally later on, when oral intake was well tolerated. Fluconazole was given as antimycotic prophylaxis. Pharmacokinetic parameter estimation was performed using nonlinear mixed effect modelling as implemented in the NONMEM program. A first order absorption model with lag time was compared with Erlang frequency distribution and Weibull distribution models. The influence of demographic variables on the individual empirical Bayesian estimates of clearance and distribution volume was tested. Subsequently two limited sampling strategies (LSS) were evaluated: posterior Bayesian fitting and limited sampling equations. RESULTSTwenty patients were included and 435 samples were collected after i.v. and oral administration of CsA. A two compartment model with first order absorption best described the data. Clearance (CL) was 21.9 l h -1 (relative standard deviation [RSD] Ϯ 5.2%) with an inter-individual variability of 21%. The central volume of distribution (Vc) was 18.3 l (RSD Ϯ 8.7%) with an inter-individual variability of 29%. Bioavailability (F) was 0.71 (RSD Ϯ 9.9%) with and inter-individual variability of 25% and lag time (tlag) was 0.44 h (RSD 5.5%). Weight, body surface area, haematocrit, albumin, ALAT...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics of ciclosporin in haematopoietic allogeneic stem cell transplantation with emphasis on limited sampling strategy

Wilhelm¹,

Graaf²,

Veldkamp³

et al. 2012

Brit J Clinical Pharma

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“…Furthermore, important pharmacokinetic differences between adults and children have been reported, both in SCT and in solid organ transplantation. In studies of the pharmacokinetics after oral administration of ciclosporin in SCT patients, dosed per kg BW, significantly lower AUCs were reached in children compared with adults [6, 14]. In renal transplant patients a greater apparent steady‐state volume of distribution and more rapid apparent blood clearance in young children (2–5 years) were found than in those >10 years old [15].…”

Section: Discussionmentioning

confidence: 99%

Ciclosporin kinetics in children after stem cell transplantation

Willemze¹,

Cremers

Schoemaker

et al. 2008

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Ciclosporin is an immunosuppressant drug that is commonly used as prophylaxis against graft-versus-host disease (GVHD) after allogeneic haematopoietic stem cell transplantation (SCT) in children.• Therapeutic drug monitoring is necessary because of its unpredictable absorption and narrow therapeutic window.• Data on the pharmacokinetics of ciclosporin and the relation between its systemic exposure, as reflected by the AUC (area-under-the-curve), and the biological effect as GVHD prophylaxis are scarce in children after SCT. WHAT THIS STUDY ADDS• An adequate estimate of the systemic exposure of ciclosporin, following limiting sampling after intravenous and oral administration, can be obtained in children after SCT by determining the AUC using a two-compartment pharmacokinetic model with lag time in combination with a limited sampling strategy.• Large interindividual variability in ciclosporin clearance was found, which was independent of body weight; this finding justifies a dosing strategy distinct from that per kg body weight.• Limited sampling modelling may serve as a tool to study the relationship between systemic exposure (~AUC) and biological effects of ciclosporin, i.e. facilitation of engraftment, prevention of GVHD and avoidance of toxic effects of ciclosporin. AIMSTo develop a limited sampling strategy to determine ciclosporin systemic exposure [area-under-the-curve(AUC)]. This is meant to be the first step in a future study of the relationship between AUC and the biological effects of ciclosporin. METHODSThe pharmacokinetics of ciclosporin was investigated prospectively following stem cell transplantation (SCT) in 17 children, aged 1.8-16.1 years. Ciclosporin was given twice daily, intravenously over a short infusion of 2 h duration during the early post-SCT period, or orally later on, when oral medication was well tolerated. Parameter estimation was performed using nonlinear mixed effect modelling as implemented in the NONMEM program. Individual empirical Bayes estimates of clearance and distribution volume were correlated with the demographic variables. RESULTSPharmacokinetics was described adequately with a two-compartment model with lag time (population estimates: CL = 11.3 l h -1; Vc = 16.5 l; Vp = 59.9 l; t1/2 absorption = 0.78 h, tlag = 0.6 h). The AUCs, determined for the combination of trough level with one time point between 2 and 3 h after dosing, correlated very well with the reference AUC (r 2 = 0.97). No correlation was found between clearance and distribution volume, and the demographic patient variables length, body weight, age and glomerular filtration rate. CONCLUSIONA two-point limited sampling strategy, in combination with a Bayesian fitting procedure using the pharmacokinetic population model described, can adequately determine the AUC of ciclosporin. Since no correlation between clearance and body weight was found, dosing ciclosporin per kg bodyweight is not supported by the results of this study. We suggest starting with a fixed dose, fol...

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“…[14][15][16] Absorption of Neoral is more rapid and less variable than with Sandimmun (traditional oil-based formulation of CsA). 17 In renal and heart transplantation, the authors converted from the conventional to the microemulsion CsA formulation in a dose ratio of 1 to 1 mg. [14][15][16] In this study we attempted to determine the dose conversion from intravenous CsA to Neoral in allogeneic BMT recipients. Our results show that the conversion in a dose ratio of 1 mg Neoral to 1 mg CsA in the switch from intravenous to oral administration leads to an important under exposure for some patients (four patients of the eight in group 1).…”

Section: Discussionmentioning

confidence: 99%

New oral formulation of cyclosporin A (Neoral) pharmacokinetics in allogeneic bone marrow transplant recipients

Parquet

Reigneau

Humbert

et al. 2000

Bone Marrow Transplant

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Summary:Cyclosporin A (CsA) absorption is variable in bone marrow transplant (BMT) patients compromising the efficacy of graft-versus-host disease prevention. Neoral, a new microemulsion formulation of CsA which has an improved bioavailibility, increases intestinal absorption of the drug with less variable pharmacokinetic parameters in non-BMT patients. In order to predict the best dosage of Neoral when patients are switched from i.v. to oral administration we performed a randomised study comparing two oral doses, either the same or twice the last i.v. dose used after BMT. Fourteen adults were randomised around day 25 after BMT. Whole blood CSA concentrations were measured 2 and 12 h after the oral administration of Neoral on days 0, 7 and 14 to determine residual and maximum concentration, and modified whenever necessary to maintain blood level CsA concentration within therapeutic range (150-250 ng/ml). We found that patients who received twice the last i.v. dose had better concentrations than patients from the other group while toxicity was identical in both groups. We conclude that doubling the last i.v. dose during the switch to oral administration of Neoral gives the best therapeutic range concentration and should be recommended for graft-versus-host prevention. Bone Marrow Transplantation (2000) 25, 965-968. Keywords: bone marrow transplantation; cyclosporin A; pharmacokineticsIn an attempt to improve the bioavailibility of oral cyclosporin A (CsA) and to reduce variability in absorption, a new microemulsion formulation of CsA has been developed (Neoral).Pharmacokinetic studies conducted in healthy volunteers and renal, liver and cardiac transplant recipients have consistently demonstrated that absorption was increased by an average of 30% in the area-under-the-curve and was faster after Neoral than after Sandimmun. This results in an increased bioavailibility, a lower dependency on food, bile or pancreatic enzymes and a markedly reduced variability

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The pharmacokinetics of oral cyclosporin a (neoral) during the first month after bone marrow transplantation

Cited by 13 publications

References 6 publications

Population pharmacokinetics of ciclosporin in haematopoietic allogeneic stem cell transplantation with emphasis on limited sampling strategy

Population pharmacokinetics of ciclosporin in haematopoietic allogeneic stem cell transplantation with emphasis on limited sampling strategy

Ciclosporin kinetics in children after stem cell transplantation

New oral formulation of cyclosporin A (Neoral) pharmacokinetics in allogeneic bone marrow transplant recipients

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