Disposition of Two Oral Formulations of Cyclosporine in Pediatric Patients Receiving Hematopoietic Stem Cell Transplants

Dupuis, L. Lee; Taylor, Tracey; Saunders, E F

doi:10.1592/phco.2006.26.1.15

Cited by 9 publications

(10 citation statements)

References 27 publications

(31 reference statements)

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“…[49][50][51][52][53] No information regarding the relationship between CSA area under the concentration versus time curve and the incidence of aGvHD exists; HSCT clinicians only recently have begun discussions of parameters other than trough CSA concentrations as possible correlates of HSCT outcomes. [54][55][56][57] Future prospective research will elaborate on the nature and extent of any such relationships.…”

Section: Discussionmentioning

confidence: 99%

Achievement of Target Cyclosporine Concentrations as a Predictor of Severe Acute Graft Versus Host Disease in Children Undergoing Hematopoietic Stem Cell Transplantation and Receiving Cyclosporine and Methotrexate Prophylaxis

Punnett

Sung²,

Price³

et al. 2007

Therapeutic Drug Monitoring

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This study evaluates our institution's target trough cyclosporine (CSA) concentrations as predictors of severe acute graft versus host disease (aGvHD) in children receiving either matched related or unrelated hematopoietic stem cell transplantation (HSCT). The outcomes of 87 consecutive children who underwent allogeneic HSCT and received CSA and methotrexate as prophylaxis against aGvHD between October 1, 1999 and September 30, 2002 were retrospectively evaluated. The proportion of time that each patient maintained a whole blood CSA concentration within or above the initial target range (105-155 ng/mL or 155-210 ng/mL) was calculated for each of the following time periods: in each week after HSCT from day 0 to +28; in the week preceding engraftment; and in the week preceding the onset of aGvHD. Patients were prospectively evaluated twice weekly for the presence and severity of aGvHD by senior attending physicians. The relationship between potential predictors and the development of severe aGvHD was examined using univariate logistic regression. The main variables of interest were the proportion of time that therapeutic or supratherapeutic CSA concentrations were maintained; median CSA concentrations; the number of methotrexate doses received; and the use of folinic acid rescue. Mean follow-up time was 3.0+/-1.9 years among children who survived beyond day +100. Three variables were significantly associated with the development of severe aGvHD on univariate analysis: initial CSA target concentration [odds ratio (OR), 0.24; P=0.03], proportion of time the target CSA concentration was achieved during the second week after transplant (OR, 0.16; P=0.02), and proportion of time the target CSA concentration was achieved during the week before engraftment (OR, 0.22; P=0.0489). Multivariable analysis demonstrated an inverse relationship between the median CSA concentration during the week before engraftment and the development of severe aGvHD (OR, 0.99; P=0.045). These results suggest that achievement of our CSA target concentrations is important to aGvHD outcomes.

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Section: Discussionmentioning

confidence: 99%

Achievement of Target Cyclosporine Concentrations as a Predictor of Severe Acute Graft Versus Host Disease in Children Undergoing Hematopoietic Stem Cell Transplantation and Receiving Cyclosporine and Methotrexate Prophylaxis

Punnett

Sung²,

Price³

et al. 2007

Therapeutic Drug Monitoring

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“…Therefore, a model that predicts ciclosporin pharmacokinetics and dose requirements to achieve the desired therapeutic target in an individual HSCT patient would be highly useful. CsA pharmacokinetic studies in HSCT recipients are scarce and most have evaluated only small numbers of subjects [9, [23][24][25][26][27][28].…”

Section: Introductionmentioning

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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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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“…Previously, we also observed a moderate relationship between trough CYA concentrations and AUC following oral administration to HSCT patients (Spearman's r coefficient ¼ 0.584). 12 It is therefore not possible to provide a target trough CYA concentration range that corresponds to the target AUC range recommended in renal transplant. We consequently chose to use the lower limit of the AUC target range recommended for solid organ transplant patients (4200-11 500 mg Â h/l) on which to base our i.v.…”

Section: Discussionmentioning

confidence: 99%

“…Methodology and results pertaining to the oral phase of this study have been published elsewhere. 12 In brief, patients who were undergoing allogeneic HSCT and were scheduled to receive CYA for aGVHD prophylaxis were eligible to participate. Patients with impaired liver function (defined as serum transaminase concentrations 43 times the upper limit of normal for their age and/or total bilirubin levels 42 mg per 100 ml (34 mmol/l) on the day of pharmacokinetic sampling were excluded.…”

Section: Patientsmentioning

confidence: 99%

See 1 more Smart Citation

Determination of initial i.v. CYA dosage to achieve target AUC values in pediatric hematopoietic stem cell transplant patients

Jin

Seto

Taylor

et al. 2008

Bone Marrow Transplant

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Disposition of Two Oral Formulations of Cyclosporine in Pediatric Patients Receiving Hematopoietic Stem Cell Transplants

Cited by 9 publications

References 27 publications

Achievement of Target Cyclosporine Concentrations as a Predictor of Severe Acute Graft Versus Host Disease in Children Undergoing Hematopoietic Stem Cell Transplantation and Receiving Cyclosporine and Methotrexate Prophylaxis

Achievement of Target Cyclosporine Concentrations as a Predictor of Severe Acute Graft Versus Host Disease in Children Undergoing Hematopoietic Stem Cell Transplantation and Receiving Cyclosporine and Methotrexate Prophylaxis

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

Determination of initial i.v. CYA dosage to achieve target AUC values in pediatric hematopoietic stem cell transplant patients

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