Posttransplant day significantly influences pharmacokinetics of cyclosporine after hematopoietic stem cell transplantation

Jacobson, Pamala A.; Ng, Juki; Green, Kathleen G.E.; Rogosheske, John; Brundage, Richard C.

doi:10.1016/s1083-8791(03)00076-4

Cited by 35 publications

(47 citation statements)

References 33 publications

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“…It is not surprising that the effect of body weight on CL/F of CsA was significant, which was consistent with previous reports (Rui et al, 1995;Charles, 1998, 2000;Jacobson et al, 2003). A 0.118 l/h change on CL/F would occur on every kilogram variation on CBW, which was comparable to the value (0.101-0.183 l/h) previously reported (Jacobson et al, 2003). It is common that the patients can gain body weight by 10% after transplantation.…”

Section: Discussionsupporting

confidence: 91%

Population Pharmacokinetics of Cyclosporine in Clinical Renal Transplant Patients

Cui²,

Guo³

et al. 2005

Drug Metab Dispos

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Section: Discussionsupporting

confidence: 91%

Population Pharmacokinetics of Cyclosporine in Clinical Renal Transplant Patients

Cui²,

Guo³

et al. 2005

Drug Metab Dispos

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“…When we discussed the optimal starting dose of cyclosporine, we must consider clearance of cyclosporine, which decreases over time during the first 2 weeks after transplantation. 11,12 When the constant cyclosporine clearance during days 22-60 is 1.00, the clearance during days 0-7, 8-14, 15-21 are 1.46, 1.32, and 1.20, respectively. 11 The change of clearance in the natural course of transplant recipients may be related to our observation that cyclosporine levels were elevated in many patients, requiring dose reduction.…”

Section: Discussionmentioning

confidence: 99%

“…11,12 When the constant cyclosporine clearance during days 22-60 is 1.00, the clearance during days 0-7, 8-14, 15-21 are 1.46, 1.32, and 1.20, respectively. 11 The change of clearance in the natural course of transplant recipients may be related to our observation that cyclosporine levels were elevated in many patients, requiring dose reduction. However, the present study showed that cyclosporine levels exceeded the target levels within a week in some patients, necessitating dose reduction (Figure 1).…”

Section: Discussionmentioning

confidence: 99%

“…The median day of cyclosporine dose reduction was day 14, when the decrease in its clearance was only 9.6%. 11 The change of clearance cannot fully explain the dose reduction requirement. When the target range of cyclosporine levels is determined at 150-250 ng/ml as in the Japanese standard, the starting dose of 6 mg/kg is probably unnecessarily high.…”

Section: Discussionmentioning

confidence: 99%

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Optimal initial dose of oral cyclosporine in relation to its toxicities for graft-versus-host disease prophylaxis following reduced-intensity stem cell transplantation in Japanese patients

Kishi¹,

Murashige²,

Kami³

et al. 2005

Bone Marrow Transplant

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Summary:Since the introduction of reduced-intensity stem-cell transplantation (RIST), allogeneic stem-cell transplantation has become available for elderly patients. While pharmacokinetics of cyclosporine might differ according to age or other factors, cyclosporine is uniformly started at an oral dose of 6 mg/kg/day. We retrospectively reviewed medical records of 35 patients aged between 32 and 65 (median 52) years who had undergone RIST. Doses of cyclosporine were adjusted to the target blood trough level of 150-250 ng/ml. Cyclosporine dosages were changed in 33 patients (94%). Dose reduction was required in 32 patients because of high blood levels (n ¼ 25), renal dysfunction (n ¼ 3), hepatic dysfunction (n ¼ 2), and hypertension (n ¼ 2). Cyclosporine doses were increased in one because of the suboptimal level. The median of the achieved stable doses was 3.1 mg/kg/day (range, 1.0-7.4). Five patients sustained Grade III toxicities according to NCI-CTC version 2.0: renal dysfunction (n ¼ 4), hyperbilirubinemia (n ¼ 2), and hypertension (n ¼ 2). No patients developed grade IV toxicity. There was no statistically significant difference in the frequency and severity of cyclosporine toxicities between patients aged 50 years and above and those below 50 years. The initial oral cyclosporine dose of 6 mg/kg/day was unnecessarily high irrespective of age. The possible overdose of cyclosporine might have aggravated regimen-related toxicities.

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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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Posttransplant day significantly influences pharmacokinetics of cyclosporine after hematopoietic stem cell transplantation

Cited by 35 publications

References 33 publications

Population Pharmacokinetics of Cyclosporine in Clinical Renal Transplant Patients

Population Pharmacokinetics of Cyclosporine in Clinical Renal Transplant Patients

Optimal initial dose of oral cyclosporine in relation to its toxicities for graft-versus-host disease prophylaxis following reduced-intensity stem cell transplantation in Japanese patients

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

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