Monitoring C2 Level Predicts Exposure in Maintenance Lung Transplant Patients Receiving the Microemulsion Formulation of Cyclosporine (Neoral)

Jaksch, Péter; Kocher, Alfred; Neuhauser, P.; Sarahrudi, Kambiz; Seweryn, J; Wisser, Wilfried; Klepetko, Walter

doi:10.1016/j.healun.2003.05.002

Cited by 29 publications

(20 citation statements)

References 22 publications

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“…Studies on CsA monitoring involving different types of organ transplantation have revealed that trough concentrations are not the best estimators of systemic exposure of this drug [48][49][50]. although they are still used in most HSCT centres for therapeutic drug monitoring of CsA.…”

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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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%

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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“…Significantly, the utility of C2 in predicting AUCs is consistent with reports from the solid organ transplant literatures. [24][25][26][27][28][29][30][31][32] It is worth noting that the CsA concentration that gives the best single point prediction of CsA AUCs may vary between the different AUCs. In renal transplant recipients, C2 was the most accurate one-point predictor for AUC 0À4h , whereas C3 was better for AUC 0À12h .…”

Section: Discussionmentioning

confidence: 99%

CsA 2-h concentration correlates best with area under the concentration–time curve after allo-SCT compared with trough CsA

Kong

Shuttleworth

Bailey

et al. 2011

Bone Marrow Transplant

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The relationship between CsA levels and area under the curve (AUC) in allo-SCT recipients, and the effect of age, concomitant use of steroid and MDR-1 polymorphism on this relationship remain largely unexplored. Steady-state CsA blood concentrations at time 0 (C0), 1 (C1), 1.5 (C1.5), 2 (C2), 3 (C3), 4 (C4), 6 (C6), 8 (C8) and 12 (C12) h post oral CsA dose were taken from 27 consenting allo-SCT recipients (receiving myeloablative or nonmyeloablative conditioning) at D 15 -D 25 (all participants) and D 40 -D 80 (participants with myeloablative conditioning). The CsA AUC 0À4h , AUC 0À8h and AUC 0À12h were determined using trapezoidal rule, and the relationships between AUCs and CsA concentrations at various time points were examined. Poor correlation was observed between C0 and AUC 0À4h (r 2 ¼ 0.15), AUC 0À8h (r 2 ¼ 0.21) and AUC 0À12h (r 2 ¼ 0.53). C2 was better correlated with AUC 0À4h (r 2 ¼ 0.88), AUC 0À8h (r 2 ¼ 0.76) and AUC 0À12h (r 2 ¼ 0.83). The aforementioned factors did not influence the observed relationship. CsA levels taken at 2 h post oral CsA administration may represent the optimal time point for monitoring the biological effects of calcineurin inhibitors in allo-SCT recipients.

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“…For example, experience in renal transplantation has shown that ciclosporin exposure during the absorption phase (AUC 0-4) is the critical factor for optimizing immunosuppression [39]. Thus, a partial AUC was indeed found to be a clinically relevant and useful PK metric.…”

Section: Drug Regulatory Issuesmentioning

confidence: 97%

Exposure–response analysis reveals that clinically important toxicity difference can exist between bioequivalent carbamazepine tablets

Tóthfalusi

Speidl

Endrényi

2007

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The occurrence of central nervous system-related adverse effects has been apparently related to the absorption rate of carbamazepine (CBZ).• However, the differing absorption rate metrics of four carbamazepine formulations in a bioequivalence study were unclearly associated with the incidence of adverse effects. WHAT THIS STUDY ADDS• The relationship between the incidence of most neurological adverse effects and the absorption rate of CBZ was quantitatively established.• A mixed-effect PK-PD model demonstrated the rapid development of acute tolerance to these effects.• Characterization of PD and PK-PD sensitivities showed that clinically significant differences in toxicity can exist between bioequivalent CBZ formulations. AIMSTo assess whether, using the current regulatory criteria, therapeutically important differences can exist between bioequivalent carbamazepine (CBZ) tablets. A secondary goal was to demonstrate quantitatively the relationship between the risk of neurological adverse effects to orally ingested CBZ and the rate of absorption. METHODSResults of a bioequivalence study by Olling et al. (Biopharm Drug Dispos 1999; 20: 19-28) were reanalysed. Following an exploratory data analysis step, a mixed-effect pharmacokinetic-pharmacodynamic (PK-PD) model was built to describe the dependence of adverse events on the CBZ concentration. RESULTSRapid development of tolerance was demonstrated for most neurological adverse effects, with a characteristic half-life of 02.29 h and an initial EC50 of 2.33 mg l -1. The resulting tolerance PK-PD model was characterized further using the tools and terminology of sensitivity analysis. It was demonstrated that the maximum concentration (Cmax) exhibits poor PK and PD sensitivities, and that clinically significant differences can exist between formulations which otherwise comply with the bioequivalence requirements. In contrast, another PK metric, the partial AUC, was a much better marker of the early neurological adverse events observable during the absorption phase of the drug. CONCLUSIONSIn clinical and regulatory considerations, the development of acute tolerance for adverse effects of CBZ must be taken into account. Partial AUC reflects more sensitively the risk of adverse events than Cmax. Instead of the current trend of tightening of the bioequivalence criteria for narrow therapeutic index drugs, the use of alternative, more sensitive PK metrics is proposed.

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Monitoring C2 Level Predicts Exposure in Maintenance Lung Transplant Patients Receiving the Microemulsion Formulation of Cyclosporine (Neoral)

Cited by 29 publications

References 22 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

CsA 2-h concentration correlates best with area under the concentration–time curve after allo-SCT compared with trough CsA

Exposure–response analysis reveals that clinically important toxicity difference can exist between bioequivalent carbamazepine tablets

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