Pharmacokinetics Of Ciclosporin Research Articles

Population pharmacokinetics of ciclosporin in allogeneic hematopoietic stem cell transplant recipients: C-reactive protein as a novel covariate for clearance.

Ciclosporin (CsA), a potent immunosuppressive agent used to prevent graft-versus-host disease in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients, is characterized by large inter-individual variability and a narrow therapeutic range. The aim of this study was to develop a population pharmacokinetic model for CsA in Chinese allo-HSCT recipients and to identify covariates influencing CsA pharmacokinetics. A total of 758 retrospective drug monitoring data points were collected after intravenous infusion or oral administration of CsA from 59 patients. Population pharmacokinetic analysis was performed using nonlinear mixed effects modelling expressed by differential equations. Monte Carlo simulation was applied to optimize dosage regimens. The final model was validated using bootstrap and normalized prediction distribution errors. The results showed that the daily CsA dose, haematocrit, total bile acid, C-reactive protein (CRP) and co-administration of triazole antifungal agent were identified as significant covariates for clearance (CL) of CsA. The typical value of CL was 19.8L/h with an inter-individual variability of 13.1%. The volume of distribution was 1340L. Bioavailability was 67.2% with an inter-individual variability of 8.5%. Dosing simulation based on the developed model indicated that patients with high CRP concentration required a higher daily dose to attain the therapeutic trough concentration. The influence of CRP ultimately on the therapy outcome of CsA is not clear, which needs further study. CRP concentration was identified as a novel marker associated with CsA pharmacokinetics, which should be considered when determining the appropriate dosage of CsA in allo-HSCT recipients.

Influence of hepatic Graft-Versus-Host-Disease (GVHD) on the pharmacokinetics of ciclosporin in a case of acute myeloid leukemia treated at the EHU Oran

Acute myeloid leukemia (AML) is a malignant blood disease that affects hematopoietic cells in the bone marrow. The best treatment for AML is allogeneic hematopoietic stem cell transplantation (HSC). To prevent and treat the main complication of allogeneic marrow transplant, graft versus host disease (GVHD), it is necessary to combine immunosuppressive therapy which includes ciclosporin (CsA). The objective of our work is to study the influence of hepatic GVHD on the pharmacokinetics of cyclosporin in an AMLcase. This is an allografted patient (CSH), presented to our Pharmacovigilance department at the EHU of Oran in Algeria, with the aim of carrying out therapeutic pharmacological monitoring (TPM) of ciclosporin. We proceeded to assay for residual ciclosporinaemia from D1 of the allogeneic transplant. The patient presented a fluctuation of the trough concentrations, the explanation of which was an onset of acute hepatic GVHD, confirmed by biopsy with an elevated hepatic function, which represents an incidence varying between 10 and 50% in patients receiving transplant from a genoidentical donor. Without forgetting the great inter-individual and intra-individual variability of the response to ciclosporin, the environmental and pathological factors and the numerous drug interactions which can be the cause of modification of the pharmacokinetics and the pharmacodynamics of this drug. In conclusion, the pharmacological monitoring of cyclosporin, which is the treatment of choice to prevent or treat GVHD, is mandatory due to its low therapeutic index and high inter- and intra-individual variability.

PXR haplotype clusters will affect the pharmacokinetics of ciclosporin in Chinese renal transplant recipients.

PXR was reported to be the key nuclear receptor regulating the expression of metabolizing enzymes and transporters. The aim of this study was to evaluate the influence of PXR haplotype clusters on ciclosporin concentration in Chinese renal transplant recipients during the early stage after transplantation. A total of 98 recipients receiving ciclosporin were genotyped by PCR-RFLP, and the ciclosporin concentration was determined by EMIT. The frequency of IVS2+55A>G, IVS2+78A>G, IVS6-17C>T, 1792A>G, 1944T>C and 2654T>C variant alleles was 0.343, 0.332, 0.378, 0.515, 0.520 and 0.393, which fitted Hardy-Weinberg equilibrium. Only the IVS6-17C>T and 2654T>C were significantly associated with the ciclosporin C2 /D during the end of the first month. The mean ciclosporin C2 /D level of the PXR*1B haplotype clusters was 1.3-fold and 1.2-fold higher compared with the *1A and *1C. No significant difference was observed in CsA C2 /D between the PXR*1A and PXR*1C. We found no difference in C0 /D among the six genotypes or the three haplotype clusters. The PXR*1B in Chinese renal transplant patients was associated with ciclosporin concentration. Genetic polymorphisms and specific haplotype clusters in PXR could have significant contributory roles in affecting interethnic variations in drug disposition in the Chinese population.

Baicalin reduces ciclosporin bioavailability by inducing intestinal p-glycoprotein in rats.

To investigate the effects of multiple doses of baicalin (BG) on the pharmacokinetics of ciclosporin (CsA) in rats and the potential mechanisms. Pharmacokinetic parameters of CsA were determined in male rats after administration of CsA (3mg/kg, i.g. or i.v.) to rats in the presence and absence of BG (80mg/kg, i.g. or i.v.) for 7days. The livers and intestines of rats were isolated and the CYP3A and p-glycoprotein (P-gp) expression were analysed. The effect of BG on the intestinal absorptive behaviour of CsA was also investigated using in-vitro everted rat gut sac model. Baicalin (80mg/kg, i.v., 7days) had no effect on the intravenously administered CsA. However, BG (80mg/kg, i.g., 7days) significantly decreased the Cmax , AUC0-t and AUC0-∞ of orally administered CsA by 38, 26 and 25%, respectively (P<0.01 or P<0.05). Further study revealed that the expression of P-gp in intestine increased in oral multiple doses of BG-treated rats. The in-vitro everted rat gut sac model demonstrated BG (10μm) significantly decreased the absorption of CsA (10μm) in intestine (P<0.05). Multiple doses of BG decreased the oral bioavailability of CsA in rats significantly, which may be mainly attributable to inhibition of absorption of CsA in intestine and induction of P-gp. The interaction between BG and CsA may occur when BG and CsA were co-administered for long-term use. The dosage adjustment and blood concentration monitoring of CsA may be required in clinic.

Personalizing initial calcineurin inhibitor dosing by adjusting to donor CYP3A-status in liver transplant patients.

Inter-individual variability in dose requirements of calcineurin inhibitors (CNI) has been linked to genetic polymorphisms of CYP3A enzymes. CYP3A5*3, CYP3A4*1B and CYP3A4*22 alleles of liver grafts may explain about one third of the inter-individual differences in pharmacokinetics of ciclosporin and tacrolimus in recipients. However, non-genetic factors, influencing CYP3A expression, can contribute to the variability of CYP3A function due to phenoconversion. The present study evaluated the association between CYP3A4 expression combined with CYP3A5 genotype of donor livers and recipients' CNI therapy after transplantation. The contribution of donors' CYP3A5 genotype and CYP3A4 expression to the blood concentrations and dose requirements of CNIs was evaluated in 131 liver transplant recipients. The recipients with grafts from normal CYP3A4 expresser donors carrying CYP3A5*3/*3 required CNI maintenance doses more or less similar to the bodyweight-controlled starting doses (9.1 mg kg(-1) of ciclosporin and 0.1 mg kg(-1) of tacrolimus). The patients transplanted with grafts from low CYP3A4 expressers required substantial reduction (by about 50%, 4.2 mg kg(-1) of ciclosporin, 0.047 mg kg(-1) of tacrolimus, P < 0.001), while the recipients with grafts from high expressers or with grafts carrying at least one copy of the functional CYP3A5*1 allele required an increase (by about 50% [12.8-13.8 mg kg(-1)] for ciclosporin and 100% [0.21 mg kg(-1) ] for tacrolimus, P < 0.001) of the initial CNI dose for achieving target blood concentrations. Donor livers' CYP3A-status, taking both CYP3A5 allelic variations and CYP3A4 expression into account, can better identify the risk of CNI over- or underexposure, and may contribute to the avoidance of misdosing-induced graft injury in the early post-operative period.

Comparison of the stability and pharmacokinetics in dogs of modified ciclosporin capsules stored at −20°C and room temperature

Placement of ciclosporin (Atopica(®); Novartis Animal Health, Greensboro, NC, USA) capsules in a freezer prior to administration may reduce the incidence of vomiting in dogs. However, its impact on ciclosporin stability and pharmacokinetics is unknown. The purpose of this study was to evaluate the stability of Atopica(®) capsules and pharmacokinetics of ciclosporin in dogs after storage at -20°C in comparison with storage of capsules at 15-25°C. We hypothesized that there would be no difference in stability or pharmacokinetic parameters between freezer-stored and room-temperature Atopica(®) capsules. Eight healthy research beagle dogs received one 5.0 mg/kg oral dose each of freezer-stored and room-temperature Atopica(®) capsules with a 1 week washout period between. Ciclosporin concentrations of all available Atopica(®) capsule strengths were assessed for stability after -20°C storage at five time points over 30 days and at room temperature (15-25°C). A blinded, randomized cross-over study was also performed to compare blood concentrations of ciclosporin after capsule storage for 28 days at -20 versus 15-25°C. Blood samples were obtained over a 24 h period after administration. Capsule and whole-blood ciclosporin concentrations were assessed via high-performance liquid chromatography-tandem mass spectrometry. There was no significant difference in stability between freezer-stored and room-temperature Atopica(®) capsules at any time point. In the cross-over study, there were no significant differences in pharmacokinetic parameters assessed. Placing Atopica(®) capsules in a -20°C freezer for 28 days does not affect stability or absorption in the dog.

Pharmacokinetics of a Three-Way Drug Interaction Between Danoprevir, Ritonavir and the Organic Anion Transporting Polypeptide (OATP) Inhibitor Ciclosporin

Danoprevir (RG7227) is a potent macrocyclic inhibitor of the hepatitis C virus NS3/4A protease, which is currently in development in combination with low-dose ritonavir for the treatment of chronic hepatitis C infection. Danoprevir is a substrate of cytochrome P450 3A4, and the organic anion transporting polypeptides (OATP) 1B1 and 1B3. The objective of this study was to evaluate the effect of a potent OATP inhibitor, ciclosporin, on danoprevir pharmacokinetics, when administered as danoprevir/ritonavir. The effect of danoprevir/ritonavir on ciclosporin pharmacokinetics was also investigated. This was a single-dose, randomized, open-label, two-sequence, three-period, crossover study in healthy volunteers. In the first period, subjects were randomized to receive either a single oral dose of danoprevir 100mg in combination with ritonavir 100mg or a single oral dose of ciclosporin 100mg. After a 14-day washout, patients were crossed over to receive the opposite treatment. In period 3, all subjects received the combination of danoprevir/ritonavir and ciclosporin following a 14-day washout from period 2. Blood samples were collected serially with each dose for pharmacokinetic assessment. Pharmacokinetic parameters were estimated using non-compartmental analysis. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were used to compare pharmacokinetic parameters [maximum concentration (C max), area under the concentration-time curve from time zero to infinity (AUC∞), and concentration 12h post-dose (C 12h)] of danoprevir/ritonavir and ciclosporin when administered alone or in combination. Measures of safety and tolerability were also evaluated. A total of 18 subjects were enrolled, and 17 completed the study. The C max, AUC∞, and C 12h GMRs (90% CI) when danoprevir/ritonavir and ciclosporin were co-administered versus danoprevir/ritonavir or ciclosporin alone were 7.22 (5.42-9.62), 13.6 (11.2-16.6), and 22.5 (17.4-29.3), respectively, for danoprevir, 1.97 (1.72-2.27), 2.23 (2.07-2.42), and 2.50 (2.22-2.81), respectively, for ritonavir, and 1.42 (1.29-1.57), 3.65 (3.27-4.08), and 6.15 (5.32-7.11), respectively, for ciclosporin. All treatments were well tolerated, with no laboratory abnormalities, and no clinically significant changes in vital signs, electrocardiograms, or physical examinations observed. A significant drug-drug interaction was observed between ciclosporin and danoprevir/ritonavir, leading to substantial increases in exposure to danoprevir and a lesser impact on exposure to ritonavir. Therefore, co-administration of danoprevir/ritonavir with potent OATP inhibitors should be undertaken with appropriate precautions.

Population pharmacokinetics of ciclosporin in Chinese children with aplastic anemia: effects of weight, renal function and stanozolol administration

To develop a population pharmacokinetic model for the immunosuppressant ciclosporin in Chinese children with aplastic anemia and to identify covariates influencing ciclosporin pharmacokinetics. A total of 102 children with either acquired or congenital aplastic anemia aged 8.8±3.6 years (range 0.9-17.6 years) were included. Therapeutic drug monitoring (TDM) data for ciclosporin were collected. The population pharmacokinetic model of ciclosporin was described using the nonlinear mixed-effects modeling (NONMEM) VI software. The final model was validated using bootstrap and normalized prediction distribution errors. A one-compartment model with first-order absorption and elimination was developed. The estimated CL/F was 15.1, which was lower than those of children receiving stem cell or kidney transplant reported in the West (16.9-29.3). The weight normalized CL/F was 0.45 (range: 0.27-0.70) Lh(-1)·kg(-1). The covariate analysis identified body weight, serum creatinine and concomitant administration of the anabolic steroid stanozolol as individual factors influencing the CL/F of ciclosporin. Our model could be used to optimize the ciclosporin dosing regimen in Chinese children with aplastic anemia.

Ciclosporin Population Pharmacokinetics and Bayesian Estimation in Thoracic Transplant Recipients

Therapeutic drug monitoring of ciclosporin has been recognized as an essential tool in the management of allograft transplant recipients, as it could help improve their outcome. However, there is still no consensus about the optimal method for monitoring ciclosporin after thoracic transplantation. Better knowledge of the pharmacokinetics of ciclosporin in thoracic transplant patients and design of tools dedicated to ciclosporin monitoring could help its practice and its outcome in this population of patients. The aims of this study were to (i) investigate the population pharmacokinetics of ciclosporin in thoracic (heart or lung) transplant patients and study the influence of a range of potential covariates, including demographic, clinical and genetic factors, on pharmacokinetic parameters; and (ii) develop a Bayesian estimator able to predict the individual pharmacokinetic parameters and exposures indices in this population of patients. The analysis was performed with 187 full pharmacokinetic profiles obtained in 57 lung and 19 heart transplant patients within the first year post-transplantation. A population pharmacokinetic model was developed by non-linear mixed-effects modelling using NONMEM(®) (version 7.1) from an index dataset (118 profiles). On the basis of this population model and a limited number of blood samples, a Bayesian estimator able to determine ciclosporin area under the blood concentration-time curve (AUC) during a dosage interval was built and evaluated in the validation dataset (69 profiles). Ciclosporin pharmacokinetics were described using a two-compartment model with time-lagged first order absorption and first-order elimination. The final population model included sex as a covariate: ciclosporin apparent oral clearance was on average 37 % faster in male than in female patients (34.8 vs. 25.4 L/h, p < 0.001). Good predictive performance of the Bayesian estimator was obtained using three blood concentrations measured at 40 min, 2 h and 4 h post-dose, with a non-significant bias of -5 % between the estimated and the reference trapezoidal AUC and a good precision (relative mean square error = 13 %). Ciclosporin population pharmacokinetic analysis in thoracic transplant patients (including patients with cystic fibrosis) showed a significant influence of sex on apparent clearance. The Bayesian estimator developed in this study yielded accurate prediction of ciclosporin exposure in this population throughout the first year post-transplantation. This tool may allow routine ciclosporin dose individualization.

Association of Donor and Recipient Calcineurin Inhibitor Pharmacogenomic Variation with Long-Term Allograft Survival

Introduction: Calcineurin inhibitors (CNI) remain a cornerstone of renal transplantation immunosuppression. Whilst monitoring of blood CNI levels have been the traditional tool for adjusting CNI administration, it is clear that this is an imperfect strategy. Although data is conflicting, there is evidence that single nucleotide polymorphisms (SNPs) within genes involved in ciclosporin metabolism and transport are associated with ciclosporin pharmacokinetics. Less data is available in regard to polymorphisms of the donor, although small studies suggest an association between genetic variation in the ABCB1 gene and “acute ciclosporin nephrotoxicity” and allograft failure. Both focussed on the C3435T polymorphism within ABCB1, an exonic SNP for which the TT genotype is associated with reduced P-gp expression. The purpose of this study was to further assess the relationship of both donor and recipient genotype with the hard outcomes of allograft survival and mortality. Methods: Positive findings from an initial study cohort were examined in two further independent populations, in a study incorporating a total of 6169 transplant recipients and their respective donors followed for a period of up to 20 years. The initial cohort consisted of 811 Caucasian transplant donors and their respective recipients transplanted at he Queen Elizabeth Hospital Birmingham between 1996 and 2006, for which genomic DNA was available. All patients received ciclosporin and corticosteroids as primary immunosuppression, with 23% receiving mycophenolate (77% azathioprine). A comprehensive survey of sequence variation in the target genes was assessed using a “gene tagging” approach based on data from the Hapmap Project, as well as specifically investigating previously identified relevant polymorphisms. Genes studied were: CyP3A4, CyP3A5, ABCB1 (MDR1), PXR, Cyclophilin. Results: Kaplan-Meier analysis revealed that the donor ABCB1 genotype at C3435T was associated with death-censored allograft failure. Inferior outcomes were seen for kidneys from donors expressing the CC genotype. This difference persisted in a Cox proportional hazards model (donor CC versus non-CC genotype: Hazard Ratio [HR]: 1.69; 95%CI: 1.20, 2.40; p=0.003), adjusted for the following: donor age, gender, source (living versus deceased), serum creatinine, hypertension history; recipient age, race, duration of dialysis, cause of renal failure, transplant number, panel reactive anti-HLA antibodies; donor-recipient HLA mismatch. This association between donor ABCB1 genotype at C3435T was next examined in the 2 replication cohorts, the first consisting of 697 patients transplanted in Belfast, and the second consisting of 4656 recipients reported to the Collaborative Transplant Study. In neither of these cohorts was there evidence of an association between donor genotype and death-censored graft failure. No association between any other gene variants (donor or recipient) and either death-censored graft survival or mortality were seen in the Birmingham cohort, and so no attempt was made to replicate these analyses in the other cohorts. Conclusion: This study does not support the concept that either donor or recipient variation at genes relevant for CNI metabolism and transport influences the hard outcomes of kidney transplantation, and reaffirms the importance of replication cohorts prior to assigning relevance to such genetic biomarkers.

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

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. AIM To 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. METHODS The 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. RESULTS Twenty 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]± 5.2%) with an inter-individual variability of 21%. The central volume of distribution (V(c) ) was 18.3 l (RSD ± 8.7%) with an inter-individual variability of 29%. Bioavailability (F) was 0.71 (RSD ± 9.9%) with and inter-individual variability of 25% and lag time (t(lag) ) was 0.44 h (RSD 5.5%). Weight, body surface area, haematocrit, albumin, ALAT and ASAT had no significant influence on pharmacokinetic parameters. The best multiple point combination for posterior Bayesian fitting, in terms of estimating systemic CsA exposure, appeared to be C0 + C2 + C3. Two selected LSS two time point equations and all selected three and four time point equations predicted de all AUC(0,12 h) within 15% bias and prediction. CONCLUSIONS The i.v. and oralcurves were best described with a two compartment model with first-order absorption with lag time. With the Bayesian estimators from this model, the area under the concentration-time curve in HSCT patients taking fluconazole can be estimated with only three blood samples (0, 2, 3 h) with a bias of 1% and precision of 4%.

Moxifloxacin does not Alter Ciclosporin Pharmacokinetics in Transplant Patients

Background: Moxifloxacin has a broad antibacterial spectrum and rapid bactericidal activity, and is thus a good option for the treatment of bacterial infections in patients who have undergone organ or bone marrow transplantation. Transplant patients also receive immunosuppressant therapy such as ciclosporin. Objectives: The primary objective of this study was to assess the steady-state pharmacokinetics of ciclosporin with and without concomitant treatment with moxifloxacin in transplant recipients. A secondary objective was to determine the safety and tolerability of the combined treatment. Methods: Patients (n = 9) with stable graft function after bone marrow or renal transplantation and who were already receiving ciclosporin therapy were enrolled into the study. The patients were given ciclosporin (Sandimmun® Optoral) capsules twice daily (total daily dosage 150–380 mg/day) throughout the study period. Moxifloxacin (Avolox®) tablets 400 mg once daily were given on days 2–8 inclusive. The primary outcome measure was the change in ciclosporin pharmacokinetics on coadministration with moxifloxacin. Secondary outcomes were the steady-state pharmacokinetics of moxifloxacin and ciclosporin plus its metabolites in patients receiving moxifloxacin and ciclosporin concomitantly. Moxifloxacin pharmacokinetic parameters in the presence of ciclosporin were compared with previously published pharmacokinetic data for moxifloxacin in healthy individuals. Results: No significant changes occurred in the concentration-time curves of ciclosporin and its metabolites following combination therapy with moxifloxacin. The geometric means of whole blood concentrations of ciclosporin and ciclosporin plus its metabolites on day 1 were similar to those on day 8 following combined administration of ciclosporin and moxifloxacin for 7 days. The ratio of combination treatment to monotherapy for ciclosporin was 1.01 (90% CI 0.91, 1.11) for the area under the blood concentration-time curve from time zero to 12 hours at steady state (AUC12ss) and 0.96 (90% CI 0.88, 1.04) for the maximum steady-state blood drug concentration (Cmax,ss). For ciclosporin plus its metabolites the ratio was 1.07 (90% CI 0.99, 1.17) for AUC12,ss and 1.03 (90% CI 0.98, 1.09) for Cmax,ss. The pharmacokinetic parameters for moxifloxacin were unaffected by the presence of ciclosporin. Conclusions: Concomitant administration of moxifloxacin does not alter the pharmacokinetic parameters of ciclosporin or ciclosporin plus its metabolites in immunosuppressed patients. Therefore, no dose adjustments or additional drug monitoring are required when ciclosporin is coadministered with moxifloxacin.

Effect of CYP3A and ABCB1 Single Nucleotide Polymorphisms on the Pharmacokinetics and Pharmacodynamics of Calcineurin Inhibitors: Part I

The calcineurin inhibitors ciclosporin (cyclosporine) and tacrolimus are immunosuppressant drugs used for the prevention of organ rejection following transplantation. Both agents are metabolic substrates for cytochrome P450 (CYP) 3A enzymes--in particular, CYP3A4 and CYP3A5--and are transported out of cells via P-glycoprotein (ABCB1). Several single nucleotide polymorphisms (SNPs) have been identified in the genes encoding for CYP3A4, CYP3A5 and P-glycoprotein, including CYP3A4 -392A>G (rs2740574), CYP3A5 6986A>G (rs776746), ABCB1 3435C>T (rs1045642), ABCB1 1236C>T (rs1128503) and ABCB1 2677G>T/A (rs2032582). The aim of this review is to provide the clinician with an extensive overview of the recent literature on the known effects of these SNPs on the pharmacokinetics of ciclosporin and tacrolimus in solid-organ transplant recipients. Literature searches were performed, and all relevant primary research articles were critiqued and summarized. Influence of the CYP3A4 -392A>G SNP on the pharmacokinetics of either ciclosporin or tacrolimus appears limited. Variability in CYP3A4 expression due to environmental factors is likely to be more important than patient genotype. Influence of the CYP3A5 6986A>G SNP on the pharmacokinetics of ciclosporin is also uncertain and likely to be small. CYP3A4 may play a more dominant role than CYP3A5 in the metabolism of ciclosporin. The CYP3A5 6986A>G SNP has a well established influence on the pharmacokinetics of tacrolimus. Several studies in kidney, heart and liver transplant recipients have reported an approximate halving of tacrolimus dose-adjusted trough concentrations and doubling of tacrolimus dose requirements in heterozygous or homozygous carriers of a CYP3A5*1 wild-type allele compared with homozygous carriers of a CYP3A5*3 variant allele. Carriers of a CYP3A5*1 allele take a longer time to reach target blood tacrolimus concentrations. Influence of ABCB1 3435C>T, 1236C>T and 2677G>T/A SNPs on the pharmacokinetics of ciclosporin and tacrolimus remains uncertain, with inconsistent results. Genetic linkage between the three variant genotypes suggests that the pharmacokinetic effects are complex and not related to any one ABCB1 SNP. It is likely that these polymorphisms exert a small but combined effect, which is additive to the effects of the CYP3A5 6986A>G SNP. In liver transplant patients, recipient and donor liver genotypes may act together in determining overall drug disposition, hence the importance of assessing both. Studies with low patient numbers may account for many inconsistent results to date. Meta-analyses of the current data should help resolve some discrepancies. The majority of studies have only evaluated the effects of individual SNPs; however, multiple polymorphisms may interact to produce a combined effect. Further haplotype analyses are likely to be useful. It is not yet clear whether pharmacogenetic profiling of calcineurin inhibitors will be a useful clinical tool for personalizing immunosuppressant therapy.

Moxifloxacin does not Alter Ciclosporin Pharmacokinetics in Transplant Patients

Moxifloxacin does not Alter Ciclosporin Pharmacokinetics in Transplant Patients

Carvedilol increases ciclosporin bioavailability by inhibiting P-glycoprotein-mediated transport

Carvedilol is often used to treat hypertension and for prophylaxis in vascular sclerosis in renal transplant recipients, who require concomitant treatment with ciclosporin. However, there are few reports regarding the pharmacokinetic interactions between carvedilol and ciclosporin. We have investigated the potential effects of carvedilol on the pharmacokinetics of ciclosporin, and examined the inhibitory effects of carvedilol on P-glycoprotein-mediated transcellular transport using Caco2 cells. Ciclosporin alone or with carvedilol was orally or intravenously administered to rats. The oral administration of carvedilol (10 mg kg(-1)) with ciclosporin (10 mg kg(-1)) increased the whole blood concentration of ciclosporin. When ciclosporin (3 mg kg(-1)) was intravenously administered with carvedilol (3 mg kg(-1)), there was no difference in the whole blood ciclosporin concentration between administration with and without carvedilol. Co-administration with carvedilol increased ciclosporin bioavailability from 33% to 70%. In Caco2 cells, carvedilol caused a concentration-dependent increase in the intracellular accumulation of ciclosporin, and its effect was comparable with that of verapamil. Carvedilol considerably raised the concentration of ciclosporin in the blood and this interaction was associated with the absorption phase of ciclosporin. This interaction was caused by the inhibition of P-glycoprotein-mediated transport by carvedilol in the intestine.

Effect of plasma lipid on pharmacokinetics of ciclosporin and its relationship with plasma prednisolone level in renal transplant patients

Ciclosporin (cyclosporine A, CyA) is a potent immunosuppressant used after organ transplantation. The pharmacokinetic properties of CyA vary widely and lipoproteins are the major complexing constituents for CyA in the plasma. Therefore, a change in lipoprotein level may influence the pharmacokinetic properties of CyA. Prednisolone (PSL) is concomitantly used with CyA as an immunosuppressant. After organ transplantation, hyperlipidaemia resulting from PSL therapy has been mostly observed and PSL increased the plasma lipoprotein level. Therefore, in this study, to obtain more useful information of the therapeutic drug monitoring (TDM) of CyA, the relationship between the plasma PSL level, plasma lipoprotein level and blood CyA level was investigated in detail. An open-label, non-randomized, retrospective study was performed. Data from 21 male and 11 female patients (age 11-65 years) who received a living-related renal transplantation from 2002 to 2004 were included. On postoperative days (PODs) 7, 14 and 28, the area under the plasma concentration-time curve until 9 h after 40 mg of PSL administration (AUCPSL40(0-9)) correlated well with total cholesterol (T-cho) (r=0.558, 0.768, 0.660, all P<0.05) and high-density lipoprotein (HDL) (r=0.688, P<0.05; 0.835, P<0.01; 0.508, p<0.05), and correlated negatively with very-low-density lipoprotein (VLDL) (r=-0.486, p<0.01; -0.776, p<0.01; -0.967, p<0.01). In addition, AUC until 9 h after CyA administration (AUCCyA0-9) also correlated with T-cho (r=0.797, p<0.01; 0.577, p<0.05; 0.901, p<0.01), HDL (r=0.514, p<0.05; 0.614, p<0.05; 0.893, p<0.01) and low-density lipoprotein (LDL) (r=0.906, p<0.01; 0.573, p<0.05; 0.537, p<0.05), and there was a negative correlation with VLDL (r=-0.480, -0.630, -0.632, all p<0.05). Moreover, AUCCyA0-9 correlated well with AUCPSL40(0-9) (r=0.728, p<0.01; 0.482, p<0.05; 0.688, p<0.05); namely, it was considered that the variety of plasma PSL concentrations influenced the pharmacokinetic properties of CyA through the change in lipoprotein levels. These results suggested that monitoring of the biochemical parameters of the plasma lipid and plasma PSL level might be useful for the TDM of CyA.

Pharmacokinetic Optimization of Immunosuppressive Therapy in Thoracic Transplantation: Part I

Although immunosuppressive treatments and therapeutic drug monitoring (TDM) have significantly contributed to the increased success of thoracic transplantation, there is currently no consensus on the best immunosuppressive strategies. Maintenance therapy typically consists of a triple-drug regimen including corticosteroids, a calcineurin inhibitor (ciclosporin or tacrolimus) and either a purine synthesis antagonist (mycophenolate mofetil or azathioprine) or a mammalian target of rapamycin inhibitor (sirolimus or everolimus). The incidence of acute and chronic rejection and of mortality after thoracic transplantation is still high compared with other types of solid organ transplantation. The high allogenicity and immunogenicity of the lungs justify the use of higher doses of immunosuppressants, putting lung transplant recipients at a higher risk of drug-induced toxicities. All immunosuppressants are characterized by large intra- and interindividual variability of their pharmacokinetics and by a narrow therapeutic index. It is essential to know their pharmacokinetic properties and to use them for treatment individualization through TDM in order to improve the treatment outcome. Unlike the kidneys and the liver, the heart and the lungs are not directly involved in drug metabolism and elimination, which may be the cause of pharmacokinetic differences between patients from all of these transplant groups. TDM is mandatory for most immunosuppressants and has become an integral part of immunosuppressive drug therapy. It is usually based on trough concentration (C(0)) monitoring, but other TDM tools include the area under the concentration-time curve (AUC) over the (12-hour) dosage interval or the AUC over the first 4 hours post-dose, as well as other single concentration-time points such as the concentration at 2 hours. Given the peculiarities of thoracic transplantation, a review of the pharmacokinetics and TDM of the main immunosuppressants used in thoracic transplantation is presented in this article. Even more so than in other solid organ transplant populations, their pharmacokinetics are characterized by wide intra- and interindividual variability in thoracic transplant recipients. The pharmacokinetics of ciclosporin in heart and lung transplant recipients have been explored in a number of studies, but less is known about the pharmacokinetics of mycophenolate mofetil and tacrolimus in these populations, and there are hardly any studies on the pharmacokinetics of sirolimus and everolimus. Given the increased use of these molecules in thoracic transplant recipients, their pharmacokinetics deserve to be explored in depth. There are very few data, some of which are conflicting, on the practices and outcomes of TDM of immunosuppressants after thoracic transplantation. The development of sophisticated TDM tools dedicated to thoracic transplantation are awaited in order to accurately evaluate the patients' exposure to drugs in general and, in particular, to immunosuppressants. Finally, large cohort TDM studies need to be conducted in thoracic transplant patients in order to identify the most predictive exposure indices and their target values, and to validate the clinical usefulness of improved TDM in these conditions. In part I of the article, we review the pharmacokinetics and TDM of calcineurin inhibitors. In part II, we will review the pharmacokinetics and TDM of mycophenolate and mammalian target of rapamycin inhibitors, and provide an overall discussion along with perspectives.

Ciclosporin kinetics in children after stem cell transplantation

To 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. The 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. Pharmacokinetics was described adequately with a two-compartment model with lag time (population estimates: CL = 11.3 l h(-1); V(c) = 16.5 l; V(p) = 59.9 l; t(1/2) absorption = 0.78 h, t(lag) = 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. A 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, followed by AUC determination and dose adjustment.

Place du suivi biologique des traitements immunosuppresseurs : exemple de la mesure de l’activité calcineurine en transplantation hépatique

Therapeutic monitoring of calcineurin inhibitors (ciclosporin and tacrolimus) consists in pharmacokinetic monitoring. Pharmacodynamics based on calcineurin activity may be particularly interesting in liver transplantation due to the large intra- and interindividual variability of pharmacokinetics of ciclosporin and tacrolimus. A recent investigation on the pharmacokinetic-pharmacodynamic relationship of tacrolimus showed that monitoring of calcineurin activity in PBMC may be particularly relevant within the first three post-transplantation months. Thereafter, the monitoring of trough blood concentrations of tacrolimus remains adequate. Moreover, two clinical investigations carried out within the early and late post-transplantation periods reported a promising result which is a positive correlation between calcineurin activity and incidence of graft rejection, whatever graft type and calcineurin inhibitors. In each study, transplanted recipients with a graft rejection exhibited a greater trough calcineurin activity compared to patients without graft rejection. However, prospective investigations are required because of the small cohorts of patients enrolled in both studies. The aim of these investigations will be to confirm the interest of calcineurin activity monitoring as a marker of cellular immunity and its positive link with pharmacokinetic monitoring.

Blood and Plasma Pharmacokinetics of Ciclosporin in Diabetic Kidney Transplant Recipients

Long-term diabetes mellitus may affect the absorption, distribution and metabolism of immunosuppressive agents used after organ transplantation. The aims of this study were to characterize ciclosporin pharmacokinetics in blood and plasma and to compare the ciclosporin unbound concentration and the blood : plasma concentration (B : P) ratio in diabetic kidney transplant recipients. Ciclosporin 12-hour steady-state pharmacokinetics were studied in eight diabetic and nine nondiabetic patients. Ciclosporin concentrations in whole blood and in plasma were measured using liquid chromatography-tandem mass spectrometry, and the ciclosporin fraction unbound (f(u)) was determined by an equilibrium dialysis method utilizing [(3)H]ciclosporin as a tracer. Oral absorption of paracetamol (acetaminophen) was used as a marker for gastric emptying. In diabetic patients, the time to the peak blood ciclosporin concentration at steady state (t(max)(,ss)) was prolonged (128 minutes vs 93 minutes in nondiabetic patients, p < 0.01) and, on average, the paracetamol t(max) was prolonged by 30 minutes. The whole-blood dose-normalized area under the concentration-time curve from 0 to 12 hours (AUC(12)) was marginally lower in diabetic patients (p = 0.09) and the plasma AUC(12) was significantly lower (p = 0.03). The ciclosporin f(u) was numerically higher in diabetic patients (1.20 +/- 0.65% vs 0.72 +/- 0.28% in nondiabetic patients, p = 0.066); however, the unbound concentration values were essentially similar in the two groups (0.58 +/- 0.76 microg/L in diabetic patients and 0.52 +/- 0.48 microg/L in nondiabetic patients; p = 0.59). No difference was observed in the ciclosporin B : P ratio between the two groups. This study indicates that diabetes delays ciclosporin absorption, reduces ciclosporin exposure and increases the ciclosporin f(u) but not the pharmacologically active unbound concentration.