Pharmacokinetics Of Cyclosporine Research Articles

Population pharmacokinetics of cyclosporine A in pediatric patients with thalassemia undergoing allogeneic hematopoietic stem cell transplantation.

To establish the population pharmacokinetics (PPK) model of cyclosporine A(CsA) in pediatric patients with thalassemia undergoing allogeneic hematopoietic stem cell transplantation (HSCT), aiming at providing a reference for clinical dose individualization of CsA. Children with thalassemia who underwent allogeneic HSCT were enrolled retrospectively. The PPK structural model and the random variable model of CsA were established on NONMEN. And goodness of fit plots (GOFs), visual predictive check (VPC), and bootstrap and normalized prediction distribution errors (NPDE) were used to evaluate the final model. A one-compartment model with first-order absorption was employed to fit the base model. A total of 74 pediatric patients and 600 observations of whole blood concentration were included. The final model included weight (WT) in clearance (CL), alongside post-operative day (POD), fluconazole (FLUC), voriconazole (VORI), posaconazole (POSA), and red blood cell count (RBC) significantly. All the model evaluations were passed. In the PPK model based on the pediatric cohort on CsA with thalassemia undergoing allogeneic HSCT, WT, POD, FLUC, VORI, POSA, and RBC were found to be the significant factors influencing CL of CsA. The reliability and robustness of the final model were excellent. It is expected that the PPK model can assist in individualizing dosing strategy clinically.

Effects of intestinal microbiota on pharmacokinetics of cyclosporine a in rats.

Intestinal microbiota has been confirmed to influencing the pharmacokinetic processes of a variety of oral drugs. However, the pharmacokinetic effects of the gut microbiota on cyclosporine A, a drug with a narrow therapeutic window, remain to be studied. Twenty-one rats were randomly divided into three groups: (a) control group (CON), (b) antibiotic treatment group (ABT) and (c) fecal microbe transplantation group (FMT). The ABT group was administrated with water containing multiple antibiotics to deplete microorganisms. FMT was with the same treatment, followed by oral administration of conventional rat fecal microorganisms for normalization. The bioavailability of CSA increased by 155.6% after intestinal microbes were consumed by antibiotics. After intestinal microbiota reconstruction by fecal transplantation, the increased bioavailability was significantly reduced and basically returned to the control group level. Changes in gut microbiota alter the protein expression of CYP3A1, UGT1A1 and P-gp in liver. The expressions of these three proteins in ABT group were significantly lower than those in CON and FMT groups. The relative abundance of Alloprevolleta and Oscillospiraceae UCG 005 was negatively correlated with CSA bioavailability while the relative abundance of Parasutterella and Eubacterium xylanophilum group was negatively correlated with CSA bioavailability. Intestinal microbiota affects the pharmacokinetics of CSA by regulating the expression of CYP3A1, UGT1A1 and P-GP.

A Review of the Pharmacokinetics of Cyclosporin

This papers provides a review of the pharmacokinetics (PK) of Cyclosporin A (CsA), a potent immunosuppressant that has been effectively used to prevent graft rejection in transplantation medicine and to treat several autoimmune diseases. The extensive variability of CsA kinetics along with its narrow therapeutic index make regular PK profiling of patients as part of routinely carried out therapeutic drug monitoring very important to ensure safety and efficacy of the treatment. Classical as well as population based PK studies provide information that aid in that regard. It is anticipated that CsA will continue to be extensively used, especially with the emergence of advanced delivery systems which target specific sites of action and reduce its toxicity.

A Phase 1, open-label, crossover study evaluating the effect of a single dose of sodium zirconium cyclosilicate on the pharmacokinetics of tacrolimus and cyclosporin.

Sodium zirconium cyclosilicate (SZC) is an oral, highly selective potassium binder approved for the treatment of hyperkalaemia in adults. SZC may change the absorption of co-administered drugs that exhibit pH-dependent bioavailability. This study evaluated whether the pharmacokinetic (PK) profiles of tacrolimus and cyclosporin were altered by concomitant SZC administration in healthy participants. This was an open-label, randomised sequence, two-cohort crossover, single-centre study. Healthy adults were assigned to one of two cohorts: Cohort 1 (tacrolimus) received a single dose of tacrolimus 5mg and tacrolimus 5mg+SZC 15g in a random order; Cohort 2 (cyclosporin) received a single dose of cyclosporin 100mg and cyclosporin 100mg+SZC 15g in a random order. Primary PK endpoints were maximum observed blood concentration (Cmax) and area under the concentration-time curve (AUC) from time zero to infinity (AUCinf). Differences in mean Cmax and AUCinf were analysed using a mixed effects model. Thirty participants in Cohort 1 and 29 in Cohort 2 completed the study. Tacrolimus exposure was lower with tacrolimus+SZC versus tacrolimus alone: Cmax geometric mean ratio (GMR) 71.10% [90% confidence interval (CI) 65.44-77.24], AUCinf 62.91% (55.64-71.13). Cyclosporin exposure was similar with cyclosporin+SZC compared with cyclosporin alone: Cmax GMR 102.9% (90% CI 96.11-110.10), AUCinf 97.23% (92.93-101.70). Tacrolimus exposure was lower when co-administered with SZC 15g and should be administered ≥2h before or after SZC. The PK profile of cyclosporin was not affected by SZC co-administration.

Population Pharmacokinetics of Cyclosporine in Chinese Pediatric Patients With Acquired Aplastic Anemia.

Cyclosporine (CsA) is a component of the first-line treatment for acquired aplastic anemia (acquired AA) in pediatric patients. This study aimed to develop a population pharmacokinetic (PK) model of CsA in Chinese pediatric patients with acquired AA to inform individual dosage regimens. A total of 681 CsA whole blood concentrations and laboratory data of 157 pediatric patients with acquired AA were retrospectively collected from two hospitals in Shanghai. A nonlinear mixed-effect model approach was used to build the population PK model. Potential covariate effects of age, body weight, and biochemical measurements (renal and liver functions) on CsA PK disposition were evaluated. Model fit was assessed using the basic goodness of fit and a visual predictive check. The CsA concentration data were accurately described using a two-compartment disposition model with first-order absorption and elimination. Body weight value was implemented as a fixed allometric function on all clearance and volume of distribution parameters. Total bilirubin level was identified as a significant covariate on apparent clearance (CL/F), with a 1.07% reduction per 1 nmol/L rise in total bilirubin level. The final estimates for CL/F and central volume (Vc/F) were 29.1 L/h and 325 L, respectively, for a typical 28 kg child. Other covariates (e.g., gender, age, albumin, hemoglobin, hematocrit, serum creatinine, and concomitant medication) did not significantly affect the PK properties of CsA. This population PK model, along with a maximum a posteriori Bayesian approach, could estimate individual PK parameters in pediatric patients with acquired AA to conduct individual CsA therapy.

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.

Pharmacokinetic and Pharmacodynamic Considerations in Relation to Calcineurin Usage in Elderly Kidney Transplant Recipients.

This review summarizes how possible age-related changes in tacrolimus and cyclosporine pharmacokinetics and pharmacodynamics may influence drug dosing and monitoring in the elderly, and highlights how micro-sampling may be useful in this cohort in the future. Advancing biological age leads to physiological changes that can affect drug absorption, distribution, metabolism and excretion, as well as immune system responsiveness. Some studies have shown that elderly recipients may have higher dose-adjusted exposure and/or lower clearance of the calcineurin inhibitors, suggesting that doses may need to be lowered in elderly recipients. Only one study has examined how aging effects drug target enzyme activity and demonstrated that age does not correlate with the calcineurin inhibitor half-maximal inhibitory concentration. Several studies have shown elderly kidney transplant recipients have increased risk of both morbidity and mortality, compared to younger adults due to increased susceptibility to immunosuppressant side effects, particularly cardiovascular disease, infection and malignancy. Current immunosuppressant dosing and monitoring protocols often make no adjustments for age. Lower maintenance immunosuppressant targets in elderly recipients may decrease patient susceptibility to drug side effects, however, further studies are required and appropriate targets need to be established. Blood draw by micro-sampling may be useful for drug monitoring in this cohort in the future, as blood collection is minimally invasive and less painful than venepuncture. Micro-sampling could also make further pharmacokinetic, pharmacodynamics and outcome studies in the elderly more feasible.

Inhibition effect of epigallocatechin-3-gallate on the pharmacokinetics of calcineurin inhibitors, tacrolimus, and cyclosporine A, in rats

ABSTRACT Background Epigallocatechin-3-gallate (EGCG) is the most biologically active catechin of green tea. Tacrolimus (TAC) and cyclosporine A (CsA) are immunosuppressive agents commonly used in clinical organ transplantation. The present study investigated the effect of EGCG on the pharmacokinetics of TAC and CsA in rats and its underlying mechanisms. Research design and methods Either TAC or CsA was administered to rats intravenously or orally with or without concomitant EGCG. Polymerase Chain Reaction and Western Blot were used to determine the effect of EGCG on drug-metabolizing enzymes (DMEs), drug transporters (DTs) and nuclear receptors (NRs). Results The Cmax and AUC of TAC were reduced, and V/F and CL/F of TAC were enhanced after co-administration of EGCG. EGCG increased the Cmax, AUC of CsA at 3 ~ 30 mg∙kg-1 dosages, while decreased those parameters at the dosage of 100 mg∙kg-1. EGCG inhibited the mRNA and protein expressions of DMEs and DTs, such as CYP3A1, A2, UGT1A1, Mdr1 and Mrp2, but upregulated the expressions of Car, Pxr and Fxr. Conclusions These results revealed consumption of high dose EGCG may cause a significant alteration in pharmacokinetics of TAC and distribution/elimination profiles of CsA through the regulation of DMEs, DTs and NRs.

Food and lipid intake alters the pharmacokinetics of cyclosporine in kidney transplants.

Prevention of kidney graft rejection with cyclosporine leads to a large interindividual pharmacokinetic variability. However, food intake is likely to alter cyclosporine pharmacokinetics, and therefore its efficacy. The aim of our study was to evaluate the influence of food and lipid intake on cyclosporine pharmacokinetics. Twenty-four kidney grafted patients treated with Neoral® were included in this prospective monocentric study. In all patients, the pharmacokinetics of cyclosporine was evaluated in two occasions, after meal ('feed') and without meal ('fasting'). At each occasion, blood samples were collected at trough, and 0.5, 1, 2, 3, and 4h after administration. Cyclosporine pharmacokinetics was described using a Bayesian pharmacokinetic model including two-compartments with first-order transfer and elimination rate constants, and a gamma absorption model. Influence of meal or olive oil, very common in Morocco, was tested as covariates on interoccasion variability parameters. Cyclosporine concentration-time data were satisfactorily described using the Bayesian pharmacokinetic model. Food intake significantly increased volume of distribution and decreased elimination of cyclosporine. The influence of oil intake explained a large part of this effect, suggesting that lipid intake was the main factor of pharmacokinetic variability due to food. This intake resulted in a decrease in area under the concentration curve between two administrations of 14.6%. Food, and especially lipid intake is likely to decrease the exposure to cyclosporine and may therefore lead to a decrease in treatment efficacy. Therefore, to ensure optimal immunosuppression in time, meal composition should remain as steady as possible.

Dextran sulfate sodium-induced colitis and ginseng intervention altered oral pharmacokinetics of cyclosporine A in rats

Ethnopharmacological relevanceApplication of cyclosporine A (CsA) as a rescue treatment in acute severe ulcerative colitis (UC) is limited by its narrow therapeutic window and great interpatient variability. As a substrate of cytochrome P450 3A enzyme (CYP3A) and P-glycoprotein (P-gp), the oral pharmacokinetics of CsA is susceptible to disease status and concomitant medications. Combined treatment with ginseng, a famous medicinal herb frequently prescribed for ameliorating abnormal immune response in many diseases including UC, showed immunologic safety in CsA-based immunosuppression. Aim of the studySince the therapeutic levels of CsA can be achieved within 24 h, this study first assessed the impact of acute colitis and ginseng intervention on the single oral dose pharmacokinetics of CsA and explored the underlying mechanisms in dextran sulfate sodium (DSS)-induced colitis rats and Caco-2 cells. Materials and methodsRats received drinking water (normal group), 5% DSS (UC group), or 5% DSS plus daily oral ginseng extract (GS+UC group). On day 7, GS+UC group only received an oral dose of CsA (5 mg/kg), while animals of normal or UC group received an oral, intravenous (1.25 mg/kg), or intraperitoneal dose of CsA (1.25 mg/kg), respectively. Blood, liver/intestine tissues and fecal samples were collected for determining CsA and main hydroxylated metabolite HO-CsA or measuring hepatic/intestinal CYP3A activity. Caco-2 cells were incubated with gut microbial culture supernatant (CS) of different groups or ginseng (decoction or polysaccharides), and then CYP3A, P-gp and tight junction (TJ) proteins were determined. ResultsOral CsA exhibited enhanced absorption, systemic exposure and tissue accumulation, and lower fecal excretion, while intravenous or intraperitoneal CsA showed lower systemic exposure and enhanced distribution, in colitis rats. Diminished intestinal and hepatic P-gp expression well explained the changes with DSS-induced colitis. Moreover, blood exposures of HO-CsA in both normal and colitis after oral dosing were significantly higher than intravenous/intraperitoneal dosing, supporting the dominant role of intestinal first-pass metabolism. Interestingly, colitis reduced CYP3A expression in intestine and liver but only potentiated intestinal CYP3A activity, causing higher oral systemic exposure of HO-CsA. Oral ginseng mitigated colitis-induced down-regulation of CYP3A and P-gp expression, facilitated HO-CsA production, biliary excretion and colonic sequestration of CsA, while not affected CsA oral systemic exposure. In Caco-2 cells, gut microbial CS from both colitis and GS+UC group diminished P-gp function, while ginseng polysaccharides directly affected ZO-1 distribution and suppressed TJ proteins expression, explaining unaltered oral CsA systemic exposure. ConclusionsDSS-induced colitis significantly altered oral CsA disposition through regulating intestinal and hepatic P-gp and CYP3A. One-week ginseng treatment enhanced colonic accumulation while not altered the systemic exposure of CsA after single oral dosing, indicating pharmacokinetic compatibility between the two medications.

Pomegranate Juice does not Affect the Bioavailability of Cyclosporine in Healthy Thai Volunteers.

BackgroundIt is still controversial whether pomegranate causes drug interactions. Pomegranate juice has been shown to inhibit CYP3A in-vitro and animal studies. The co-administration of pomegranate juice with cyclosporine, a narrow therapeutic drug that is the substrate of CYP3A, might lead to drug toxicity. The objective of this study is to investigate the effect of pomegranate juice on the pharmacokinetics of cyclosporine in healthy Thai volunteers.MethodsThe study design was an open-label, randomized, single dose, crossover study with a 2-week washout period. Each fasting subject received 2 microemulsion tablets of 100 mg of cyclosporine with 500 ml of pomegranate juice (test) or 500 ml of water (control). Serial blood samples were collected up to 24 h after dosing, and blood samples were analyzed for cyclosporine concentrations by using chemiluminescent microparticle immunoassay. Fourteen healthy volunteers completed the study.ResultsThe 90% confidence intervals for the test/control ratio using logarithmically transformed data of area under the concentration-time curve (AUC) from time zero until the last measured concentration (AUC0-t), AUC from time zero to infinity (AUC0-∞), and maximum concentration (Cmax) were 91.6-105.6, 92.0-105.2 and 82.3-102.5, respectively. The results were within the accepted bioequivalence range for narrow therapeutic index drugs (90-111% for AUC and 80-125% for Cmax). There were no differences in adverse event between the groups.ConclusionSingle dose administration of pomegranate juice with cyclosporine did not significantly affect the oral bioavailability of cyclosporine. However, further work is needed to thoroughly evaluate the effect of pomegranate on narrow therapeutic drugs.

Effects of coadministrations of unripe fruits and ripe peels of citrus aurantium on cyclosporine pharmacokinetics in rats

The unripe fruits (UF) and ripe peels (RP) of Citrus aurantium are two widely used Chinese herbs. Cyclosporine, an important immunosuppressant with narrow therapeutic window, is clinically subject to relevant interaction with Citrus herbs as with grapefruit juice. This study investigated the effects of coadministration of UF and RP on cyclosporine pharmacokinetics in rats. Sprague-Dawley rats received cyclosporine (2.5 mg/kg) orally with and without the UF and RP decoctions individually. Blood samples taken via cardiopuncture were assayed for cyclosporine by a specific monoclonal fluorescence polarization immunoassay. After coadministration orally with UF decoction, the Cmax and AUC0-t of cyclosporine were significantly decreased by 72.8% and 55.6%, respectively. However, when RP was coadministered orally, no conspicuous alteration of cyclosporine pharmacokinetics was observed. It can be concluded that UF, but not RP decoction, significantly decreased the bioavailability of oral cyclosporine. We suggest that coadministration of Citrus herbs with cyclosporine is better avoided to ensure the efficacy and safety of cyclosporin medication.

Marked decrease of cyclosporin absorption caused by coadministration of Cordyceps sinensis in rats

Cordyceps (Cordyceps sinensis Saccardo.) is a popular traditional tonic used in Taiwan and mainland China. Cyclosporin is an important immunosuppressant with narrow therapeutic index. This study investigated the effect of coadministration of cordyceps on cyclosporin pharmacokinetics in rats. Cyclosporin was intravenously (0.8 mg/kg) and orally (2.5 mg/kg) administered with and without cordyceps (2.0 g/kg), respectively, in crossover designs. Blood samples were collected by cardiopuncture and quantitated by a specific monoclonal fluorescence polarization immunoassay. Pharmacokinetic parameters of cyclosporin were calculated using noncompartment model. Paired Student's t-test was used for statistical comparison. Our results indicated that oral coadministration of cordyceps significantly decreased the Cmax and AUC0-540 of cyclosporin by 85.5% and 83.2%, respectively. In addition, when rats were given cordyceps 1 hr before cyclosporin dosing, the Cmax and AUC0-540 of cyclosporin were significantly decreased by 85.9% and 84.4%, respectively. By contrast, when cyclosporin was given as an intravenous bolus, the disposition of cyclosporin was not altered by cordyceps, indicating that the interaction between oral cyclosporin and cordyceps occurred during the absorption phase. In conclusion, cordyceps markedly decreased the oral bioavailability of cyclosporin. Patients treated with cyclosporin are suggested to avoid the concurrent use of cordyceps for efficacy and safety.

Erectile Dysfunction after Kidney Transplantation.

Patients with kidney transplantation often have a worse quality of life than the general population. One of the reasons for this, in male patients, is the high prevalence of erectile dysfunction. This is mainly due to the presence of comorbidities, surgery for kidney transplantation, adverse drug effects, psychological changes related to chronic disease, as well as hyperprolactinemia and hypogonadism. Whenever these endocrine dysfunctions occur after kidney transplantation, they must be corrected with appropriate treatment, i.e., testosterone replacement therapy. Administration of the phosphodiesterase-5 inhibitor (PDE5i) sildenafil at the recommended posology does not significantly alter the pharmacokinetics of the calcineurin inhibitors cyclosporin A or tacrolimus and does not impair kidney allograft function. Tacrolimus increases the peak concentration and prolongs the half-life of PDE5i in kidney transplant patients and, therefore, daily administration cannot be recommended due to the significant drop in blood pressure. Intracavernous injection or topical application of alprostadil can be a second-line option for the treatment of erectile dysfunction after kidney transplantation, which does not alter cyclosporine concentrations and does not deteriorate kidney function. Finally, penile prostheses can be successfully implanted following pelvic organ transplantation after eliminating the risk of infection associated with surgery.

Population pharmacokinetics of cyclosporine A in Chinese patients with nephrotic syndrome in individualized drug administration

To establish a population pharmacokinetic (PopPK) model of cyclosporine A (CsA) in Chinese patients with nephrotic syndrome (NS) and to use the model to guide the adjustment of individualized dosage regimens. 216 CsA therapeutic drug monitoring (TDM) concentration observations were collected from 127 Chinese patients with NS. The basic model was developed as a one-compartment PK model with first-order absorption and linear elimination. The first-order conditional estimation (FOCE) method was applied to establish the final model with covariates using NONMEM software. The final model was evaluated through internal validation including goodness-of-fit analysis and bootstrap method as well as external validation using 39 additional PK observations from 35 patients with NS. A PopPK model of CsA was established in Chinese NS patients with influence of body weight on clearance. The internal and external validation results showed that the final model was stable. The established population model adequately characterized the PK of CsA in Chinese patients and could support individualized medication during treatment of NS with CsA.

Possible Role of P-Glycoprotein in Cyclosporine -Acitretin Drug Interaction

P-glycoprotein, an efflux transporter prevents intracellular accumulation of xenobiotics. Cyclosporine A and acitretin are used to treat psoriasis. The present research work aims to investigate the possible role of P-glycoprotein in Cyclosporine- Acitretin drug interaction due to evidence of both drugs having affinity for P-glycoprotein.The study has three different objective namely to assess apparent permeability coefficient of cyclosporine in presence of acitretin by non-everted sac technique, to study the intestinal permeation and absorption kinetics of cyclosporine in presence of acitretin by single pass intestinal perfusion (SPIP) technique and to study the influence of acitretin on oral bioavailability of cyclosporine in Wistar rats.The result of ex vivo, in situ and in vivo study showed that cyclosporine level increased in a time dependent manner. As the dose of acitretin increases the cyclosporine concentration in all three methods tend to increase and was statistically significant. The improvement in absorption of cyclosporine may be due to the inhibition of P-glycoprotein transporter in the intestine by acitretin. Thus acitretin may enhance the oral pharmacokinetics of cyclosporine. Hence this combination may require close monitoring for better therapeutic outcome. Our study confirmed the inhibitory role of acitretin on P-glycoprotein leading to increase concentration of cyclosporine.

Population pharmacokinetics of cyclosporine in Chinese children receiving hematopoietic stem cell transplantation.

Cyclosporine (CsA) is characterized by a narrow therapeutic window and high interindividual pharmacokinetic variability, particularly in juvenile patients. The aims of this study were to build a population pharmacokinetic model of CsA in Chinese children with hematopathy who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) and to identify covariates affecting CsA pharmacokinetics. A total of 86 Chinese children aged 8.4 ± 3.8 years (range 1.1–16.8 years) who received allo-HSCT were enrolled. Whole blood samples were collected before allo-HSCT. Genotyping was performed using an Agena MassARRAY system. A total of 1010 trough plasma concentration values of CsA and clinical data were collected. The population pharmacokinetic model of CsA was constructed using nonlinear mixed-effects modeling (NONMEM) software. The stability and performance of the final model were validated using bootstrapping and normalized prediction distribution errors. We showed that a one-compartment model with first-order elimination adequately described the pharmacokinetics of CsA. The typical values for clearance (CL) and volume of distribution (V) were 42.3 L/h and 3100 L, respectively. Body weight, postoperative days, CYP3A4*1 G genotype, estimated glomerular filtration rate and coadministration of triazole antifungal drugs were identified as significant covariates for CL. Weight and postoperative days were significant covariates for the V of CsA. Our model can be adopted to optimize the CsA dosing regimen for Chinese children with hematopathy receiving allo-HSCT.

The Pharmacokinetic Prediction of Cyclosporin A after Coadministration with Wuzhi Capsule

We aim to describe the influence of principal ingredients of Wuzhi capsule, schisandrin A (SIA) and schisantherin A (STA), on the pharmacokinetics of cyclosporin A (CsA) and to quantify the herb-drug interactions (HDIs) between SIA, STA, and CsA. CsA is a first-line immunosuppressant for anti-rejection therapy after solid organ transplantation, while narrow therapeutic window associated with strong hepatotoxicity largely limited its use. Wuzhi capsule, a liver-protective drug, was approved for coadministration with CsA to reduce the hepatotoxicity. There are few studies exploring HDIs of CsA when coadministered with Wuzhi capsule. The essential adjusted physicochemical data and pharmacokinetic parameters of SIA, STA, and CsA were collected. Then physiologically based pharmacokinetic (PBPK) models of SIA, STA, and CsA were built and verified in healthy subjects using Simcyp respectively. The refined PBPK models were used to estimate potential HDIs between CsA and SIA, STA. The simulated plasma concentration-time curves of CsA, SIA, and STA were in good accordance with the observed profiles respectively. CsA pharmacokinetics were improved after coadministration. After a single dose and multiple doses, the area under the plasma concentration-time curve (AUC) of CsA was increased by 47% and 226% when coadministered with STA, respectively, and by 8% and 36% when coadministered with SIA, respectively. PBPK models sufficiently described the pharmacokinetics of CsA, SIA, and STA. Compared with SIA, STA inhibited CsA metabolism to a greater extent. Our result revealed the dose of CsA can be reduced to maintain similar profile when used concomitantly with Wuzhi capsule.

Efficacy of telaprevir-based therapy in stable liver transplant patients with chronic genotype 1 hepatitis C

Background and rationale. The REPLACE study (NCT01571583) investigated telaprevir-based triple therapy in patients who have recurrent genotype 1 hepatitis C virus (HCV) infection following liver transplantation and are on a stable immunosuppressant regimen of tacrolimus or cyclosporin A. Patients received telaprevir 750 mg 8-hourly with pegylated interferon 180 μg weekly and ribavirin 600 mg daily, followed by a further 36 weeks of pegylated interferon and ribavirin alone and 24 weeks of follow-up. Efficacy (sustained virological response [SVR] 12 weeks after last planned study dose), safety and tolerability of telaprevir throughout the study were assessed. Pharmacokinetics of telaprevir, tacrolimus and cyclosporin A were also examined.Results. In total, 74 patients were recruited. Overall, 72% (53/74; 95% CI: 59.9 to 81.5) of patients achieved SVR at 12 weeks following completion of treatment. Anticipated increases in plasma concentrations of tacrolimus and cyclosporin A occurred during telaprevir treatment and were successfully managed through immunosuppressant dose reduction and, for tacrolimus, reduced dosing frequency. Safety and tolerability of telaprevir-based triple therapy were generally comparable with previous data in non-transplant patients, although rates of reported anemia (55% [41/74]) were higher. Elevated plasma creatinine (46% [34/74]) was observed during REPLACE - consistent with the post-liver transplant population and the co-administered immunosuppressants.Conclusion. Telaprevir-based triple therapy in patients with recurrent genotype 1 HCV infection following liver transplantation produced high rates of SVR. Therapeutic concentrations of immunosuppressants were maintained successfully through dose modification during telaprevir treatment.

A Single Dose of Baicalin Has No Clinically Significant Effect on the Pharmacokinetics of Cyclosporine A in Healthy Chinese Volunteers.

Despite its narrow therapeutic window and large interindividual variability, cyclosporine A (CsA) is the first-line therapy following organ transplantation. Metabolized mainly by CYP3A and being a substrate of P-glycoprotein (P-gp), CsA is susceptible to drug–drug interactions. Baicalin (BG) is a drug used for adjuvant therapy of hepatitis in traditional Chinese medicine. Since its aglycone baicalein (B) inhibits CYP3A and P-gP, co-administration might affect CsA pharmacokinetics. This study investigated the effect of BG on CsA pharmacokinetics. In a two-period study, 16 healthy volunteers received a single 200 mg oral CsA dose alone (reference period) or in combination with 500 mg BG (test period). Pharmacokinetic evaluation of CsA was carried out using non-compartmental analysis (NCA) and population pharmacokinetics (popPK). Treatments were compared using the standard bioequivalence method. Based on NCA, 90% CIs of AUC and Cmax test-to-reference ratios were within bioequivalence boundaries. In the popPK analysis, a two-compartment model (clearance/F 62.8 L/h, central and peripheral volume of distribution/F 254 L and 388 L) with transit compartments for absorption appropriately described CsA concentrations. No clinically relevant effect of 500 mg BG co-administration on CsA pharmacokinetics was identified and both treatments were well tolerated.