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

WHAT IS KNOWN AND OBJECTIVES: 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. METHODS: 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. RESULTS AND DISCUSSION: 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 19.8 L/h with an inter-individual variability of 13.1%. The volume of distribution was 1340 L. 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. WHAT IS NEW AND CONCLUSION: 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.

Effects of CYP3A5, ABCB1 and POR*28 polymorphisms on pharmacokinetics of tacrolimus in the early period after renal transplantation.

1. We aimed to establish a population pharmacokinetic (PK) model of tacrolimus and identify clinical covariates, especially the genetic polymorphisms of CYP3A5, ABCB1 and POR*28 that affected the PK to prevent fluctuation in the trough concentration of tacrolimus during the early period after renal transplantation. 2. Tacrolimus trough concentration, clinical data and CYP3A5/ABCB1/POR28 genotypes were retrospectively collected from 234 kidney transplant recipients during the first month post-transplantation. The population PK model was built using the non-linear mixed effects modeling software NONMEM. Dosing simulation was performed based on the final model. 3. A one-compartment model with first-order absorption and elimination was used to characterize the PK of tacrolimus. Among the genotypes, only CYP3A5 genotype was confirmed to have clinical significance. The final model describing CL/F (l/h) was as follows: 23.3 × ( HCT / 0.309 ) - 0.445   × [ ( 0.897 ,   i f   POD   > 10 ) o r   ( 1 , i f   POD   ≤ 10 ) ] × ( 0.657 , i f   CYP 3 A 5 * 3 / * 3   genotype ) . The inter-individual variability in CL/F was 21.9%. Monte Carlo simulation based on the final model was carried out to determine the optimal dosage regimen. 4. CYP3A5 genotype, post-operative day and hematocrit were confirmed as critical PK factors of tacrolimus. The model could be used to accurately predict individual PK parameters of tacrolimus and provide valuable insights into the dosage optimization.

Efficacy and safety of canagliflozin in subjects with type 2 diabetes: systematic review and meta-analysis.

PURPOSE: To assess the efficacy and safety of the novel sodium glucose co-transporter 2 (SGLT2) inhibitor-canagliflozin for type 2 diabetes (T2DM). METHODS: A search of Medline (1946-January 2014), Embase (1950-January 2014), and The Cochrane Library for randomized controlled trials of canagliflozin compared to placebo or active comparator in T2DM was performed. Clinical Trials website and unpublished U.S. Food and Drug Administration data were also searched. RESULTS: Ten trials including 6,701 patients were analyzed. Compared with placebo, canagliflozin produced absolute reductions in glycated hemoglobin A1c levels when used as monotherapy (weighted mean difference (WMD) -1.08%, 95% confidence interval (CI) [-1.25 to -0.90], p < 0.00001) or add-on treatment (WMD -0.73%, 95%CI [-0.84 to -0.61], p < 0.00001). When compared with other active comparators, canagliflozin significantly reduced HbA1c by -0.21% (WMD, 95%CI [-0.33 to -0.08], p = 0.001). Canagliflozin led to greater body weight loss (vs. placebo, WMD -2.81 kg, 95%CI [-3.26 to -2.37]; vs. active comparators, WMD -3.49 kg, 95%CI [-4.86 to -2.12]). Hypoglycemia with canagliflozin was similar to placebo or sitagliptin, and was lower than glimepiride (risk ratio (RR) 0.15, 95%CI [0.10 to 0.22]). Genital tract infections were more common with canagliflozin (vs. placebo, RR 3.76, 95%CI [2.23 to 6.35]; vs. active comparators, RR 4.95, 95%CI [3.25 to 7.52]). Similar incidences of urinary tract infections were noted with canagliflozin compared with control groups. CONCLUSION: Canagliflozin led to improvements in reducing glycated hemoglobin A1c levels and body weight with low risk of hypoglycemia in patients with T2DM. Common adverse effects including genital tract infections and osmotic diuresis-related AEs were identified and reviewed. Risks of cardiovascular events are even less certain, and more data on long-term effects are needed.