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.
Valproic acid (VPA) is a classic medication for several types of epilepsy and mood disorders, and some of its effectiveness and toxicity is associated with metabolites.Although many reports have reported the drug-drug interactions of VPA, no study has focused on the influence of carbapenems (CBPMs) on VPA's active metabolites.An LC-MS/MS method for determining VPA and its six metabolites (3-hydroxy valproic acid, 4-hydroxy valproic acid, 2-propyl-2-pentenoic acid, 2-propyl-4-pentenoic acid, 3-keto valproic acid, and 2-propylglutaric acid) in human serum was established and applied to evaluate the drug-drug interaction with CBPMs in epileptic patients.The stable isotope valproic acid-d6 was used as an internal standard. Analytes in serum samples (50 μl) were isolated using a Kinetex C 18 column (3 Â 100 mm, 2.6 μm) and detected via negative electrospray ionization after protein precipitation.It was linear (r > 0.99) over the calibration range for different analytes. The accuracy was 91.44-110.92%, and the precision was less than 9.98%. The matrix effect, recovery, and stability met the acceptance criteria. According to the data collected from 150 epileptic patients, the concentration-dose ratio for VPA and its metabolites decreased with CBPM polytherapy. This method is simple and rapid with great accuracy and precision. It is suitable for routine clinical analysis of VPA and its metabolites in human serum.
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