OBJECTIVES: The objective of this study was to investigate the relationship between both short-term and long-term tacrolimus exposure and overall survival after allogeneic stem cell transplantation and to propose individualized tacrolimus dosing based on the population pharmacokinetic model. STUDY DESIGN: Tacrolimus exposure during the first 3 months of therapy after transplantation was calculated using therapeutic drug monitoring data from all patients who underwent allogeneic stem cell transplantation from 2016 to 2018. The optimal upper level was determined using ROC analysis, and the impact of cutoff tacrolimus exposure values on overall survival of patients was assessed together with other transplant variables using multivariate analysis. The population pharmacokinetic model was developed using a nonlinear mixed-effects modeling method, and the optimal tacrolimus dose was proposed. RESULTS: A total of 86 patients were included in the outcome analyses. Except for the disease risk category, age ≥55 years, and female-to-male donor, tacrolimus exposures of the area under the curve of trough concentrations (AUCtc) ≥ 222 ng h/mL, ≥258 ng h/mL, and ≥160 ng h/mL during the whole three-month period, second month, and third month of therapy, respectively, were also found to be statistically significant for overall survival in univariate analysis. These AUCtc values were independent variables for overall survival in multivariate analysis, with RR of 3.01 (P = 0.0056), 3.22 (P = 0.0058), and 2.93 (P = 0.0184) for the whole three-month period, second month, and third month of therapy, respectively. The disease risk category (RR 7.11; P < 0.0001), age (RR 2.45; P = 0.0214), and non-myeloablative conditioning (RR 3.39; P = 0.0014) were also significant factors influencing survival in multivariate analysis. Tacrolimus volume of distribution was 127.1 L and was not affected by any of the tested covariates, whereas clearance decreased with age according to the equation CL = 7.94 × e - 0.0085 × age and was reduced by 23% in patients who underwent repeat transplantation. CONCLUSION: Except for the disease risk category, age, and non-myeloablative conditioning, exposure to tacrolimus is an independent predictor of overall survival and should not exceed trough levels of 10.7 ng/mL during the second month and 6.8 ng/mL during third month after transplantation. In order to reach this target, nomogram for estimation of the maximal initial tacrolimus daily dose was developed based on the population pharmacokinetic model.

• Klíčová slova
• allogeneic stem cells, nonlinear mixed-effects model, pharmacokinetics, tacrolimus, transplantation,
• Publikační typ
• časopisecké články MeSH

OBJECTIVES: Levetiracetam is an anticonvulsive drug increasingly used in paediatric populations. Ontogenesis may alter its pharmacokinetics, demanding dose individualisation of levetiracetam in paediatric populations. We therefore aimed to explore levetiracetam pharmacokinetics and to propose its optimal dosing in the paediatric population. METHODS: Individual levetiracetam pharmacokinetic parameters were calculated based on therapeutic drug monitoring data, using a one-compartmental model, and regression models were used to explore possible covariates. RESULTS: 56 patients aged from 47 days to 18 years were included in the analysis. The median (IQR) volume of distribution and clearance of levetiracetam were 0.7 (0.58-0.85) L/kg and 0.123 (0.085-0.167) L/hour/kg, respectively. Levetiracetam pharmacokinetics were influenced by postnatal age, body size descriptors and renal functional status. CONCLUSIONS: Based on observed relationships, an individualised loading dose of 26.2 mg/kg body weight and maintenance dose of 20.7 mg/mL/min of estimated glomerular filtration rate were calculated as optimal. Since we observed increased levetiracetam clearance in association with valproate co-medication, caution should be used when combining these two drugs.

• Klíčová slova
• drug monitoring, drug-related side effects and adverse reactions, pediatrics, pharmacokinetics, therapeutic drug monitoring,
• MeSH
• antikonvulziva * MeSH
• dítě MeSH
• kyselina valproová * MeSH
• levetiracetam MeSH
• lidé MeSH
• monitorování léčiv MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antikonvulziva * MeSH
• kyselina valproová * MeSH
• levetiracetam MeSH

Although posaconazole tablets show relatively low variability in pharmacokinetics (PK), the proportion of patients achieving the PK/PD target at the approved uniform dose for both prophylaxis and therapy is not satisfactory. The aim of this study was to develop a posaconazole population PK model in lung-transplant recipients and to propose a covariate-based dosing optimization for both prophylaxis and therapy. In this prospective study, 80 posaconazole concentrations obtained from 32 lung-transplant patients during therapeutic drug monitoring were analyzed using nonlinear mixed-effects modelling, and a Monte Carlo simulation was used to describe the theoretical distribution of posaconazole PK profiles at various dosing regimens. A one-compartment model with both linear absorption and elimination best fit the concentration-time data. The population apparent volume of distribution was 386.4 L, while an apparent clearance of 8.8 L/h decreased by 0.009 L/h with each year of the patient's age. Based on the covariate model, a dosing regimen of 200 mg/day for prophylaxis in patients ˃60 years, 300 mg/day for prophylaxis in patients ˂60 years and for therapy in patients ˃60 years, and 400 mg/day for therapy in patients ˂60 years has been proposed. At this dosing regimen, the PK/PD target for prophylaxis and therapy is reached in 95% and 90% of population, respectively, representing significantly improved outcomes in comparison with the uniform dose.

• Klíčová slova
• antimycotics, covariates, lung transplantation, nonlinear mixed-effects model, posaconazole, therapeutic drug monitoring,
• Publikační typ
• časopisecké články MeSH

The aim of this prospective study was to evaluate the pharmacokinetics of ganciclovir in lung transplant recipients, to explore its covariates, and to propose an individualized dosing regimen. Ganciclovir was administered according to the protocol in a standardized intravenous dose of 5 mg/kg twice daily. Serum ganciclovir concentrations were monitored as a trough and at 3 and 5 h after dosing. Individual ganciclovir pharmacokinetic parameters were calculated in a two-compartmental pharmacokinetic model, while regression models were used to explore the covariates. Optimal loading and maintenance doses were calculated for each patient. In lung transplant recipients (n = 40), the median (IQR) ganciclovir total volume of distribution and clearance values were 0.65 (0.52-0.73) L/kg and 0.088 (0.059-0.118) L/h/kg, respectively. We observed medium-to-high inter-individual but negligible intra-individual variability in ganciclovir pharmacokinetics. The volume of distribution of ganciclovir was best predicted by height, while clearance was predicted by glomerular filtration rate. Bodyweight-normalized clearance was significantly higher in patients with cystic fibrosis, while distribution half-life was reduced in this subgroup. On the basis of the observed relationships, practical nomograms for individualized ganciclovir dosing were proposed. The dosing of ganciclovir in patients with cystic fibrosis requires special caution, as their daily maintenance dose should be increased by approximately 50%.

• Klíčová slova
• covariates, cystic fibrosis, ganciclovir, lung transplant recipients, therapeutic drug monitoring,
• Publikační typ
• časopisecké články MeSH

Phenobarbital is a first-line treatment of various seizure types in newborns. Dosage individualization maximizing the proportion of patients with drug levels in therapeutic range or sufficient treatment response is still challenging. The aim of this review was to summarize the available evidence on phenobarbital pharmacokinetics in neonates and to identify its possible covariates suitable for individualization of initial drug dosing. Several covariates have been considered: body weight and height, body surface area, gestational and postnatal age, laboratory parameters of renal and hepatic functions, asphyxia, therapeutic hypothermia, extracorporeal membrane oxygenation (ECMO), drug interactions, and genetic polymorphisms. The most frequently studied and well-founded covariate for the estimation of phenobarbital dosing is actual body weight. Loading dose of 15-20 mg/kg followed by a maintenance dose of 3-5 mg/kg/day seems to be accurate. However, the evidence for the other covariates with respect to dosing individualization is not sufficient. Doses at the lower limit of suggested range should be preferred in patients with severe asphyxia, while the upper limit of the range should be targeted in neonates receiving ECMO support.

• Klíčová slova
• asphyxia, dosing, neonates, pharmacokinetics, phenobarbital,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH