Populační farmakokinetika je oblast farmakologie, jejímž cílem je tvorba matematického modelu popisujícího farmakokinetiku léčiva v populaci včetně její variability. Tento článek přináší vhled do této problematiky a osvětluje terminologii pro lepší orientaci ve studiích. V úvodu je představena metoda v rámci farmakologie jako celku s důrazem na farmakokinetiku a využití statistických modelů pro optimální dávkování. Další část je rychlým shrnutím historie farmakokinetiky po vytvoření programu NONMEM s navázáním na počítačové zpracování dat v současnosti. Následující část je zaměřena na tvorbu modelu, různé přístupy odhadu parametrů včetně Bayesovské metody, na to navazují metody validace, a dále krátká část týkající se kovariance parametrů. V závěru jsou shrnuty přínosy a pozitiva populační farmakokinetiky a diskuse o jejích limitacích a perspektivách.

Population pharmacokinetics is a field of pharmacology that aims to create a mathematical model describing the pharmacokinetics of a drug in a population, including its variability. This article provides an insight into this field and explains the terminology to better understand the studies. The method is introduced in the context of pharmacology as a whole, with an emphasis on pharmacokinetics and the use of statistical models for optimal dosing. The next section is a quick summary of the history of pharmacokinetics after the creation of NONMEM with a follow-up on computerized data processing today. The following section focuses on model building, various approaches to parameter estimation including the Bayesian method, and continues with validation methods, followed by a short section on parameter covariance. Finally, the benefits and positives of population pharmacokinetics are summarized and a discussion of its limitations and perspectives is provided.

• Klíčová slova
• farmakokinetická analýza, populační farmakokinetika,
• MeSH
• Bayesova věta MeSH
• farmakokinetika * MeSH
• farmakologie metody   přístrojové vybavení   MeSH
• léčivé přípravky aplikace a dávkování   MeSH
• lidé MeSH
• software MeSH
• statistické modely * MeSH
• statistika jako téma MeSH
• validace softwaru MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

This study aimed to explore pharmacokinetics of voriconazole and its covariates in lung transplant recipients using population approach in order to propose dosing individualization. Data from routine therapeutic drug monitoring in adult lung transplant recipients treated with oral voriconazole were analysed with a three-stage population pharmacokinetic model using nonlinear mixed-effects modelling. Monte Carlo simulations based on final voriconazole pharmacokinetic model were used to generate the theoretical distribution of pharmacokinetic profiles at various dosing regimens. A total of 78 voriconazole serum concentrations collected from 40 patients were included in pharmacokinetic analysis. The only significant covariate was age for voriconazole clearance. Population voriconazole apparent clearance started at 32.26 L/h and decreased by 0.021 L/h with each year of patient's age, while population apparent volume of distribution was 964.46 L. Based on this model, we have proposed an easy-to-use dosing regimen consisting of a loading dose of 400 mg every 12 h for the first 48 h of treatment followed by maintenance dose of 300 mg every 12 h in patients aged up to 59 years, or by maintenance dose of 200 mg every 12 h in patients aged above 59 years.

• MeSH
• biologické modely MeSH
• dospělí MeSH
• lidé MeSH
• metoda Monte Carlo MeSH
• monitorování léčiv * MeSH
• plíce MeSH
• příjemce transplantátu * MeSH
• senioři MeSH
• vorikonazol farmakokinetika   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH

AIMS: The aim of this pharmacokinetic study was to describe and quantify population pharmacokinetics of three antibiotics, cefazolin, ampicillin, and ciprofloxacin, used as antibacterial prophylaxis during cardiovascular surgery with the use of extracorporeal circulation (ECC). METHODS: Adult patients undergoing cardiac surgery with ECC were enrolled to this prospective, pharmacokinetic study. An intravenous bolus of 2 g of ampicillin, 2 g of cefazolin or 400 mg of ciprofloxacin was administered 60-30 min before surgery. Blood samples were collected at 15, 30, 45, 60, 120 and 180 min after the administration and at the end of the surgery. Plasma concentrations of the antibiotics were measured using HPLC methods. Serum concentration-time profiles were analyzed using nonlinear mixed-effects modeling approach. RESULTS: A total of 54 patients were enrolled into the study, 20 with ampicillin, 25 cefazolin and 9 ciprofloxacin. For all antibiotics, population pharmacokinetic models have been successfully developed. CONCLUSION: We identified estimated glomerular filtration rate (eGFR) as the main factor determining the achievement of the pharmacokinetic/pharmacodynamic (PK/PD) target in ampicillin or cefazolin and body weight in ciprofloxacin prophylaxis during cardiac surgery with ECC support.

• MeSH
• ampicilin MeSH
• antibakteriální látky terapeutické užití   MeSH
• antibiotická profylaxe metody   MeSH
• cefazolin * farmakokinetika   terapeutické užití   MeSH
• ciprofloxacin MeSH
• dospělí MeSH
• kardiochirurgické výkony * MeSH
• lidé MeSH
• mimotělní oběh MeSH
• prospektivní studie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• epilepsie farmakoterapie   MeSH
• farmakokinetika MeSH
• fixní kombinace léků farmakokinetika   terapeutické užití   MeSH
• karbamazepin farmakologie   terapeutické užití   MeSH
• lidé MeSH
• populační charakteristiky MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH

Pharmacokinetic data for riociguat in patients with chronic thromboembolic pulmonary hypertension (CTEPH) have previously been reported from randomized clinical trials, which may not fully reflect the population encountered in routine practice. The aim of the current study was to characterize the pharmacokinetic of riociguat and its metabolite M1 in the patients from routine clinical practice. A population pharmacokinetic model was developed in NONMEM 7.3, based on riociguat and its metabolite plasma concentrations from 49 patients with CTEPH. One sample with riociguat and M1 concentrations was available from each patient obtained at different time points after last dose. Age, bodyweight, sex, smoking status, concomitant medications, kidney and liver function markers were tested as potential covariates of pharmacokinetic of riociguat and its metabolite. Riociguat and M1 disposition was best described with one-compartment models. Apparent volume of distribution (Vd/F) for riociguat and M1 were assumed to be the same. Total bilirubin and creatinine clearance were the most predictive covariates for apparent riociguat metabolic clearance to M1 (CLf,M1/F) and for apparent riociguat clearance through remaining pathways (CLe,r/F), respectively. CLf,M1/F, CLe,r/F, Vd/F of riociguat and M1, and clearance of M1 (CLe,M1/F) for a typical individual with 70 mL/min creatinine clearance and 0.69 mg/dL total bilirubin were 0.665 L/h (relative standard error = 17%)), 0.66 (18%) L/h, 3.63 (15%) L and 1.47 (19%) L/h, respectively. Upon visual identification of six outlying individuals, an absorption lag-time of 2.95 (6%) h was estimated for these patients. In conclusion, the only clinical characteristics related to riociguat exposure in patients with CTEPH from routine clinical practice are total bilirubin and creatinine clearance. This confirms the findings of the previous population pharmacokinetic studies based on data from randomized clinical trials.

• Publikační typ
• časopisecké články MeSH

Diabetické onemocnění ledvin, dříve označované jako diabetická nefropatie, je pozdní komplikací obou základních typů diabetu. Je charakterizované komplexem morfologických a funkčních změn, které jsou odrazem systémového metabolického onemocnění. Odchylky od normální morfologie postupně postihují všechny etáže nefronu a ledvinné intersticium. Následně dochází k pozorovatelným funkčním změnám – rozvoji albuminurie a proteinurie, snížení glomerulární filtrace, odchylkám tubulárních funkcí a potenciální patologii vylučování moče, včetně postižení močových cest infekcí nebo neuropatií. Cílem léčby diabetického onemocnění ledvin je snížit kardiovaskulární a renální morbiditu a mortalitu. Terapie je komplexní zahrnuje režimová opatření a potenciálně rozsáhlou farmakointervenci. Diabetes může v různé míře ovlivnit jednotlivé fáze farmakokinetiky – absorpci, distribuci, metabolismus a eliminaci. Na úrovni absorpce zvažujeme vliv viscerální neuropatie a prokrvení tkání. Distribuce je ovlivněna tělesnou kompozicí. Metabolické odchylky vlivem změněné aktivity enzymů, kde se významně uplatňuje vliv patologie jater i ledvin. Typická pro postup renální insuficience při diabetickém onemocnění ledvin je zejména změna eliminace léčiv vedoucí k riziku kumulace nejen mateřské látky, ale i aktivních metabolitů. Uvědomění si uvedených rozdílů pacientů s nefropatií od běžné populace přispěje k bezpečné farmakoterapii u této nadále se rozšiřující skupiny pacientů.

Diabetic kidney disease, formerly referred to as diabetic nephropathy, is a late complication of both basic types of diabetes. It ischaracterized by a complex of morphological and functional changes that are a reflection of systemic metabolic disease. Deviationsfrom normal morphology gradually affect all nephron levels and the renal interstitium. Subsequently, observable functionalchanges occur – the development of albuminuria and proteinuria, reduced glomerular filtration rate, tubular function abnormalities,and potential voiding pathology, including urinary tract infection or neuropathy. The goal of the treatment of diabetic kidneydisease is to reduce cardiovascular and renal morbidity and mortality rates. The treatment is comprehensive and includes lifestylemeasures and potentially extensive pharmacological intervention. Diabetes can, in varying degree, have an impact on the phases ofpharmacokinetics – absorption, distribution, metabolism, and elimination. In terms of absorption, the effects of visceral neuropathyand tissue blood perfusion are considered. Distribution is influenced by body composition. Metabolic abnormalities due to alteredenzymatic activity where the effect of both liver and kidney disease is exerted significantly. The progression of renal insufficiencyin diabetic kidney disease is typically associated with altered drug elimination resulting in a risk of accumulation of not only theparent compound, but also of active metabolites. Awareness of the above-mentioned differences from the general population cancontribute to safe pharmacotherapy in this ever-expanding group of patients.

• MeSH
• diabetické nefropatie * epidemiologie   farmakoterapie   MeSH
• eliminace ledvinami MeSH
• farmakokinetika MeSH
• hypoglykemika farmakologie   terapeutické užití   MeSH
• komplikace diabetu MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy 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.

• 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

Nanoliposomal irinotecan (nal-IRI) is a liposomal formulation of irinotecan with a longer half-life (t1/2 ), higher plasma total irinotecan (tIRI), and lower SN-38 maximum concentration (Cmax ) compared with nonliposomal irinotecan. Population pharmacokinetic (PK) analysis of nal-IRI was performed for tIRI and total SN-38 (tSN38) using patient samples from six studies. PK-safety association was evaluated for neutropenia and diarrhea in 353 patients. PK-efficacy association was evaluated from a phase III study in pancreatic cancer NAPOLI1. Efficacy was associated with longer duration of unencapsulated SN-38 (uSN38) above a threshold and higher Cavg of tIRI, tSN38, and uSN38. Neutropenia was associated with uSN38 Cmax and diarrhea with tIRI Cmax . Baseline predictive factors were race, body surface area, and bilirubin. Analysis identified PK factors associated with efficacy, safety, and predictive baseline factors. The results support the benefit of nal-IRI dose of 70 mg/m2 (free-base; equivalent to 80 mg/m2 salt base) Q2W over 100 mg/m2 Q3W.

• MeSH
• dospělí MeSH
• kamptothecin škodlivé účinky   analogy a deriváty   krev   farmakokinetika   MeSH
• klinické zkoušky jako téma MeSH
• lidé středního věku MeSH
• lidé MeSH
• liposomy škodlivé účinky   krev   farmakokinetika   MeSH
• nádory krev   farmakoterapie   metabolismus   MeSH
• neutropenie chemicky indukované   MeSH
• průjem chemicky indukované   MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

PURPOSE: Data on the anti-Xa efficacy of fondaparinux in dialysis-dependent chronic kidney disease (DD-CKD) patients are scarce. This study characterizes the pharmacokinetics (PK) and pharmacodynamics (PD) of fondaparinux in DD-CKD patients undergoing renal replacement therapy (RRT), to assess dosing strategies. METHODS: A retrospective, observational study was conducted using data on anti-Xa activity (112 samples) from 12 (3 male and 9 female) DD-CKD patients (median (IQR) age 71 years (63-88), weight 73 kg (59-98.5)). Eleven patients underwent high-flux or low-flux hemodialysis (HD) and one patient underwent peritoneal dialysis. Three patients were also treated with therapeutic plasma exchange (TPE). A non-linear mixed effects analysis was performed using NONMEM 7.3.0. RESULTS: The lab-specific slope of the relationship between fondaparinux concentration and anti-Xa levels was 1.18 IU/μg. In a one-compartment model, clearance (CL) and volume of distribution (Vd) were 0.05289 L/h and 5.55 L, respectively. High-flux HD was found to increase the CL of fondaparinux 2.26 times. TPE also considerably increased CL, but the fold-change could not be accurately estimated. Low-flux HD and peritoneal dialysis did not impact PK parameters. CONCLUSIONS: Model-based simulations showed that standard dosing (2.5 mg three times weekly before HD) results in a median anti-Xa activity of 0.55 IU/mL and 0.98 IU/mL, pre- and post-low-flux HD, respectively. In patients undergoing high-flux HD, these values are approximately 27% lower. Additional caution is warranted with TPE, as this treatment can reduce anti-Xa activity even further.

• MeSH
• chronická renální insuficience metabolismus   terapie   MeSH
• fondaparinux farmakokinetika   farmakologie   MeSH
• inhibitory faktoru Xa farmakokinetika   farmakologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• náhrada funkce ledvin * MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• tělesná hmotnost MeSH
• věkové faktory MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH

BACKGROUND AND OBJECTIVES: Besides allergic reactions, antibodies against polyethylene glycol (PEG) have been associated with reduced PEG-asparaginase (PEG-ASNase) activity. Population pharmacokinetics (popPK) allow for an in-depth investigation of the influence of anti-PEG antibodies on PEG-ASNase pharmacokinetics. METHODS: PEG-ASNase activity (6261 samples) and anti-PEG antibodies (2082/6412 samples prior to/post administration) in 1444 children with acute lymphoblastic leukaemia treated in the AIEOP-BFM ALL 2009 trial were evaluated. Patients received two doses of PEG-ASNase during induction (2500 U/m2, intravenous, biweekly) and a third dose during reinduction treatment. Anti-PEG IgG and IgM measured prior to and post administration were explored for their influence on the initial clearance of PEG-ASNase using a previously established popPK model. Categorical and continuous antibody data, including each isotype individually as well as in combination, were assessed. RESULTS: High pre-existing levels of anti-PEG antibodies increase the initial drug clearance. Analysed separately, both anti-PEG IgGprior and IgMprior were significant covariates; the stronger effect was observed for anti-PEG IgMprior. Hockey stick models best described the data. For anti-PEG IgMprior, each additional log unit above the estimated cut point was related to a 41.4% increase in initial clearance after the first dose in induction. Antibody levels below the cut point were not associated with an effect on clearance. The combination of both isotypes did not provide additional information compared to anti-PEG IgMprior alone. Antibody levels post administration were not associated with an effect on clearance. CONCLUSION: Pre-existing antibodies against PEG-ASNase significantly increased the initial clearance in a subgroup of patients showing high antibody levels. (Trial registration: EU clinical trials register; EudraCT No: 2007-004270-43; first registered 23 October 2009.).

• MeSH
• akutní lymfatická leukemie * farmakoterapie   MeSH
• asparaginasa MeSH
• dítě MeSH
• lidé MeSH
• polyethylenglykoly farmakokinetika   MeSH
• protinádorové látky * MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH