Terapeutické monitorování léků umožňuje úpravu dávkování u pacienta na základě stanovení koncentrace léčiva v krvi. Software pro farmakokinetické modelování umožňuje predikovat průběh koncentrací při pravidelném i nepravidelném dávkování, při nestandardních odběrových časech, před dosažením ustáleného stavu nebo při měnící se funkci eliminačních orgánů, zejména ledvin. Příčinou neočekávaných výsledků může být chyba odběru (při odběru ze stejného místa, jako je léčivo aplikováno, nebo odběru z centrálního žilního katétru), neúplná léková anamnéza při změnách dávkování před odběrem, chybějící informace o použití nasycovací dávky, nebo léková interakce. Specifickým případem je podávání léčiva dialyzovaným pacientům, kdy při intermitentní dialýze je nezbytná výrazná redukce dávek, zatímco u kontinuální dialýzy je dávkování úměrné hodnotám sérového kreatininu. Ke správné interpretaci výsledků jsou nezbytné správné a úplné vstupní údaje pacienta a zejména správná dávková anamnéza.
Therapeutic drug monitoring allows the adjustment of the patient's dosage based on the drug concentration. Pharmacokinetic modelling software enables to predict the concentrations with regular and irregular dosing, with non-standard sampling times, before reaching a steady state or with changing function of elimination organs, in particular kidneys. Unexpected results can be caused by a sampling error (esp. when sample was taken from the same site as the drug was administered, or sampling from a central venous catheter), an incomplete drug history during dosage changes before sampling, missing information on the use of a loading dose, or a drug interaction. A specific case is the administration of the drug to dialysis patients, where a significant dose reduction is necessary in intermittent dialysis, while in continuous dialysis the dosage is proportional to serum creatinine values. To correctly interpret the results, correct and complete input data of the patient and, in particular, a full dose history are necessary.
- Keywords
- farmakokinetická analýza,
- MeSH
- Biomarkers, Pharmacological analysis blood MeSH
- Pharmacokinetics MeSH
- Pharmaceutical Preparations analysis administration & dosage blood MeSH
- Humans MeSH
- Drug Monitoring * methods instrumentation statistics & numerical data MeSH
- Specimen Handling MeSH
- Check Tag
- Humans MeSH
- Publication type
- Case Reports MeSH
- MeSH
- Cladribine * administration & dosage economics pharmacology MeSH
- Clinical Decision-Making MeSH
- Humans MeSH
- Drug Monitoring methods statistics & numerical data MeSH
- Multiple Sclerosis * drug therapy prevention & control MeSH
- Check Tag
- Humans MeSH
- Publication type
- Practice Guideline MeSH
- Geographicals
- Slovakia MeSH
Účel studie: Hodnocení vlivu kyseliny valproové (VPA) na hladinu karbamazepinu (CBZ) a karbamazepin-10,11-epoxidu (CBZ-E) při dlouhodobé léčbě přípravky s pomalým uvolňováním. Metoda: U 262 vzorků odebraných před podáním od 175 dětských pacientů (<15 let) byla hodnocena celková denní dávka (PDD), dávka na kg (DBW), koncentrace CBZ, CBZ-E, poměry CBZ koncentrace/PDD, CBZ-E koncentrace/PDD, CBZ-E/CBZ a rozložení koncentrací CBZ ve vztahu k terapeutickému rozmezí 4-9mg. Podrobná analýza byla provedena u 11 pacientů, kteří byli vlastní kontrolou. Výsledky (uvedeny jako průměr ± směrodatná odchylka): Ačkoliv pacienti léčení CBZ + VPA užívali vyšší dávky než pacienti na monoterapii: PDD 557 ± 204 vs. 400 ± 187mg, p <0.001; DBW 20.2 ± 10.5 vs. 13.5 ± 5.8mg/kg, p <0.001, nebyl zaznamenán rozdíl v průměrné koncentraci CBZ (5.1 ± 1.4 vs. 5.3 ± 1.9mg/l), CBZ-E (1.2 ± 0.8 vs. 1.1 ± 0.9mg/l), poměru CBZ-E/CBZ (0.24 ± 0.12 vs. 0.22 ± 0.19) ani v rozložení koncentrací podle terapeutického rozmezí. V terapeutickém optimu bylo 86% vs. 77% koncentrací. Koncentrace nad horní hranicí terapeutického rozmezí se nevyskytovaly. U CBZ + VPA byly nižší poměry koncentrace CBZ/PDD: 10.3 × 10-3 ± 4.2 × 10-3, vs. 14.9 × 10-3 ± 6.4 × 10-3 mg × L-1/mg, p <0.001; CBZ/DBW: 0.31 ± 0.17, vs. 0.44 ± 0.19 mg × l-1/mg × kg-1, p < 0.001. Obdobně u 11 pacientů, kteří byli vlastní kontrolou: poměr koncentrace CBZ/PDD 10.9 × 10-3 ± 3.7 × 10-3 vs. 15.0 × 10-3 ± 5.7 × 10-3, p < 0.01; CBZ/DBW 0.35 ± 0.10 vs. 0.40 ± 0.14, p <0.05. Zdá se, že VPA má indukční efekt na metabolismus CBZ. Na dávce závislé nežádoucí účinky (ataxie, bolest hlavy) byly popsány u 4 pacientů na monoterapii. Koncentrace CBZ a CBZ-E se nelišila od pacientů bez NÚL, byl však vyšší poměr CBZ-E/CBZ 6.8 × 10-3 ± 1.6 × 10-3 vs. 3.1 × 10-3 ± 3.6 × 10-3, a CBZ-E/PDD 0.32 ± 0.06 vs. 0.21 ± 0.20, p < 0.05. Závěr: Významná interakce mezi CBZ a VPA byla úspěšně eliminována úpravou dávkování pomocí TDM.
The effect of valproic acid (VPA) on plasma level of carbamazepine (CBZ) and carbamazepine-10,11-epoxide (CBZ-E) in long-term treatment was evaluated. Method: A total of 262 samples were obtained predose from 175 pediatric patients (<15 years). Daily dose (PDD), dose related to bodyweight (DBW), plasma levels (PL) of CBZ, CBZ-E, CBZ level/dose ratio, CBZ-E level/dose ratio and CBZ-E/CBZ ratio, the distribution of PL according to the therapeutic range 4-9mg/L, and seizure frequency were compared. A detailed analysis was done in 11 individuals who served as their own control. Results (given as mean ± SD): Patients on a CBZ + VPA regimen were treated with higher daily doses: PDD 557 ± 204 vs. 400 ± 187mg, respectively, p <0.001; DBW 20.2 ± 10.5 vs. 13.5 ± 5.8mg/kg, respectively, p <0.001. The mean CBZ PL and the distribution of PL according to the therapeutic range were not different: 5.1 ± 1.4 vs. 5.3 ± 1.9mg/L, respectively. There was 86% of therapeutic PL CBZ + VPA and 77% in monotherapy. No toxic level was found. CBZ-E PL remained unchanged in CBZ + VPA (1.2 ± 0.8 vs. 1.1 ± 0.9mg/L, respectively) as did the CBZ-E/CBZ ratio (0.24 ± 0.12 vs. 0.22 ± 0.19, respectively). The CBZ level/dose was decreased in CBZ + VPA: 10.3× 10-3 ± 4.2×10-3 vs. 14.9×10-3 ± 6.4×10-3mg×L-1/mg, respectively, p<0.001; so was the CBZ level/DBW: 0.31 ± 0.17 vs. 0.44 ± 0.19mg×L-1/mg×kg-1, p <0.001. These findings suggest an inductive effect of VPA on CBZ metabolism. Similar outcomes were found in 11 individuals who served as their own control: CBZ level/dose 10.9×10-3 ± 3.7×10-3 vs. 15.0×10-3 ± 5.7×10-3, respectively, p <0.01; CBZ level/DBW 0.35 ± 0.10 vs. 0.40 ± 0.14, respectively, p <0.05. Dose-dependent adverse drug reactions (ataxia, headache) were reported in four individuals on CBZ monotherapy. No difference in the mean PL of CBZ or CBZ-E was found, while the CBZ-E/CBZ ratio and CBZ-E level/dose ratio were increased: 6.8×10-3 ± 1.6×10-3 vs. 3.1×10-3 ± 3.6×10-3, and 0.32 ± 0.06 vs. 0.21 ± 0.20, p <0.05). No difference in seizure frequency was found. Conclusion: The CBZ-VPA interaction is considerable, but it is sufficiently eliminated due to TDM dose adjustment. Key words: carbamazepine, carbamazepine-epoxide, valproic acid, drug-drug, interaction, slow-release drug formulations.
- MeSH
- Anticonvulsants pharmacokinetics blood MeSH
- Child MeSH
- Carbamazepine * analogs & derivatives pharmacokinetics blood MeSH
- Valproic Acid * pharmacokinetics blood MeSH
- Drug Interactions MeSH
- Delayed-Action Preparations pharmacokinetics MeSH
- Humans MeSH
- Drug Monitoring statistics & numerical data MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Publication type
- Clinical Study MeSH
OBJECTIVE: In patients with chronic coronary or peripheral artery disease enrolled in the Cardiovascular Outcomes for People Using Anticoagulation Strategies trial, randomised antithrombotic treatments were stopped after a median follow-up of 23 months because of benefits of the combination of rivaroxaban 2.5 mg two times per day and aspirin 100 mg once daily compared with aspirin 100 mg once daily. We assessed the effect of switching to non-study aspirin at the time of early stopping. METHODS: Incident composite of myocardial infarction, stroke or cardiovascular death was estimated per 100 person-years (py) during randomised treatment (n=18 278) and after study treatment discontinuation to non-study aspirin (n=14 068). RESULTS: During randomised treatment, the combination compared with aspirin reduced the composite (2.2 vs 2.9/100 py, HR: 0.76, 95% CI 0.66 to 0.86), stroke (0.5 vs 0.8/100 py, HR: 0.58, 95% CI 0.44 to 0.76) and cardiovascular death (0.9 vs 1.2/100 py, HR: 0.78, 95% CI 0.64 to 0.96). During 1.02 years after early stopping, participants originally randomised to the combination compared with those randomised to aspirin had similar rates of the composite (2.1 vs 2.0/100 py, HR: 1.08, 95% CI 0.84 to 1.39) and cardiovascular death (1.0 vs 0.8/100 py, HR: 1.26, 95% CI 0.85 to 1.86) but higher stroke rate (0.7 vs 0.4/100 py, HR: 1.74, 95% CI 1.05 to 2.87) including a significant increase in ischaemic stroke during the first 6 months after switching to non-study aspirin. CONCLUSION: Discontinuing study rivaroxaban and aspirin to non-study aspirin was associated with the loss of cardiovascular benefits and a stroke excess. TRIAL REGISTRATION NUMBER: NCT01776424.
- MeSH
- Aspirin * administration & dosage adverse effects MeSH
- Fibrinolytic Agents administration & dosage adverse effects MeSH
- Myocardial Infarction * etiology mortality prevention & control MeSH
- Ischemic Stroke * etiology mortality prevention & control MeSH
- Drug Therapy, Combination methods MeSH
- Coronary Disease * diagnosis drug therapy MeSH
- Humans MeSH
- Drug Monitoring methods statistics & numerical data MeSH
- Mortality MeSH
- Drug Substitution adverse effects MeSH
- Withholding Treatment statistics & numerical data MeSH
- Peripheral Arterial Disease * diagnosis drug therapy MeSH
- Rivaroxaban * administration & dosage adverse effects MeSH
- Aged MeSH
- Duration of Therapy MeSH
- Outcome and Process Assessment, Health Care MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Randomized Controlled Trial MeSH
BACKGROUND AND AIMS: Ontamalimab, a fully-human monoclonal antibody targeting MAdCAM-1, induced remission in patients with moderate-to-severe ulcerative colitis [UC] in the TURANDOT study. We aimed to assess long-term safety, tolerability, and efficacy of ontamalimab in TURANDOT II. METHODS: TURANDOT II was a phase 2, multicentre, open-label [OL] study in patients with moderate-to-severe UC who completed TURANDOT on placebo or ontamalimab (NCT01771809). Patients were randomised to 75 mg or 225 mg ontamalimab every 4 weeks for 72 weeks [OL1]. The dosage could be increased to 225 mg from Week 8 at the investigator's discretion. All patients then received 75 mg every 4 weeks for 72 weeks [OL2], followed by 6-month safety follow-up. The primary objective was safety, measured by adverse events [AEs], serious AEs [SAEs], and AEs leading to withdrawal. Mucosal healing [MH; centrally read endoscopy] was assessed. RESULTS: Of 330 patients, 180 completed OL1; 94 escalated to 225 mg; 127 completed OL2. Overall, 36.1% experienced drug-related AEs. The most common SAE [10.0%] was worsening/ongoing UC; 5.5% of patients had serious infections, the most common being gastroenteritis [0.9%]. One death and four cancers [all unrelated to ontamalimab] occurred. No PML [progressive multifocal leukoencephalopathy]/lymphoproliferative disorders occurred. Geometric mean high-sensitivity C-reactive protein [hsCRP] and faecal calprotectin decreased across OL1 in both dose groups. The proportion of patients assigned to placebo in TURANDOT achieving MH increased from 8.8% [6/68] at baseline to 35.3% at Week 16 [24/68; non-responder imputation]. The corresponding increase in the ontamalimab group was from 23.3% [61/262] to 26.7% [70/262]. CONCLUSIONS: Ontamalimab was well tolerated up to 144 weeks in patients with moderate-to-severe UC, with good safety and efficacy.
- MeSH
- C-Reactive Protein analysis MeSH
- Adult MeSH
- Endoscopy, Gastrointestinal methods statistics & numerical data MeSH
- Gastrointestinal Agents administration & dosage adverse effects MeSH
- Antibodies, Monoclonal, Humanized * administration & dosage adverse effects MeSH
- Dose-Response Relationship, Immunologic MeSH
- Leukocyte L1 Antigen Complex analysis MeSH
- Humans MeSH
- Cell Adhesion Molecules antagonists & inhibitors MeSH
- Drug Monitoring * methods statistics & numerical data MeSH
- Mucoproteins antagonists & inhibitors MeSH
- Colitis, Ulcerative * diagnosis drug therapy immunology MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase II MeSH
- Multicenter Study MeSH
- Randomized Controlled Trial MeSH
Introduction: The aim of the study was to investigate current practice and policies of therapeutic drug monitoring (TDM) service requesting and result reporting in Czechia and Slovakia. Materials and methods: All 149 laboratories that measure plasma drug concentrations were given an online questionnaire during a regular external quality assessment TDM cycle. The questionnaire consisted of 17 questions. The optimal TDM practice was defined as the application of all elements (age, body weight, time of sampling, date of the first administration, time of the last dose administration, the dose, the dosing interval, the route of administration, information on reason of testing, and information on other co-administered drugs) needed for reporting a recommendation for further drug dosing (positive response to question number 16). Results: The response rate was 69%, 103 out of 149 laboratories measuring drug concentrations. Only 12% (12 out of 103 laboratories) of the laboratories implemented all elements needed for optimal TDM practice and reported a recommendation. Both paper and electronic request forms were used by 77 out of 103 (75%) laboratories. A total of 69 out of 103 laboratories (67%) specified the type of sampling tube on their request form. Cystatin C was used for prediction of renal drug elimination by 24% (25 out of 103) of participants. Conclusions: Small number of laboratories implemented all elements needed for optimal TDM practice and report a recommendation on further dosing. Further efforts in education on optimal TDM practice as well as harmonization of service are desirable.
- MeSH
- Internet MeSH
- Laboratories standards statistics & numerical data MeSH
- Humans MeSH
- Drug Monitoring methods statistics & numerical data trends MeSH
- Surveys and Questionnaires MeSH
- Reproducibility of Results MeSH
- Quality Control MeSH
- Quality Assurance, Health Care MeSH
- Health Policy MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Czech Republic MeSH
- Slovakia MeSH
- Keywords
- koagulometr, CoaguChek Pro II,
- MeSH
- International Normalized Ratio MeSH
- Humans MeSH
- Drug Monitoring * methods instrumentation statistics & numerical data MeSH
- Partial Thromboplastin Time MeSH
- Point-of-Care Testing * MeSH
- Prothrombin Time MeSH
- Statistics as Topic MeSH
- Blood Coagulation Tests * methods instrumentation statistics & numerical data MeSH
- Warfarin therapeutic use MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Comparative Study MeSH
- MeSH
- Afatinib MeSH
- Bevacizumab MeSH
- Biological Therapy economics statistics & numerical data MeSH
- Carcinoma, Bronchogenic economics drug therapy MeSH
- Molecular Targeted Therapy economics statistics & numerical data MeSH
- Erlotinib Hydrochloride MeSH
- Gefitinib MeSH
- Humans MeSH
- Drug Monitoring statistics & numerical data MeSH
- Drug Costs * statistics & numerical data MeSH
- Pemetrexed MeSH
- Registries MeSH
- Check Tag
- Humans MeSH
Úvod a cíl: Při terapii vankomycinem je rutinní terapeutické monitorování hladin (TDM) doporučováno jako metoda optimalizace dávkování. Podle nových doporučení pro TDM vankomycinu je dostačující měřit pouze údolní koncentrace, přičemž tato doporučení uvádí pro řadu indikací vyšší cílová rozmezí. Cílem naší studie bylo zhodnotit frekvenci TDM vankomycinu ve Fakultní nemocnici Olomouc a dále zhodnotit, jaký vliv by nová doporučení mohla mít na dávkovací strategie. Metodika: Byla provedena retrospektivní analýza všech hladin vankomycinu změřených během dvouletého období. Hemodialyzovaní pacienti byli vyloučeni. Hladiny byly zhodnoceny podle starších a nových doporučení a následně také s využitím farmakokinetického modelování. Výsledky: Ve studii bylo zhodnoceno celkem 468 hladin, což představovalo 260 jednotlivých měření vankomycinu provedených u 131 pacientů. Nejčastější indikací pro vankomycin byla sepse (49,6% pacientů). Méně citlivé etiologické agens s hodnotou MIC >1 mg/l bylo identifikováno u 18,5% pacientů. Konzultace klinického farmakologa se zkušenostmi s TDM byla vyžádána u 18,1% měření. Podle nových doporučení by bylo aktuální dávkování vyhodnoceno jako příliš nízké u 38,5% měření a jako příliš vysoké u 39,2% měření. Podle farmakokinetické predikce by bylo doporučeno navýšit dávkování u 28,1% měření a naopak snížit u 36,9% měření. Závěr: Úprava dávkování může být neadekvátní, pokud je prováděna pouze na základě údolních koncentrací bez farmakokinetické analýzy, obzvláště pokud jsou hladiny interpretovány osobou s nedostatečnou zkušeností v oblasti TDM.
Introduction and objective: Routine therapeutic drug monitoring (TDM) of vancomycin is recommended in clinical practice in order to optimize dosing and drug exposure. Recent guidelines on vancomycin TDM recommend monitoring of only through concentrations with rather higher target ranges for dosage adjustment. The aim of the study was to evaluate the practice of vancomycin TDM in University Hospital in Olomouc and to assess the potential influence of new recommendations on dosing strategies. Methods: A retrospective analysis of vancomycin plasma levels determined during a two-year period was performed. Values with uncertain sample timing and patients on haemodialysis were excluded. The values were assessed according to the older and the new guidelines. Consecutively, pharmacokinetic modelling was performed for every patient to estimate individual PK/PD indices. Results: A total of 468 vancomycin concentrations were included, which represented 260 events of monitoring performed in 131 patients. Vancomycin was mostly used for suspected or proven sepsis (49.6 % of all patients). Pathogens with MIC > 1 mg/L were responsible for 18.5 % of all infections. Clinical pharmacologist trained in TDM was consulted in 18.1 % of all events. According to the new guidelines, patients were underdosed in 38.5 % of the events, and overdosed in 39.2 % of the events of monitoring. PK simulations showed suboptimal dosing in 28.1 % of the events, and too high dosing in 36.9 % of the events. Conclusion: Dosage adjustments based only upon pre-dose concentrations may be inappropriate, especially if the value is interpreted by a person with lack of experience in the field of TDM.
- MeSH
- Bacterial Infections etiology drug therapy MeSH
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Microbial Sensitivity Tests * MeSH
- Drug Monitoring * methods standards statistics & numerical data MeSH
- Retrospective Studies MeSH
- Aged MeSH
- Practice Guidelines as Topic MeSH
- Vancomycin * administration & dosage pharmacokinetics MeSH
- Dose-Response Relationship, Drug MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Aged MeSH
- Publication type
- Evaluation Study MeSH
- Research Support, Non-U.S. Gov't MeSH
