Fingolimod is an oral drug for the escalation of treatment of relapsing-remitting multiple sclerosis in patients with persistent disease activity on first-line drugs or in patients with rapidly progressive severe relapsing-remitting multiple sclerosis. An ultra-high-performance liquid chromatography-tandem mass spectrometry method for determining the concentrations of fingolimod and its active metabolite fingolimod phosphate in whole blood has been developed and validated. The advantages of this method are the easy, fast and cheap sample preparation using protein precipitation from blood with a mixture of acetonitrile-methanol (40:60, v/v). Chromatographic separation was performed on a ultra-high performance liquid chromatography BEH C18 1.7 μm (100 × 2.1 mm) column. Two modes of ionization, electrospray ionization and atmospheric pressure chemical ionization, were tested and compared. For validation, the electrospray ionization mode was chosen. As internal standard, isotopically labeled fingolimod-D4 was used to quantify the analytes. The method was validated according to the rules of the European Medicines Agency. The coefficients of variation for fingolimod were in the range of 1.13-11.88%, and the recovery was 98.80-106.00%. The coefficients of variation for fingolimod phosphate were in the range of 2.73-9.31%, and the recovery was 90.08-107.00%. The method is quite easy and fast and can be used for routine analysis.
- MeSH
- chromatografie kapalinová metody MeSH
- dospělí MeSH
- fingolimod hydrochlorid * krev farmakokinetika terapeutické užití chemie MeSH
- imunosupresiva krev farmakokinetika MeSH
- lidé MeSH
- limita detekce MeSH
- lineární modely MeSH
- reprodukovatelnost výsledků MeSH
- roztroušená skleróza krev farmakoterapie MeSH
- tandemová hmotnostní spektrometrie * metody MeSH
- vysokoúčinná kapalinová chromatografie metody MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Dimethyl fumarate is used to treat patients with relapsing-remitting multiple sclerosis. After ingestion, it is rapidly hydrolyzed to the active primary metabolite monomethyl fumarate. OBJECTIVE: The main objective of our study was to analyze serum concentrations of monomethyl fumarate during routine health care in patients with multiple sclerosis treated with a fixed dose of dimethyl fumarate. METHODS: In the pilot cross-sectional study, data from 42 patients treated with dimethyl fumarate at a dose of 240 mg twice daily were collected. Concentrations of the active metabolite monomethyl fumarate were determined at 1-8 h (median, 3 h) or 10-14 h (median, 13 h) after taking the dose. The relationship between monomethyl fumarate concentrations and absolute lymphocyte count was evaluated. RESULTS: Concentrations of monomethyl fumarate ranged from 2.5-3177.9 μg/L, with most concentrations being undetectable approximately 10 hours after administration. In the 1-8 h (median, 3 h) post-dose subgroup, the concentration/dose ratio ranged widely from 0.04-6.62. The median concentration of monomethyl fumarate in the group with the absolute lymphocyte count <0.8 x 10^9/l was more than four times higher than in the group with the absolute lymphocyte count ≥0.8 x 10^9/l (median 440.1 μg/L versus 98.4 μg/L). CONCLUSION: The wide interindividual variability in monomethyl fumarate pharmacokinetics could contribute to the differential response to dimethyl fumarate in multiple sclerosis patients. A nonsignificant but noticeable trend was observed in the relationship of higher serum monomethyl fumarate concentrations to absolute lymphocyte counts.
- MeSH
- dimethyl fumarát * terapeutické užití MeSH
- dospělí MeSH
- fumaráty * terapeutické užití krev MeSH
- imunosupresiva * terapeutické užití krev MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- pilotní projekty MeSH
- počet lymfocytů MeSH
- průřezové studie MeSH
- relabující-remitující roztroušená skleróza farmakoterapie krev MeSH
- roztroušená skleróza farmakoterapie krev MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Metotrexát (MTX) je konvenční imunosupresivum první volby k perorální farmakoterapii středně těžké a těžké ložiskové psoriázy. Léčba je komfortní a cenově výhodná. Zlepšuje stav kůže hodnocený pomocí skóre PASI o 50 % nebo více až u 75 % nemocných. Vysoká interindividuální variabilita farmakokinetiky je jednou z hlavních příčin nedostatečného účinku nebo předčasného ukončení terapie z důvodu nežádoucích účinků MTX. Přehledová práce kriticky posuzuje výhody terapeutického monitorování MTX (TDM) jako prostředku personalizace farmakoterapie psoriázy. Prospektivní klinické studie odhalily vztah mezi farmakokinetikou a účinkem MTX. Byl navržen a ověřen postup TDM, který zlepšil výsledky iniciální fáze léčby (indukce remise). Kromě dávkování MTX byla individualizována i suplementace kyselinou listovou, ke které bylo přistupováno pouze u nemocných s prokázaným deficitem folátů při léčbě MTX.
Methotrexate (MTX) is a conventional immunosuppressive drug of first choice in oral therapy of moderate‑to‑severe plaque psoriasis. Its use is comfortable and cost effective. The therapy improves the skin status according to the PASI score (psoriasis area and severity index) by 50% or more in up to 75% of patients. However, a high inter‑individual variability in pharmacokinetics is one of the major factors responsible for either insufficient efficacy of the therapy or its premature discontinuation due to adverse effects of MTX. The review article critically evaluates the possible benefits of therapeutic drug monitoring (TDM) of MTX as a tool for personalized pharmacotherapy of psoriasis. Prospective clinical studies unraveled a relationship between the pharmacokinetics and the therapeutic effect of MTX. Recommendations on how to perform TDM were worked out and verified, which helped to improve the outcomes of the initial treatment phase (remission induction). Besides the individualization of MTX dosing, supplementation with folic acid was individually tailored only to patients with a proven folate deficit.
- MeSH
- aplikace orální MeSH
- dermatologické látky aplikace a dávkování farmakokinetika krev MeSH
- imunosupresiva aplikace a dávkování farmakokinetika krev MeSH
- individualizovaná medicína MeSH
- kyselina listová krev škodlivé účinky terapeutické užití MeSH
- kyselina polyglutamová krev MeSH
- lidé MeSH
- methotrexát * aplikace a dávkování farmakokinetika krev MeSH
- monitorování léčiv * metody MeSH
- plocha pod křivkou MeSH
- psoriáza * farmakoterapie krev MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
- Klíčová slova
- plazmatická koncentrace léčiva,
- MeSH
- analgetika MeSH
- antiastmatika farmakokinetika farmakologie krev škodlivé účinky MeSH
- antibakteriální látky farmakokinetika farmakologie krev MeSH
- antidepresiva farmakokinetika farmakologie krev MeSH
- antifungální látky farmakologie krev MeSH
- antikonvulziva farmakologie krev MeSH
- antipyretika MeSH
- cytostatické látky farmakologie krev MeSH
- farmakoterapie metody trendy MeSH
- hodnocení rizik MeSH
- imunosupresiva farmakologie krev škodlivé účinky MeSH
- individualizovaná medicína trendy MeSH
- kardiovaskulární látky farmakologie krev MeSH
- lidé MeSH
- monitorování léčiv * klasifikace metody statistika a číselné údaje trendy MeSH
- trankvilizéry farmakokinetika farmakologie krev MeSH
- Check Tag
- lidé MeSH
Background. Cyclosporine A (CsA) is an immunomodulatory agent used in standard immunosuppressive regimens in solid organ transplantations as well as in the treatment of autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus and psoriasis. Its immunosuppressive activity is primarily due to parent drug. However, following oral administration, absorption is incomplete and varies between individuals. Further, there is a dearth of pharmacokinetic data for CsA in autoimmune patients compared to transplant recipients. Aim. The goal of this study was to investigate the single-dose and steady state pharmacokinetics of CsA and two main primary metabolites, AM1 and AM4N, in patients with rheumatic/autoimmune diseases. Methods. Thirty-eight subjects, average age (years± SD) 46.8 (±11.6) years with rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis, ankylosing spondylitis and undifferentiated SpA were included in an observational open study. The single dose pharmacokinetics (area under the concentration–time curve of CsA and its metabolites (AUC) and other PK parameters) were determined over a 24 h period following oral administration of 1.3 mg/kg oral CsA. Two CsA formulations-Neoral and the Czech generic substitute Consupren®, were used. Pharmacokinetic analysis was performed on all 38 patients after administration of a single dose of CsA (1.34 mg/ kg/day). In 12 patients only, a second series of blood samples was taken to calculate monitored PK parameters under steady state conditions. Results. Pharmacokinetic assessment showed AUC0-24 3009.66 ± 1449.78 ng/ml.h and Cmax 827.84 ± 425.84 after administration of a single dose of CSA, AUC0-24 3698.50 ± 2147 ng/ml.h and Cmax 741 ± 493 ng/ml after repeated dose. The proportion of the AM1 metabolite (AUC0-24) after a single dose of CsA corresponded to 40% of the parent compound and to approximately 35% of the parent compound in steady state conditions. The proportion of AM4N metabolite was low in both conditions and represented only 3 and 4.5% after a single dose and at steady state, respectively. Conclusion. The pharmacokinetic data (AUCCsA, Cmax) for the whole 24 h interval were similar to the published findings, mainly under steady state conditions. The AM1 (AUC0-24) after a single dose of CsA and in steady state conditions represented about 40% of the parent drug. The ratio of AM4N metabolite was low in both conditions.
- MeSH
- autoimunitní nemoci farmakoterapie imunologie MeSH
- cyklosporin aplikace a dávkování farmakokinetika metabolismus MeSH
- dospělí MeSH
- farmakokinetika MeSH
- imunosupresiva krev metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- plocha pod křivkou MeSH
- revmatoidní artritida farmakoterapie imunologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
INTRODUCTION: Area under the concentration-time curve (AUC) has been advocated as a better parameter to monitor cyclosporine A than trough concentrations. Up to now, more than 100 equations to estimate AUC using a limited sampling strategy have been published, but not all have been validated. MATERIAL AND METHODS: Eight equations for AUC0-12h and two for AUC0-8h were validated. Concentrations of cyclosporine A were analyzed by high-performance liquid chromatography (HPLC) and a specific radioimmunoassay (RIA) method. Forty male renal transplant patients were included in the study. Blood samples were taken predose and at 0.5, 1, 1.5, 2, 3, 5, 8, and 12 hours after the morning dose when the patient was in steady state. The percentage prediction error (%pe) was used for an assessment of the performance of the equations. Mean %pe less than + 15% and absolute %pe less than 30% in 95% of predictions were considered to be acceptable. Other possibilities such as %pe less than 25%, 20%, and 15% were also tested. RESULTS: Eight equations for AUC0-12h met the requirements using both assays, six in the HPLC set only and four in the RIA set only. The highest precision was obtained with AUC0-12h = 123.792 + 1.165*C1h + 3.021*C3h + 7.33*C8h proposed by de Mattos et al. The mean %pe was 1% + 8% (-16 to 19) for HPLC (values given as mean + standard deviation [range]) and -1 + 5 (-17 to 10) for RIA. Mean absolute %pe was 7 + 5 (0.0 to 19) for HPLC and 4 + 4 (0.0 to 17) for RIA. For clinical use, the most suitable equation was AUC0-12h = 363.078 + 8.77*C1h + 3.07*C3h proposed by Wacke et al, which produced the second lowest %pe and used two sampling points in the period of 1 to 3 hours after dose. The mean %pe was -7 + 10 (-25 to 25) for HPLC and 2.3 + 6 (-10 to 17) for RIA. Mean absolute %pe was 10 + 7 (0.4 to 25) for HPLC and 5 + 4 (0.0 to 17) for RIA. The equation: AUC0-8h = 55.37 + 2.89*C0h + 1.08*C1h0.9*C2h + 2.23*C3h proposed by Foradori et al met the criteria with 95% of prediction with absolute %pe less than 15% in the HPLC set and 10% in the RIA set. CONCLUSION: The validation of equations is of major importance for prediction precision, whereas the analytical method for limited sampling strategy proposals had no influence. Because of the wide interassay variability, it is also important to know which analytical method was used for AUC calculation when interpreting the results.
- MeSH
- časové faktory MeSH
- cyklosporin farmakokinetika krev terapeutické užití MeSH
- imunosupresiva farmakokinetika krev terapeutické užití MeSH
- lidé středního věku MeSH
- lidé MeSH
- monitorování léčiv metody MeSH
- odběr vzorku krve MeSH
- plocha pod křivkou MeSH
- radioimunoanalýza MeSH
- transplantace ledvin MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- práce podpořená grantem MeSH
- MeSH
- cyklosporin krev MeSH
- imunosupresiva krev MeSH
- lidé MeSH
- monitorování léčiv metody MeSH
- radioimunoanalýza metody MeSH
- transplantace ledvin MeSH
- vysokoúčinná kapalinová chromatografie metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- srovnávací studie MeSH
