Higher efficacy of oral nitrendipine admininstration in comparison with sublingual route. Pharmacokinetic and pharmacodynamic evaluation in hypertensive urgencies

Wstęp Istnieje opinia, że leki hipotensyjne podawane w stanach podwyższonego ciśnienia drogą podjęzykową powodują skuteczniejsze obniżenie ciśnienia niż preparaty podawane drogą doustną. Celem badania była ocena stężeń w surowicy oraz efektu działania: redukcji ciśnienia tętniczego po podaniu drogą podjęzykową [SL], doustną [PO] oraz podjęzykową i doustną [SL + PO] 5 mg nitrendipiny. Materiał i metody Nitrendipinę w kroplach w dawce 5 mg podawano 12 chorym z podwyższonym ciśnieniem tętniczym (średnia wartość 167 &plusmn; 9/108 &plusmn; 9 mm Hg), w wieku 55 &plusmn; 9 lat, o masie ciała 81 &plusmn; 13 kg, w sposób randomizowany, z zastosowaniem placebo, drogą podjęzykową [SL] (utrzymanie leku w jamie ustnej przez 20 min i usunięcie pozostałości), doustną [PO] (połknięcie) oraz podjęzykową i doustną [SL + PO] (utrzymanie leku w jamie ustnej przez 20 min i połknięcie). Wartości ciśnienia rejestrowano za pomocą 24-godzinnej automatycznej rejestracji (SpaceLabs 90207), pomiary wykonywano co 10 minut. Stężenia nitrendipiny oznaczano w 16 próbkach krwi pobieranych w ciągu 8 godzin od podania leku metodą chromatografii cieczowej (HPLC), czułość wynosiła 2 ng/ml. Wyniki Najwyższe stężenia nitrendipiny stwierdzono po podaniu PO: Cmax 32,8 &plusmn; 9 ng/ml (tmax 1,0 h) i po podaniu SL + PO: 33,8 &plusmn; 8 ng/ml (tmax 0,96 h) vs. SL: 15,1 &plusmn; 4 ng/ml (tmax 0,53 h). Porównywano stężenia i biodostępność nitrendipiny podanej 3 metodami po 15 min (0,25 h), gdyż późniejsze różnice wynikały z faktu wchłonięcia po podaniu SL w ciągu 20 minut tylko 2,81 mg leku (56,2% podanej dawki). Stężenia nitrendipiny po 0,25 h od podania wyniosły po podaniu PO: 14,4 &plusmn; 71 ng/ml, SL + PO: 10,1 &plusmn; 6,9 ng/ml, a po SL: 7,3 &plusmn; 3,4 ng/ml. Wartości AUCcałk po podaniu PO wynosiły: 90,5 &plusmn; 35 ng.h/ml (AUC po 0,25 h: 1,5). Wartości AUCcałk po podaniu SL + PO: 60,0 &plusmn; 29 ng.h/ml (AUC po 0,25 h: 0,9). Pole pod krzywą stężenie&#8211;czas po podaniu SL wyniosło tylko 12,8 &plusmn; 7 ng.h/ml (po 0,25 h: 1,1). Wchłanianie leku z przewodu pokarmowego było szybsze niż ze śluzówki jamy ustnej. Redukcja ciśnienia skurczowego [SBP] po 15 minutach wyniosła w porównaniu z placebo, odpowiednio, po podaniu PO: 7,1 mm Hg (p < 0,05), po podaniu SL + PO: 3,2 mm Hg (ns), a po podaniu SL: 5,5 mm Hg (ns). Istotna redukcja SBP wystąpiła po podaniu PO przez okres 0,25&#8211;10 h (maks. w 3 h, &#8211;17,2%) , po podaniu SL + PO przez okres 1&#8211;10 h (maks. 2,5 h, &#8211;14,9%). Redukcja powyżej 10% SBP wystąpiła po 1 h u wszystkich pacjentów po podaniu PO i SL + PO. Po podaniu drogą SL nie stwierdzono istotnej redukcji SBP. Wnioski Wchłanianie nitrendipiny zachodziło szybciej z przewodu pokarmowego po połknięciu leku w porównaniu z podaniem SL. Tylko po podaniu leku PO oraz SL + PO występowało większe i dłużej utrzymujące się obniżenie ciśnienia. W praktyce nie istnieje czysta droga podjęzykowa podania leku: przy poleceniu utrzymywania leku pod językiem jedynie część jest wchłaniana ze śluzówki jamy ustnej, reszta jest połykana i wchłonięta z przewodu pokarmowego.Background In management of hypertensive urgencies the common opinion exists, that antihypertensive drugs given sublingually are more efficacious than administered orally. The aim of the study was to assess plasma concentrations and effect (blood pressure reduction) after sublingual [SL], oral [PO] and sublingual and oral [SL + PO] administration [adm] of 5 mg nitrendipine [NIT]. Material and methods NIT drops, dose 5 mg, were administered to 12 moderate hypertensive patients with mean initial blood pressure 167/108 (&plusmn; 9/9) mm Hg, mean age 55 &plusmn; 9 years, body mass 81 &plusmn; 13 kg. Patients were given NIT randomly in comparison with placebo: sublingually (keeping drops 20 minutes in the mouth and then removing the rest), orally (swallowing drops), and combined (keeping drops in the mouth for 20 min then swallowing). BP was recorded for 24 hrs using ambulatory BP monitoring (SpaceLabs 90207), readings every 10 min. NIT levels were measured in 16 blood samples drawn for 8 hrs after drug intake by HPLC method (sensitivity 2 ng/ml). Results Highest NIT concentrations were measured after POadm: Cmax 32.8 &plusmn; 9 ng/ml (tmax 1.0 h) and after SL + PO: 33.8 &plusmn; 8 ng/ml (tmax 0.96 h) vs. SL 15.1 &plusmn; 4 ng/ml (tmax 0.53). The concentrations and bioavailability of NIT after 3 ways of administration were compared after 15 min (0.25 h), because latter differences were due to low absorption after SL administration within 20 minutes: 2.81 mg only (56.2% given dose). NIT concentrations after 0.25 h were for PO administration: 14.4 &plusmn; 7 ng/ml, SL + PO: 10.1 &plusmn; 6.9 ng/ml and SL: 7.3 &plusmn; 3.4 ng/ml. Total AUC after PO administration was 90.5 &plusmn; 35 ng.h/ml (AUC after 0.25 h: 1.5 ng.h/ml). Total AUC after SL + PO was 60.0 &plusmn; 29 ng.h/ml (AUC after 0.25 h: 0.9). And finally: total AUC after SL administration was only 12.8 &plusmn; 7 ng.h/ml (after 0.25 h: 1.1). This indicated that absorption from GI tract was faster than from oral mucosa. Systolic blood pressure reductions [SBP] after 0.25 was, respectively, for PO administration: 7.1 mm Hg (p < 0.05), SL + PO: 3.2 mm Hg (ns), and for SL: 5.5 mm Hg (ns). Significant SBP reduction was observed after PO administration for 0.25&#8211;10 hrs (max after 3 h, &#8211;17.2%), after SL + PO for 1&#8211;10 hrs (max after 2.5 h, &#8211;14.9%). In all patients 1 h after PO and SL + PO administration > 10% reduction of SBP was registered. After SL no significant reduction of SBP was observed. Conclusions Study demonstrated the faster absorption of NIT from gastro-intestinal tract than from oral mucosa. Only after PO and SL+PO administration greater and prolonged reduction of SBP was observed. The pure sublingual administration does not exist in practice: only small part of drug is absorbed from oral mucosa and most part of drug after swallowing is absorbed from gastro-intestinal tract

Validated Simple HPLC-UV Method for Mycophenolic Acid (MPA) Monitoring in Human Plasma. Internal Standardization: Is It Necessary?

The aim of the work was to prepare a simple but reliable HPLC-UV method for the routine monitoring of mycophenolic acid (MPA). Sample preparation was based on plasma protein precipitation with acetonitrile. The isocratic separation of MPA and internal standard (IS) fenbufen was made on Supelcosil LC-CN column (150 × 4.6 mm, 5 µm) using a mobile phase: CH3CN:H2O:0.5M KH2PO4:H3PO4 (260:700:40:0.4, v/v). UV detection was set at 305 nm. The calibration covered the MPA concentration range: 0.1–40 µg/mL. The precision was satisfactory with RSD of 0.97–7.06% for intra-assay and of 1.92–5.15% for inter-assay. The inaccuracy was found between −5.72% and +2.96% (+15.40% at LLOQ) and between −8.82% and +5.31% (+19.00% at LLOQ) for intra- and inter-assay, respectively, fulfilling acceptance criteria. After a two-year period of successful application, the presented method has been retrospectively calibrated using the raw data disregarding the IS in the calculations. The validation and stability parameters were similar for both calculation methods. MPA concentrations were recalculated and compared in 1187 consecutive routine therapeutic drug monitoring (TDM) trough plasma samples from mycophenolate-treated patients. A high agreement (r2 = 0.9931, p < 0.0001) of the results was found. A Bland–Altman test revealed a mean bias of −0.011 μg/mL (95% CI: −0.017; −0.005) comprising −0.14% (95% Cl: −0.39; +0.11), whereas the Passing–Bablok regression was y = 0.986x + 0.014. The presented method can be recommended as an attractive analytical tool for medical (hospital) laboratories equipped with solely basic HPLC apparatus. The procedure can be further simplified by disapplying an internal standard while maintaining appropriate precision and accuracy of measurements

Assuring the Proper Analytical Performance of Measurement Procedures for Immunosuppressive Drug Concentrations in Clinical Practice: Recommendations of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology Immunosuppressive Drug Scientific Committee

Monitoring immunosuppressive drugs (ISDs) in blood or plasma is still a key therapeutic drug monitoring (TDM) application in clinical settings. Narrow target ranges and severe side effects at drug underexposure or overexposure make accurate and precise measurements a must. This overview prepared by the Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology is intended to serve as a summary and guidance document describing the current state-of-the-art in the TDM of ISDs

Therapeutic Drug Monitoring of Everolimus: A Consensus Report.

In 2014, the Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology called a meeting of international experts to provide recommendations to guide therapeutic drug monitoring (TDM) of everolimus (EVR) and its optimal use in clinical practice. EVR is a potent inhibitor of the mammalian target of rapamycin, approved for the prevention of organ transplant rejection and for the treatment of various types of cancer and tuberous sclerosis complex. EVR fulfills the prerequisites for TDM, having a narrow therapeutic range, high interindividual pharmacokinetic variability, and established drug exposure-response relationships. EVR trough concentrations (C0) demonstrate a good relationship with overall exposure, providing a simple and reliable index for TDM. Whole-blood samples should be used for measurement of EVR C0, and sampling times should be standardized to occur within 1 hour before the next dose, which should be taken at the same time everyday and preferably without food. In transplantation settings, EVR should be generally targeted to a C0 of 3-8 ng/mL when used in combination with other immunosuppressive drugs (calcineurin inhibitors and glucocorticoids); in calcineurin inhibitor-free regimens, the EVR target C0 range should be 6-10 ng/mL. Further studies are required to determine the clinical utility of TDM in nontransplantation settings. The choice of analytical method and differences between methods should be carefully considered when determining EVR concentrations, and when comparing and interpreting clinical trial outcomes. At present, a fully validated liquid chromatography tandem mass spectrometry assay is the preferred method for determination of EVR C0, with a lower limit of quantification close to 1 ng/mL. Use of certified commercially available whole-blood calibrators to avoid calibration bias and participation in external proficiency-testing programs to allow continuous cross-validation and proof of analytical quality are highly recommended. Development of alternative assays to facilitate on-site measurement of EVR C0 is encouraged

Everolimus Personalized Therapy: Second Consensus Report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology

International audienceThe Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology established the second consensus report to guide Therapeutic Drug Monitoring (TDM) of everolimus (EVR) and its optimal use in clinical practice 7 years after the first version was published in 2016. This version provides information focused on new developments that have arisen in the last 7 years. For the general aspects of the pharmacology and TDM of EVR that have retained their relevance, readers can refer to the 2016 document. This edition includes new evidence from the literature, focusing on the topics updated during the last 7 years, including indirect pharmacological effects of EVR on the mammalian target of rapamycin complex 2 with the major mechanism of direct inhibition of the mammalian target of rapamycin complex 1. In addition, various concepts and technical options to monitor EVR concentrations, improve analytical performance, and increase the number of options available for immunochemical analytical methods have been included. Only limited new pharmacogenetic information regarding EVR has emerged; however, pharmacometrics and model-informed precision dosing have been constructed using physiological parameters as covariates, including pharmacogenetic information. In clinical settings, EVR is combined with a decreased dose of calcineurin inhibitors, such as tacrolimus and cyclosporine, instead of mycophenolic acid. The literature and recommendations for specific organ transplantations, such as that of the kidneys, liver, heart, and lungs, as well as for oncology and pediatrics have been updated. EVR TDM for pancreatic and islet transplantation has been added to this edition. The pharmacodynamic monitoring of EVR in organ transplantation has also been updated. These updates and additions, along with the previous version of this consensus document, will be helpful to clinicians and researchers treating patients receiving EVR.Trial registration: ClinicalTrials.gov NCT04595513. http://clinicaltrials.gov/show/NCT0459551

Everolimus Personalized Therapy: Second Consensus Report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology

International audienceThe Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology established the second consensus report to guide Therapeutic Drug Monitoring (TDM) of everolimus (EVR) and its optimal use in clinical practice 7 years after the first version was published in 2016. This version provides information focused on new developments that have arisen in the last 7 years. For the general aspects of the pharmacology and TDM of EVR that have retained their relevance, readers can refer to the 2016 document. This edition includes new evidence from the literature, focusing on the topics updated during the last 7 years, including indirect pharmacological effects of EVR on the mammalian target of rapamycin complex 2 with the major mechanism of direct inhibition of the mammalian target of rapamycin complex 1. In addition, various concepts and technical options to monitor EVR concentrations, improve analytical performance, and increase the number of options available for immunochemical analytical methods have been included. Only limited new pharmacogenetic information regarding EVR has emerged; however, pharmacometrics and model-informed precision dosing have been constructed using physiological parameters as covariates, including pharmacogenetic information. In clinical settings, EVR is combined with a decreased dose of calcineurin inhibitors, such as tacrolimus and cyclosporine, instead of mycophenolic acid. The literature and recommendations for specific organ transplantations, such as that of the kidneys, liver, heart, and lungs, as well as for oncology and pediatrics have been updated. EVR TDM for pancreatic and islet transplantation has been added to this edition. The pharmacodynamic monitoring of EVR in organ transplantation has also been updated. These updates and additions, along with the previous version of this consensus document, will be helpful to clinicians and researchers treating patients receiving EVR.Trial registration: ClinicalTrials.gov NCT04595513. http://clinicaltrials.gov/show/NCT0459551

Therapeutic Drug Monitoring of Tacrolimus-Personalized Therapy: Second Consensus Report.

Ten years ago, a consensus report on the optimization of tacrolimus was published in this journal. In 2017, the Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicity (IATDMCT) decided to issue an updated consensus report considering the most relevant advances in tacrolimus pharmacokinetics (PK), pharmacogenetics (PG), pharmacodynamics, and immunologic biomarkers, with the aim to provide analytical and drug-exposure recommendations to assist TDM professionals and clinicians to individualize tacrolimus TDM and treatment. The consensus is based on in-depth literature searches regarding each topic that is addressed in this document. Thirty-seven international experts in the field of TDM of tacrolimus as well as its PG and biomarkers contributed to the drafting of sections most relevant for their expertise. Whenever applicable, the quality of evidence and the strength of recommendations were graded according to a published grading guide. After iterated editing, the final version of the complete document was approved by all authors. For each category of solid organ and stem cell transplantation, the current state of PK monitoring is discussed and the specific targets of tacrolimus trough concentrations (predose sample C0) are presented for subgroups of patients along with the grading of these recommendations. In addition, tacrolimus area under the concentration-time curve determination is proposed as the best TDM option early after transplantation, at the time of immunosuppression minimization, for special populations, and specific clinical situations. For indications other than transplantation, the potentially effective tacrolimus concentrations in systemic treatment are discussed without formal grading. The importance of consistency, calibration, proficiency testing, and the requirement for standardization and need for traceability and reference materials is highlighted. The status for alternative approaches for tacrolimus TDM is presented including dried blood spots, volumetric absorptive microsampling, and the development of intracellular measurements of tacrolimus. The association between CYP3A5 genotype and tacrolimus dose requirement is consistent (Grading A I). So far, pharmacodynamic and immunologic biomarkers have not entered routine monitoring, but determination of residual nuclear factor of activated T cells-regulated gene expression supports the identification of renal transplant recipients at risk of rejection, infections, and malignancy (B II). In addition, monitoring intracellular T-cell IFN-g production can help to identify kidney and liver transplant recipients at high risk of acute rejection (B II) and select good candidates for immunosuppression minimization (B II). Although cell-free DNA seems a promising biomarker of acute donor injury and to assess the minimally effective C0 of tacrolimus, multicenter prospective interventional studies are required to better evaluate its clinical utility in solid organ transplantation. Population PK models including CYP3A5 and CYP3A4 genotypes will be considered to guide initial tacrolimus dosing. Future studies should investigate the clinical benefit of time-to-event models to better evaluate biomarkers as predictive of personal response, the risk of rejection, and graft outcome. The Expert Committee concludes that considerable advances in the different fields of tacrolimus monitoring have been achieved during this last decade. Continued efforts should focus on the opportunities to implement in clinical routine the combination of new standardized PK approaches with PG, and valid biomarkers to further personalize tacrolimus therapy and to improve long-term outcomes for treated patients