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1.
J Pharm Biomed Anal ; 207: 114418, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34655987

RESUMO

Therapeutic drug monitoring (TDM) of tyrosine kinase inhibitors (TKIs) shows significant potential in guiding personalized anticancer treatment. Dried blood microsampling could be a valuable alternative for traditional plasma sampling to provide TDM results faster and to reach a wider audience. Sample collection is easy and patient friendly as only a small volume of blood is collected via a fingerprick. This enables the possibility of home sampling by the patients themselves. Therefore, an LC-MS/MS method was developed and validated for the quantification of bosutinib, dasatinib, gilteritinib, ibrutinib, imatinib, midostaurin, nilotinib and ponatinib in dried blood samples collected via volumetric absorptive microsampling (VAMS). A VAMS device collects a fixed volume of blood (± 10 µL), irrespective of the sample's hematocrit (Hct). During method validation, special attention was paid to the possible impact of Hct (range 0.18-0.55) on matrix effect (ME), robustness of the extraction, and accuracy of the method. The method was successfully validated based on international guidelines in terms of calibration curves, precision (within-run CV 2.20-14.8%; between-run CV 2.40-12.3%), accuracy (within-run bias 0.34-12.5%; between-run bias -0.15 to 16.2%), carry-over and selectivity. IS-compensated ME and recovery were Hct independent and no significant impact of Hct on the accuracy of the TKI quantifications was observed. All TKIs were stable in VAMS samples stored at -20 °C, 4 °C and room temperature for at least 4 weeks and for 2 days at 60 °C (except ibrutinib). Lastly, we demonstrated a good agreement between liquid blood obtained from patients on TKI treatment and VAMS samples prepared from that venous blood. As this implies that there is no methodological impact of liquid versus dried blood analysis, the presented method can be applied in clinical follow-up studies for determining TKIs in (capillary) VAMS samples with varying Hct levels.


Assuntos
Monitoramento de Medicamentos , Espectrometria de Massas em Tandem , Coleta de Amostras Sanguíneas , Cromatografia Líquida , Humanos , Inibidores de Proteínas Quinases
2.
Stud Health Technol Inform ; 285: 49-57, 2021 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-34734851

RESUMO

The paper describes some aspects of precision medicine and shows the importance of pharmacokinetics and pharmacodynamics for the therapeutic drug monitoring and model-informed precision dosing. A key element in the design of the pharmacokinetics and pharmacodynamics (PKPD) models is relevant literature search that represents an essential step in the procurement and validation of a new drug. Available search engine resources do not offer specific functionalities that are required for efficient and relevant search in reliable literature sources. We present a prototype of such an intelligent search engine and show its results on real project data.


Assuntos
Monitoramento de Medicamentos , Medicina de Precisão
3.
BMC Infect Dis ; 21(1): 1143, 2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-34749667

RESUMO

BACKGROUND: Ganciclovir pharmacokinetics is characterized by a high variability in drug exposure. Usually, monitoring of ganciclovir exposure is performed by measuring trough concentration. However, due to the specificity of pediatric pharmacokinetics, trough concentration measurements may not be a relevant surrogate of ganciclovir exposure. Area under the curve of concentration (AUC) may be a more appropriate biomarker. CASE PRESENTATION: We report the case of 3.6-year-old boy with Emberger syndrome with a cytomegalovirus reactivation occurring after allogenic hematopoietic stem cell transplantation. After a few days of treatment with intravenous ganciclovir, sub-therapeutic trough ganciclovir concentrations were measured (< 0.5 µg/mL) and viral load still increased. Ganciclovir dosage was increased by two-fold to deal with this treatment failure. Trough concentrations remained sub-therapeutic. The patient had hematologic disorder therefore it was decided to estimate ganciclovir AUC to assess more accurately drug exposure before any further dosage modification. AUC0-12 h was measured at 51 µg h/mL, which was within the therapeutic range (40-60 µg h/mL). Afterward, viral load decreased and became undetectable. CONCLUSIONS: This case report highlights that monitoring ganciclovir exposure based on AUC should be performed to tailor drug dosage in order to improve treatment efficacy and safety in pediatric patients.


Assuntos
Infecções por Citomegalovirus , Ganciclovir , Antivirais/uso terapêutico , Pré-Escolar , Infecções por Citomegalovirus/tratamento farmacológico , Monitoramento de Medicamentos , Ganciclovir/uso terapêutico , Humanos , Masculino , Carga Viral
4.
Acta Med Indones ; 53(3): 308-314, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34611070

RESUMO

COVID-19 became a widespread infectious disease in late 2019. Indonesia currently has the highest COVID-19 mortality rate in Asia, between 4-5 percent. Interestingly, COVID-19-associated coagulopathy characterized by an increase of several procoagulant factor levels, including fibrinogen and D-dimer, that has been associated with higher mortality and unfavorable outcomes. We report a case of a 30-year-old male admitted to the hospital with a profuse vomiting and worsening fever, cough and shortness of breath, and was diagnosed with COVID-19-associated coagulopathy. Seven days after admission, he became deteriorated with significant reduction of oxygen saturation and his coagulation parameter levels were increased with highly suspicion of pulmonary embolism. He was treated with azithromycin, isoprinosine, lopinavir, and fondaparinux with thromboprophylaxis dosage since admission. The role of increased fondaparinux dosage at the time of clinical deterioration was then followed by clinical improvement and reduced D-dimer level. Anticoagulant therapy, mainly with fondaparinux, showed a better prognosis in patients with markedly elevated D-Dimer. Fondaparinux needs to be monitored appropriately to prevent bleeding and adverse. The patient was discharged from the hospital in an improved condition and normal D-Dimer levels. There was no bleeding event nor other major side effects had been found in this case. The decision for increasing dose of anticoagulant may be determined on individual basis, considering risks, benefits, and also the most important is clinical findings.


Assuntos
COVID-19 , Fondaparinux , Hemorragia/prevenção & controle , Embolia Pulmonar , SARS-CoV-2/isolamento & purificação , Trombofilia , Adulto , Antivirais , Azitromicina/administração & dosagem , COVID-19/sangue , COVID-19/diagnóstico , COVID-19/tratamento farmacológico , COVID-19/fisiopatologia , Deterioração Clínica , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/efeitos adversos , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Fondaparinux/administração & dosagem , Fondaparinux/efeitos adversos , Hemorragia/induzido quimicamente , Humanos , Inosina Pranobex/administração & dosagem , Lopinavir/administração & dosagem , Masculino , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/tratamento farmacológico , Embolia Pulmonar/etiologia , Trombofilia/complicações , Trombofilia/diagnóstico , Trombofilia/tratamento farmacológico , Trombofilia/etiologia , Resultado do Tratamento
5.
Acta Med Indones ; 53(3): 319-325, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34611072

RESUMO

One of the main causes of death in COVID-19 is the dysregulation of the host's immune system which leads to cytokine storm, a potentially fatal systemic inflammatory syndrome. Interleukin 6 (IL-6) is a pro-inflammatory cytokine that is produced in response to infections and tissue injuries and is believed to play a pivotal role in the event of a cytokine storm, as signified by its increase in the process. Considering the role of IL-6 as a pro-inflammatory cytokine in the process of cytokine storm in COVID-19, perceiving IL-6 as a therapeutic target could prove to be promising. Tocilizumab is a monoclonal antibody that competitively inhibits the binding of IL-6 to its receptor (IL-6R). The use of IL-6R blocker is recommended for severe COVID-19 patients in the latest therapeutic guideline published by the World Health Organization (WHO), but the timing of the administration has not been specified. While previous studies about the use of tocilizumab in COVID-19 patients have shown various results, these studies do not emphasize on plasma IL-6 levels when deciding the time of tocilizumab administration. In this case series, we present three patients with moderate to severe COVID-19 infections that receive tocilizumab as an adjunct to the standard of care therapy. This case series introduces the novel idea that the timely use of tocilizumab as signified by plasma IL-6 levels in moderate to severe COVID-19 patients could potentially improve overall clinical condition and increase survival rate.


Assuntos
Anticorpos Monoclonais Humanizados , COVID-19 , Síndrome da Liberação de Citocina , Interleucina-6 , Receptores de Interleucina-6/imunologia , Tempo para o Tratamento , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , COVID-19/diagnóstico , COVID-19/tratamento farmacológico , COVID-19/imunologia , COVID-19/fisiopatologia , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/prevenção & controle , Monitoramento de Medicamentos/métodos , Humanos , Interleucina-6/antagonistas & inibidores , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença , Resultado do Tratamento
6.
J Pharm Biomed Anal ; 206: 114380, 2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34607204

RESUMO

The effectiveness and safety of anti-tumor drugs are clinically important issues, and their therapeutic drug monitoring (TDM) is recommended. This study aimed to develop an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for simultaneous TDM and exploration of clinical pharmacokinetics of anti-tumor drugs, including cyclophosphamide, ifosfamide, cisplatin, methotrexate, pemetrexed disodium, capecitabine, 5-fluorouracil, gemcitabine, doxorubicin, fulvestrant, tamoxifen, and irinotecan. After magnetic solid-phase extraction of plasma samples, the isotope internal standards and 12 anti-tumor drugs were separated using a ZORBAX Eclipse Plus C18 column (50.0 × 2.1 mm, 1.7 µm) with water containing 0.1% formic acid and acetonitrile as the mobile phase in a total run time of 5.0 min. The developed UPLC-MS/MS method was validated based on the Chinese Pharmacopoeia and the US Food and Drug Administration guidelines for bioanalytical method validation, including assessment of specificity, calibration curves, carryover, accuracy, crosstalk, precision, stability, recovery, dilution integrity, incurred sample reanalysis, and matrix effect. The results showed that a simple, fast, reliable, and specific UPLC-MS/MS method was developed and validated, and all the performance characteristics of the method met the requirements. The response function was established for concentration range of 0.10-25.00 µg/mL for gemcitabine, cyclophosphamide, ifosfamide, methotrexate, pemetrexed disodium, capecitabine, 5-fluorouracil, and cisplatin, and 0.05-12.50 µg/mL for doxorubicin, fulvestrant, tamoxifen, and irinotecan, with a coefficient of correlation of>0.9984 for all the compounds. The precision and accuracy of all the analytes were<6.5% and 5.9%, respectively. Hence, it could be used for TDM and exploration of pharmacokinetics of the aforementioned 12 anti-tumor drugs.


Assuntos
Antineoplásicos , Espectrometria de Massas em Tandem , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Monitoramento de Medicamentos , Humanos , Reprodutibilidade dos Testes
7.
BMC Infect Dis ; 21(1): 1087, 2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34674665

RESUMO

BACKGROUND: Low plasma levels of first-line antitubercular drugs can be counted among the main causes of poor response to antitubercular therapy, and therapeutic drug monitoring has been proposed as a method to promote tailored treatments for both child and adult patients. The main aim of the study was to evaluate serum concentrations of isoniazid (INH) and rifampicin (RIF) and to investigate reasons for sub-therapeutic plasma concentrations in order to fix dosages. METHODS: Children with TB were prospectively enrolled from January to August 2019. Two venous blood samples were collected (the first at least 15 days after the beginning of antitubercular treatment, and the second between 1 and 8 weeks later). Plasma concentrations were determined by a validated high-performance liquid chromatography method. RESULTS: In all, 45 children were included. Seventy blood samples for INH plasma concentration were collected between 120 and 240 min after drug intake. Adjusting for dose (mg/kg/day) and time of INH administration, when considering three different age groups (≤ 2 years, 2-12 years, > 12 years), a statistically significant lower INH plasma concentration was observed in younger children compared to the older age groups in the multivariate analysis (p < 0.001 and p < 0.001). A total of 68 blood samples were evaluated for RIF concentrations. Both for INH and RIF a statistically significant lower plasma concentration was also observed in adolescents (p < 0.001). Fifteen children (15/45, 33%) presented drug concentrations under the referral therapeutic range. CONCLUSIONS: Based on our findings, monitoring patients' drug plasma concentrations in children under 2 years of age and in adolescents can make treatment more patient-tailored.


Assuntos
Isoniazida , Tuberculose , Adolescente , Adulto , Idoso , Antituberculosos/uso terapêutico , Criança , Pré-Escolar , Monitoramento de Medicamentos , Humanos , Lactente , Isoniazida/uso terapêutico , Rifampina/uso terapêutico , Tuberculose/tratamento farmacológico
9.
World J Gastroenterol ; 27(37): 6231-6247, 2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34712029

RESUMO

Inflammatory bowel disease (IBD) is a chronic condition that significantly affects the quality of life of its patients. Biologic drugs have been the mainstay treatment in the management of IBD patients but despite their significant contribution, there remains a proportion of patients that do not respond or lose response to treatment. Therapeutic drug monitoring (TDM) involves measuring levels of serum drug concentrations and anti-drug antibodies. TDM of biologic drugs initially emerged to understand treatment failure in other immune mediated inflammatory diseases. This was then introduced in IBD to rationalize primary non-response or secondary loss of response, given that low serum drug concentrations or the formation of anti-drug antibodies are variably associated with treatment failure. The aim of this narrative review is to provide an overview regarding the current use of TDM in clinical practice and to present the evidence available regarding its use in both proactive and reactive clinical settings in preventing and managing treatment failure. This review also presents the existing evidence regarding the association of various clinical outcomes with specific thresholds of drug concentrations, in everyday practice. A narrative review of published articles and conference abstracts regarding the use of TDM in IBD management, through an electronic search using PubMed and ScienceDirect. TDM has proven to be superior and more cost effective in guiding management of patients with treatment failure compared to empiric dose escalation or change in treatment. Despite a trend towards an association between clinical outcomes and drug concentrations, proactive TDM based strategies have not been shown to achieve clear benefit in long-term outcomes. In the clinical setting, TDM has proven to be useful in managing IBD patients, and its use in the reactive setting, as an additional tool to help manage patients with treatment failure, is being promoted as newer guidelines and consensus groups implement TDM as part of the management plan.


Assuntos
Produtos Biológicos , Doenças Inflamatórias Intestinais , Produtos Biológicos/uso terapêutico , Monitoramento de Medicamentos , Fármacos Gastrointestinais/efeitos adversos , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Qualidade de Vida
10.
J Med Syst ; 45(12): 104, 2021 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-34705113

RESUMO

Vancomycin is one of the most prescribed antibiotics in pediatric intensive care units (PICU) in US hospitals. However, a detailed understanding of workflow and information flow among various stakeholders regarding vancomycin treatment processes in clinical settings is lacking. We conducted direct observations and informant interviews to develop the mapping of key processes and information flow for vancomycin treatment, with an emphasis on therapeutic drug monitoring (TDM) dose adjustment decision-making. A health information technology (HIT) sociotechnical framework was used to identify EHR related safety concerns. A total of 27 vancomycin treatment activities were observed over a 60-h duration including infusion administration, infusion completion, trough concentration blood draw and therapeutic decision making processes. Workflow and information flow mappings revealed (1) deviations between the documented timestamp used for TDM decision making and the actual time the tasks executed and (2) the lack of information flow regarding infusion completion and interruption. Missing features, insufficient usability and lack of integration with workflow and communication in the EHR were deemed safety gaps that may affect the accuracy of therapeutic decisions. Our case study identified gaps in information flow among clinical team members via EHR in TDM processes to provide insights for the improvement of the EHR system for antibiotic treatment purposes. In particular, the potential harm of the missing, uncertain, and inaccurate documented TDM task times warrant further investigations.


Assuntos
Preparações Farmacêuticas , Vancomicina , Antibacterianos/uso terapêutico , Criança , Monitoramento de Medicamentos , Registros Eletrônicos de Saúde , Humanos , Fluxo de Trabalho
11.
Lab Chip ; 21(17): 3289-3297, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34612459

RESUMO

Tacrolimus is one of the most effective and prevalent drugs used to combat vascularized composite allotransplantation rejection. We have fabricated a rapid and easy-to-use six-layer paper based microfluidic device using the principles of competitive immunoassays and vertical flow microfluidics for colorimetric detection of tacrolimus in a small volume of blood.


Assuntos
Técnicas Biossensoriais , Alotransplante de Tecidos Compostos Vascularizados , Monitoramento de Medicamentos , Rejeição de Enxerto , Tacrolimo
12.
J Med Microbiol ; 70(10)2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34633919

RESUMO

Antifungal drugs have already been established as an effective treatment option for Candida parapsilosis infections, but there is no universal consensus on the ideal target for clinical efficacy and safety of antifungal drugs for the treatment of C. parapsilosis infections. Few studies have directly compared the efficacies of antifungal drugs for the treatment of C. parapsilosis infections. We hypothesize that different antifungal drugs offer differing clinical efficacy and safety for the treatment of C. parapsilosis infections. We performed a comprehensive network meta-analysis on different strategies for C. parapsilosis infection treatment and compared the clinical efficacy and safety of antifungal drugs as interventions for C. parapsilosis infections. The Cochrane Database of Systematic Reviews, Medline, Embase, PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), Technology of Chongqing VIP database, Wan Fang Data, and SinoMed databases were searched to identify appropriate randomized trials. Among the extracted C. parapsilosis cases, the survival and death rates with treatment of C. parapsilosis infection were compared among groups treated with different antifungal drugs. According to the evidence-network analysis, echinocandins were a better choice than other drugs for treating C. parapsilosis infections, and more importantly, caspofungin showed a more preferable effect for decreasing the risk of 30 day mortality. In conclusion, this study systematically evaluated the effectiveness and safety of antifungal drugs for the purpose of helping clinicians choose the most appropriate antifungal drugs. Future studies with larger samples are needed to evaluate the effects of patient factors on the clinical efficacy and safety of antifungal drugs for C. parapsilosis infections.


Assuntos
Antifúngicos/uso terapêutico , Candida parapsilosis/efeitos dos fármacos , Candidíase/tratamento farmacológico , Monitoramento de Medicamentos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
13.
Lab Chip ; 21(22): 4445-4454, 2021 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-34651158

RESUMO

Dried blood spot (DBS) sampling by finger-pricking has recently gained a lot of interest as an alternative sample collection method. The reduced invasiveness, requirement of lower sample volumes and suitability for long-term storage at room temperature make DBS ideal for use in home settings or low-resource environments. However, traditional protocols often suffer from biased analysis data due to variable and not exactly known blood volumes present in the samples. In this work, a novel device has been developed to split-off precisely metered volumes from a blood drop and load them on pre-cut filter paper. Hereto, hydrophobic burst valves (HBV) were developed to temporarily retain a fluid flow, configurable to burst at pressures within a range of 175-600 Pa. By combining HBVs with different burst pressures, a volume metering system was developed to allow parallel metering of multiple pre-defined sample volumes. The system was shown to be accurate and consistent for blood volumes between 5-15 µL and for hematocrit levels spanning the range of 25-70%. Finally, a point-of-care DBS sampling device was developed combining the self-powered microfluidic SIMPLE technology. To evaluate the system's practical applicability, a validation study in the context of therapeutic drug monitoring of biologicals was performed using adalimumab-spiked blood samples. Microfluidic DBS samples showed good performance compared to the traditional DBS method with improved recovery rates (86% over 62%). This innovative metering system, allowing for parallelization and integration with complex liquid manipulations, will greatly impact the field of robust sampling, sample preparation, storage and analysis at the point-of-care.


Assuntos
Coleta de Amostras Sanguíneas , Teste em Amostras de Sangue Seco , Monitoramento de Medicamentos , Microfluídica
14.
Curr Hematol Malig Rep ; 16(6): 509-516, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34618316

RESUMO

PURPOSE OF REVIEW: Since the discovery of imatinib, an oral breakpoint cluster region-Abelson murine leukemia tyrosine kinase inhibitor, chronic myelogenous leukemia transformed from a hematologic malignancy primarily treated with intravenous chemotherapy to a disease almost solely managed with oral agents. While certainly there are benefits to taking a medication at home, this change in treatment modality also came with unique challenges, including patient adherence, medication acquisition and cost, and toxicity management. RECENT FINDINGS: Pharmacists are uniquely equipped to assist with educating patients, safe prescribing, and access to medications. Several studies have described the benefits of an integrated oral anticancer medication management program in the ambulatory setting, including improvements in patient adherence, side effect management, patient comprehension, and drug-interaction detection. Pharmacists are also specially trained to assist with medication dose adjustments, relative lab monitoring, and co-pay assistance. Here, we describe the multidisciplinary workflows established to manage oral therapies in chronic myelogenous leukemia patients in a malignant hematology clinic at a large academic medical center. By using the unique talents of the clinic pharmacist, clinic nurse, and specialty retail pharmacy group, patients can be triaged to help ensure the correct skill set is used to optimally care for patients. An acuity-based monitoring structure can improve the ability to reach and safely monitor a large volume of patients.


Assuntos
Antineoplásicos/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Administração Oral , Antineoplásicos/administração & dosagem , Gerenciamento Clínico , Monitoramento de Medicamentos , Humanos , Adesão à Medicação , Farmacêuticos
15.
Isr Med Assoc J ; 23(10): 662-664, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34672450

RESUMO

BACKGROUND: Iron deficiency anemia is a widespread problem. Although oral and intravenous therapy are available, iron malabsorption is a distinct possibility. OBJECTIVES: To evaluate the applicability of the oral iron absorption test (OIAT) as a simple and effective means of determining the degree of oral iron absorption. METHODS: The study comprised 81 patients diagnosed with iron deficiency anemia who were referred to a hematology outpatient clinic. Participants were given two ferrous sulphate tablets. Iron levels in the blood were evaluated at intervals from 30 to 180 minutes after iron administration. RESULTS: We divided patients into three distinct groups. The first group consisted of patients with little iron absorption with a maximum iron increment (Cmax) in the blood of 0-49 ug/dl. The second group had a moderate maximum absorption of 50-100 ug/dl, while a third group had considerable absorption of with maximum iron increase of over 100 ug/dl. CONCLUSIONS: The oral iron absorption test, although not clearly standardized, is easy to conduct in any outpatient clinic. This test can readily and clearly determine absorption or nonabsorption of iron. This test can have major implications on the need of oral or intravenous iron therapy and can also determine the need for further gastrointestinal evaluation of the small intestine, where iron absorption takes place and the success of therapy on subsequent iron absorption.


Assuntos
Administração Oral , Anemia Ferropriva , Monitoramento de Medicamentos/métodos , Compostos Ferrosos , Anemia Ferropriva/diagnóstico , Anemia Ferropriva/tratamento farmacológico , Anemia Ferropriva/fisiopatologia , Disponibilidade Biológica , Feminino , Compostos Ferrosos/administração & dosagem , Compostos Ferrosos/sangue , Absorção Gastrointestinal/fisiologia , Hematínicos/administração & dosagem , Hematínicos/sangue , Humanos , Síndromes de Malabsorção/diagnóstico , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes
20.
Adv Ther ; 38(10): 5317-5332, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34515977

RESUMO

INTRODUCTION: Tacrolimus, the cornerstone of transplantation immunosuppression, is a narrow therapeutic index drug with a low and highly variable bioavailability. Therapeutic drug monitoring based on trough level assessment is mandatory in order to target a personalised exposure and avoid both rejection and toxicity. Population pharmacokinetic (POPPK) models might be a useful tool for improving early attainment of target range by guiding initial doses until steady state is reached and trough levels can be reliably used as surrogate marker of exposure. Here we present the first POPPK for predicting the initial doses of the once-daily prolonged release tacrolimus Envarsus (LCPT) in adult kidney recipients. METHODS: The model was developed exploiting the data from a recent pharmacokinetic randomised clinical study, in which 69 de novo kidney recipients, 33 of whom treated with LCPT, underwent an intensive blood sampling strategy for tacrolimus including four complete pharmacokinetic profiles. RESULTS: The complex and prolonged absorption of LCPT is well described by the three-phase model that incorporates body weight and CYP3A5 genotype as significant covariates accounting for a great proportion of the inter-patient variability: in particular, CYP3A5*1/*3 expressors had a 66% higher LCPT clearance. We have then generated by simulation a personalised dosing strategy based on the model that could improve the early attainment of therapeutic trough levels by almost doubling the proportion of patients within target range (69.3% compared to 36.1% with the standard body weight-based approach) on post-transplantation day 4 and significantly reduce the proportion of overexposed patients at risk of toxicity. CONCLUSIONS: A POPPK model was successfully developed for LCPT in de novo kidney recipients. The model could guide a personalised dosing strategy early after transplantation. For the model to be translated into clinical practice, its beneficial impact of earlier attainment of therapeutic trough levels should be demonstrated on hard clinical outcomes in further studies.


Assuntos
Transplante de Rim , Tacrolimo , Adulto , Esquema de Medicação , Monitoramento de Medicamentos , Rejeição de Enxerto , Humanos , Imunossupressores
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