Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.097
Filtrar
1.
J Oncol Pharm Pract ; 26(1): 5-12, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30854922

RESUMO

BACKGROUND: Posaconazole reduces the risk of invasive Aspergillus in transplant patients, but significantly inhibits tacrolimus metabolism. One study demonstrated that a three-fold dose reduction of tacrolimus was required to obtain therapeutic concentrations when used with posaconazole. However, with empiric dose reduction, there is a risk of subtherapeutic tacrolimus levels and subsequent graft failure or graft-versus-host disease. Overall, the existing data on the impact of posaconazole on tacrolimus pharmacokinetics is limited. OBJECTIVE: The purpose of this study is to determine whether tacrolimus doses should be decreased upon initiation of posaconazole in patients receiving an allogeneic stem cell transplant. METHODS: This is a retrospective chart review at an academic medical center. All allogeneic stem cell transplant adults who received concomitant posaconazole and tacrolimus from February 2016 through December 2017 were included. RESULTS: Seventy-nine patients identified using an internal electronic database were analyzed. The median time to therapeutic tacrolimus concentration was significantly longer in patients who did not receive an empiric dose reduction (0% DR, 10d; 1-30% DR, 4d; 31-65% DR, 5d; >65% DR, 4d; p = 0.0395). The rate of supratherapeutic levels was highest amongst patients who did not receive an empiric DR, and was noted to be significant compared to the group that had 31-65% DR (p < 0.001). CONCLUSION: This study validates our current practice of instituting an empiric 50% dose reduction of oral tacrolimus to 0.03 mg/kg/day when used concomitantly with posaconazole to achieve therapeutic levels in allogeneic stem cell transplant patients.


Assuntos
Antifúngicos/farmacocinética , Transplante de Células-Tronco Hematopoéticas/tendências , Imunossupressores/farmacocinética , Transplante de Células-Tronco/tendências , Tacrolimo/farmacocinética , Triazóis/farmacocinética , Adulto , Antifúngicos/administração & dosagem , Esquema de Medicação , Interações de Medicamentos/fisiologia , Feminino , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Humanos , Imunossupressores/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tacrolimo/administração & dosagem , Triazóis/administração & dosagem
2.
J Oncol Pharm Pract ; 26(1): 156-174, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31354102

RESUMO

The development of BCR-ABL-targeting tyrosine kinase inhibitors has transformed chronic phase chronic myeloid leukemia (CP CML) from a disease with a terminal prognosis to a treatable chronic illness. Long-term treatment with tyrosine kinase inhibitors means that patients have to be clinically managed and monitored over extended periods of time, thus a patient-centered, medically integrated, and multidisciplinary oncology healthcare team is required to support patients through their journey. Pharmacists work with patients, physicians, and the wider support team to select the optimum therapy plan for a given patient. These decisions are based on risk factors, comorbidities, concomitant medications, and personal circumstances and pharmacists advise on the efficacy and safety of different treatment options. Additionally, pharmacists are a key point-of-contact and resource for monitoring patient response to treatment, identifying and managing adverse events and drug-drug interactions, any subsequent therapy plan modifications, and, potentially, treatment-free remission. Pharmacists also assist with patient education, medication adherence, and financial discussions with patients throughout the long course of the disease. This review provides an overview of BCR-ABL tyrosine kinase inhibitors, discusses the role of the medically integrated pharmacy team, and suggests strategies that pharmacists can use in patient management and clinical decision-making to optimize the treatment of CP CML.


Assuntos
Antineoplásicos/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Adesão à Medicação , Farmacêuticos/tendências , Inibidores de Proteínas Quinases/uso terapêutico , Interações de Medicamentos/fisiologia , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Oncologia/métodos , Oncologia/tendências , Proteínas Tirosina Quinases/antagonistas & inibidores
3.
Pharm Res ; 37(1): 13, 2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31873817

RESUMO

PURPOSE: Multiple time-point sampling is required in transcellular transport studies to accurately calculate the appropriate efflux ratio (ER). Our study sought to develop a simplified method to determine the ER in Caco-2 cells. METHODS: The equation for the ER was derived from a three-compartment model of apical to basal and basal to apical transport. Transcellular transport studies were conducted with 10 non-P-glycoprotein (P-gp) and 6 P-gp substrates in Caco-2 cells, and the ER was calculated using this equation. RESULTS: The equation for the ER used the concentration ratio in the receiver compartment at the same time-point; therefore, the ER can theoretically be calculated using only a single point. The ER of all non-P-gp substrates tested was close to 1 at all sampling times. The ERs of cyclosporine A calculated from the concentration ratio at 30, 60, 90, and 120 min incubation were 2.93, 6.43, 7.12, and 9.57, respectively, and the ER at 120 min was almost identical to the theoretical value (9.62) calculated using three-compartment model analysis. The other 5 P-gp substrates showed a similar tendency. Single-point sampling can be used to accurately calculate ER at 120 min. CONCLUSIONS: Single-point sampling is a promising approach for calculating appropriate ERs in the drug discovery stage.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Modelos Biológicos , Transporte Biológico , Técnicas Biossensoriais/métodos , Células CACO-2 , Ciclosporina , Interações de Medicamentos/fisiologia , Humanos , Permeabilidade , Ligação Proteica , Fatores de Tempo , Transcitose
4.
Drugs R D ; 19(3): 297-305, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31482303

RESUMO

BACKGROUND: Researchers have long been interested in the potential drug-drug interactions (DDIs) between opioids and benzodiazepines. However, much remains unknown concerning the interactions between these two drug classes. The objective of this work is to study the mechanism underlying the DDIs between opioids and benzodiazepines from the perspective of their pharmacokinetic (PK) interactions. A PK interaction occurs when two drugs are metabolized by the same cytochrome P450 enzymes and is one of the most common reasons for DDIs. METHODS: We quantitatively predicted the DDIs between three opioids (fentanyl, oxycodone and buprenorphine) and four benzodiazepines (alprazolam, diazepam, midazolam and triazolam) using a physiologically based pharmacokinetic (PBPK) modeling approach. A set of PBPK models was first constructed for these common opioids and benzodiazepines using SimCYP software, and the DDIs between them were then explored at various dosages. RESULTS: Our simulation results suggested there were no PK interactions between normal doses of opioids and benzodiazepines; but weak interactions can be expected with the combination of opioids and overdosed benzodiazepines. Particular attention should be given to the combination of fentanyl and overdosed alprazolam since a PK interaction can be observed between them. CONCLUSION: Our results appear to indicate that pharmacodynamics may play a more important role than PKs in causing DDIs between opioids and benzodiazepines. This study also demonstrated that molecular modeling can be a very useful tool to mitigate the problem of "missing metabolic reaction parameters" in PK modeling and simulation.


Assuntos
Analgésicos Opioides/farmacocinética , Benzodiazepinas/farmacocinética , Interações de Medicamentos/fisiologia , Simulação por Computador , Sistema Enzimático do Citocromo P-450/metabolismo , Humanos , Modelos Biológicos
5.
Molecules ; 24(16)2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31430892

RESUMO

The identification of drug-target interactions (DTIs) is a critical step in drug development. Experimental methods that are based on clinical trials to discover DTIs are time-consuming, expensive, and challenging. Therefore, as complementary to it, developing new computational methods for predicting novel DTI is of great significance with regards to saving cost and shortening the development period. In this paper, we present a novel computational model for predicting DTIs, which uses the sequence information of proteins and a rotation forest classifier. Specifically, all of the target protein sequences are first converted to a position-specific scoring matrix (PSSM) to retain evolutionary information. We then use local phase quantization (LPQ) descriptors to extract evolutionary information in the PSSM. On the other hand, substructure fingerprint information is utilized to extract the features of the drug. We finally combine the features of drugs and protein together to represent features of each drug-target pair and use a rotation forest classifier to calculate the scores of interaction possibility, for a global DTI prediction. The experimental results indicate that the proposed model is effective, achieving average accuracies of 89.15%, 86.01%, 82.20%, and 71.67% on four datasets (i.e., enzyme, ion channel, G protein-coupled receptors (GPCR), and nuclear receptor), respectively. In addition, we compared the prediction performance of the rotation forest classifier with another popular classifier, support vector machine, on the same dataset. Several types of methods previously proposed are also implemented on the same datasets for performance comparison. The comparison results demonstrate the superiority of the proposed method to the others. We anticipate that the proposed method can be used as an effective tool for predicting drug-target interactions on a large scale, given the information of protein sequences and drug fingerprints.


Assuntos
Interações de Medicamentos/fisiologia , Proteínas/metabolismo , Sequência de Aminoácidos , Biologia Computacional/métodos , Simulação por Computador , Bases de Dados de Proteínas , Desenvolvimento de Medicamentos/métodos , Matrizes de Pontuação de Posição Específica , Máquina de Vetores de Suporte
6.
Clin Drug Investig ; 39(10): 967-978, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31321631

RESUMO

BACKGROUND: Non-clinical study data suggest that DS-8500a, a G protein-coupled receptor 119 agonist, exhibits antidiabetic activity, inhibition of some transporters and induction of cytochrome P450 (CYP) 3A. Statins are substrates for some transporters and CYP3A that may be coadministered with DS-8500a in clinical practice. OBJECTIVE: To determine the potential effects of DS-8500a on the pharmacokinetics of statins, we evaluated the effects of repeated oral administration of DS-8500a 75 mg on the pharmacokinetics of rosuvastatin and atorvastatin in healthy adults. METHODS: We performed two single-center, open-label, single-sequence studies. In Study I, subjects received single-dose rosuvastatin 10 mg (Period A) and DS-8500a 75 mg once daily + single-dose rosuvastatin 10 mg (Period B). In Study II, subjects received single-dose atorvastatin 10 mg (Period A) and DS-8500a 75 mg once daily + single-dose atorvastatin 10 mg (Period B). Primary pharmacokinetic endpoints were maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of rosuvastatin and atorvastatin. Safety was evaluated. RESULTS: In Study I, the Cmax and AUC of rosuvastatin increased by 66% and 33%, respectively, when coadministered with DS-8500a, versus rosuvastatin alone. In Study II, the Cmax of atorvastatin increased by 28%, but AUC remained unchanged following coadministration with DS-8500a, versus atorvastatin alone. Treatment-emergent adverse events were mild to moderate and mostly unrelated to the study drugs. CONCLUSIONS: Multiple doses of DS-8500a increased exposure to rosuvastatin and atorvastatin. This short-term study suggests that the impact of DS-8500a coadministration on atorvastatin exposure is limited and may not be clinically relevant. Nevertheless, caution may be necessary when patients are coadministered rosuvastatin with DS-8500a. CLINICALTRIALS. GOV IDENTIFIER: NCT03699774. JAPAN PHARMACEUTICAL INFORMATION CENTER IDENTIFIER: JapicCTI-152878.


Assuntos
Atorvastatina/farmacocinética , Benzamidas/farmacocinética , Ciclopropanos/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Hipoglicemiantes/farmacocinética , Oxidiazóis/farmacocinética , Receptores Acoplados a Proteínas-G/agonistas , Rosuvastatina Cálcica/farmacocinética , Adulto , Atorvastatina/administração & dosagem , Benzamidas/administração & dosagem , Estudos Cross-Over , Ciclopropanos/administração & dosagem , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Interações de Medicamentos/fisiologia , Feminino , Voluntários Saudáveis , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hipoglicemiantes/administração & dosagem , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Oxidiazóis/administração & dosagem , Rosuvastatina Cálcica/administração & dosagem
8.
Eur J Pharm Biopharm ; 142: 435-448, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31306750

RESUMO

Acalabrutinib (Calquence®) 100 mg (bid) has received accelerated approval by FDA for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Acalabrutinib is a substrate of PgP and CYP3A4, with a significant fraction of drug metabolized by first pass gut extraction and 25% absolute bioavailability. The absorption of acalabrutinib is affected by stomach pH, with lower pharmacokinetic exposure observed following co-administration with proton pump inhibitors. During dissolution at pH values below its highest basic pKa, the two basic moieties of acalabrutinib react with protons from the aqueous solution, leading to a higher pH at the drug surface than in the bulk solution. A batch-specific product particle size distribution (P-PSD), was derived from dissolution data using a mechanistic model that was based on the understanding of surface pH and the contribution of micelles to the dissolution rate. P-PSD values obtained for various batches of acalabrutinib products in simple buffers, or in complex fluids such as fruit juices, were successfully integrated into a physiologically based pharmacokinetic (PBPK) model developed using GastroPlus v9.0™. The integrated model allowed the prediction of clinical pharmacokinetics under normal physiological stomach pH conditions as well as following treatment with proton pump inhibitors. The model also accounted for lower pharmacokinetic exposure that was observed when acalabrutinib was co-administered with the acidic beverages, grapefruit juice, (which contains CYP3A inhibitors), and orange drink (which does not contain CYP3A inhibitors), relative to administration with water. The integration of dissolution data in the PBPK model enables mechanistic understanding and the establishment of more robust in vitro-in vivo correlations (IVIVC) under a variety of conditions. The model can then distinguish the interplay between dissolution and first pass extraction and how in vivo stomach pH, saturation of gut PgP, and saturation or inhibition of gut CYP3A4, will impact the pharmacokinetics of acalabrutinib.


Assuntos
Benzamidas/química , Benzamidas/farmacocinética , Interações de Medicamentos/fisiologia , Sucos de Frutas e Vegetais/efeitos adversos , Inibidores da Bomba de Prótons/química , Inibidores da Bomba de Prótons/farmacocinética , Pirazinas/química , Pirazinas/farmacocinética , Solubilidade/efeitos dos fármacos , Disponibilidade Biológica , Química Farmacêutica/métodos , Humanos , Modelos Biológicos
9.
Nurse Educ Today ; 81: 19-25, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31306850

RESUMO

BACKGROUND: Historically nursing and midwifery students have reported difficulty understanding the concept-based science underpinning the interactions between drugs and their targets. This knowledge is crucial for the administration and monitoring of the therapeutic and adverse effects of medications. Immersive three-dimensional technology is reported to enhance understanding of complex scientific concepts but the physical effects of motion sickness may limit its use. OBJECTIVES: This project compared the effectiveness of three-dimensional immersive visualisation technology with two-dimensional visualisation technology as a teaching method to improve student understanding of a pharmacological concept, and to assess levels of student discomfort and satisfaction associated with the experience. DESIGN: Traditional lecture content and presentation about drug-receptor binding was followed by exposure to either a two- or three-dimensional artifact visualising ß-adrenoceptor binding. Two student groups were compared by type of exposure: Group 1 watched the artifact via a three-dimensional immersive facility and Group 2 on a wide, two-dimensional screen. SETTINGS: School of Nursing and Midwifery in a regional university in Southeast Queensland, Australia. PARTICIPANTS: Two hundred and two second year undergraduate nursing and midwifery students. METHODS: The study used mixed methods methodology. Pre- and post- testing of student knowledge was collected using five multiple-choice questions. A post-intervention survey elicited students' self-assessed perceptions of discomfort and satisfaction with the learning experience. RESULTS: The three-dimensional immersive learning experience was comparable to the two-dimensional experience in terms of satisfaction and comfort but resulted in statistically significant improvements in post-test scores. CONCLUSIONS: The three-dimensional experience improved understanding when compared to two-dimensional viewing, satisfied students leaning needs, and caused minimal discomfort. The results are encouraging in terms of using three-dimensional technology to enhance student knowledge of pharmacological concepts necessary for competency in medication management.


Assuntos
Interações de Medicamentos/fisiologia , Avaliação Educacional/normas , Conhecimento , Tocologia/educação , Farmacologia/educação , Estudantes de Enfermagem , Realidade Virtual , Competência Clínica , Feminino , Humanos , Masculino , Farmacologia/métodos , Aprendizagem Baseada em Problemas
10.
Eur J Pharm Biopharm ; 142: 101-113, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31226365

RESUMO

Recent studies indicated obvious impacts of nano-carriers on cytochrome P450 enzymes (CYP450s) in vitro, but the effects in vivo are still unknown. In the present research, mPEG2k-PCLx micelles with different length of hydrophobic block (2000-10,000 Da) were intravenously administrated into rats for 14 days to evaluate the sub-chronic influences in the metabolic function of hepatic CYP450s. Although CYP1A1/B2 was susceptible to mPEG2k-PCLx micelles compared with other CYP isoenzymes, induction was mainly observed and varied with micelle type, administration dose, and CYP isoform. Interestingly, mPEG2k-PCL3.5k micelles at 5 mg/kg increased the activity of CYP1A2, CYP2B1, CYP2C6, CYP2C11, and CYP3A1/2 while mPEG2k-PCL5k micelles only induced the latter three enzymes at 75 mg/kg. The mRNA expression of corresponding CYPs was mostly up-regulated by mPEG2k-PCL3.5k micelles whilst less effect in protein level except for CYP3A1/2. Moreover, mPEG2k-PCL3.5k micelles could affect the pharmacokinetic properties of phenacetin (CYP1A2), tolbutamide (CYP2C6), omeprazole (CYP2C11), and midazolam (CYP3A1/2) with a decrease of 19.6% in Cmax, 20.5% in AUC0-t, 31.6% in AUC0-t, and 40.1% in Cmax at 5 mg/kg, respectively (P < 0.05 or P < 0.01). These results unveiled nano-DDS might be involved in nanocarrier-drug interaction by intervening in the activity of CYP450s.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Portadores de Fármacos/química , Nanopartículas/química , Poliésteres/química , Polietilenoglicóis/química , Polímeros/química , Administração Intravenosa/métodos , Animais , Interações de Medicamentos/fisiologia , Masculino , Micelas , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley
12.
J Clin Pharm Ther ; 44(5): 735-741, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31119771

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Polypharmacy and age are known to increase the risk for potential drug interactions. Type 2 diabetes has been associated with polypharmacy and several comorbidities. Currently, there is no information on whether the frequency of clinically relevant drug-drug interactions and the risk for drug adverse effects differ between older persons with and without diabetes. The aim of this study was to investigate the frequency of drug-drug interactions and the risk for drug adverse effects in these two groups in primary care. METHODS: The basic study population consisted of Finnish home-dwelling primary care patients aged ≥ 65 years (N = 3039). For each person with diabetes, two controls were selected with adjusted age and gender. To collect data, electronic primary care patient records, a structured health questionnaire and a structured health examination conducted by a physician were utilized. Using the SFINX-PHARAO® database, drug-drug interactions and the risk for drug adverse effects were evaluated in 182 persons with type 2 diabetes and 176 persons without diabetes. RESULTS AND DISCUSSION: There were no significant differences in the frequency of drug-drug interactions or the risk for drug adverse effects in persons with and without diabetes. At least one clinically relevant interaction was found in 81 (44.5%) persons with diabetes and 73 (41.5%) persons without diabetes. The most common drugs causing interactions included non-steroidal anti-inflammatory drugs (NSAIDs) and warfarin. WHAT IS NEW AND CONCLUSION: There is no difference in the frequency of drug-drug interactions or risk for drug adverse effects in older home-dwelling persons with and without diabetes. Due to common comorbidities and commonly used drugs among persons with diabetes, drug-drug interactions involving warfarin or NSAIDs in particular should be carefully monitored to avoid drug adverse effects.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Interações de Medicamentos/fisiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Varfarina/efeitos adversos , Varfarina/uso terapêutico , Idoso , Comorbidade , Feminino , Finlândia , Humanos , Masculino , Polimedicação , Padrões de Prática Médica , Atenção Primária à Saúde/métodos , Inquéritos e Questionários
14.
Neuropharmacology ; 155: 104-112, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31128121

RESUMO

Galanin (1-15) [GAL(1-15)] participates in mood regulation and depression. GAL(1-15) is also able to enhance the antidepressant effects induced by Fluoxetine (FLX) in the forced swimming test through interaction between GALR1-GALR2 and 5-HT1A receptors that induced changes in the binding characteristics and mRNA of the 5-HT1AR in the hippocampus. Since the medial prefrontal cortex (mPFC) is a core region for the interaction between emotional processing and cognition with a high density of 5-HT1AR and GALR1 and GALR2, we have analyzed the binding characteristics and mRNA levels of 5-HT1AR in the mPFC after GAL(1-15)-FLX administration in the rats. GAL(1-15) increased the Kd and the Bmax of the 5HT1AR agonist binding in the mPFC as well as the mRNA levels of 5-HT1AR in mPFC. Moreover, GAL(1-15) reversed the effects of memory impairment induced by FLX(10 mg/kg) in the Novel Object Recognition task. GALR2 was involved in these effects, since the specific GALR2 antagonist M871 blocked GAL(1-15) mediated actions at behavioral level. On the contrary GAL(1-15) did not reverse the effect of FLX in the Object Location Memory task. In conclusion, our results describe an interactions between GAL(1-15) and FLX in the mPFC involving interactions at the 5-HT1AR receptor level in the plasma membrane with changes at the transcriptional level with implications also at functional level. The GALR1-GALR2-5-HT1A heteroreceptor could be postulated to be used to reverse some of the adverse effects of FLX on memory processes.


Assuntos
Fluoxetina/metabolismo , Galanina/metabolismo , Fragmentos de Peptídeos/metabolismo , Córtex Pré-Frontal/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Inibidores de Captação de Serotonina/metabolismo , Animais , Interações de Medicamentos/fisiologia , Fluoxetina/toxicidade , Galanina/farmacologia , Galanina/uso terapêutico , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Neuropeptídeos/metabolismo , Neuropeptídeos/farmacologia , Neuropeptídeos/uso terapêutico , Fragmentos de Peptídeos/farmacologia , Fragmentos de Peptídeos/uso terapêutico , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Inibidores de Captação de Serotonina/toxicidade
15.
J Clin Pharm Ther ; 44(5): 720-725, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31094010

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Teneligliptin is a DPP-4 inhibitor used for the treatment of type 2 diabetes mellitus, commonly prescribed in combination with glimepiride. Teneligliptin is metabolized by CYP3A4, and glimepiride might be partly metabolized by CYP3A4. The aim of the study was to investigate the possible effect of glimepiride on the pharmacokinetics of teneligliptin in healthy subjects. METHODS: A repeated dose, open-label, fixed-sequence study was conducted in 26 healthy subjects. All participants were administered 20 mg teneligliptin daily for 6 days. On day 7, 4 mg glimepiride was administered together with 20 mg teneligliptin. Plasma teneligliptin concentrations were measured at a steady state, and its pharmacokinetic characteristics were compared without and with glimepiride. RESULTS AND DISCUSSION: No statistically significant difference was found in the effect of glimepiride on teneligliptin pharmacokinetics. The steady-state Cmax,ss values of teneligliptin without and with glimepiride were 207.01 ng/mL and 202.15 ng/mL, respectively. Its AUCτ values at steady-state without and with glimepiride were 1527.8 ng · h/mL and 1578.6 ng · h/mL, respectively. The point estimation of geometric mean ratios (GMR) and the 90% confidence interval for both Cmax,ss and AUCτ were within the equivalence range of 0.8-1.25. The results of the present study revealed that glimepiride did not cause pharmacokinetic interaction with teneligliptin in humans. WHAT IS NEW AND CONCLUSION: Glimepiride did not affect the pharmacokinetic characteristics of teneligliptin in healthy subjects.


Assuntos
Interações de Medicamentos/fisiologia , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Pirazóis/farmacocinética , Compostos de Sulfonilureia/efeitos adversos , Compostos de Sulfonilureia/uso terapêutico , Tiazolidinas/farmacocinética , Adulto , Diabetes Mellitus Tipo 2/metabolismo , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , República da Coreia , Adulto Jovem
16.
Drug Alcohol Depend ; 200: 168-180, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31122724

RESUMO

BACKGROUND: The use of oral methadone in opioid substitution treatment (OST) for the management of opioid use disorder is established clinical practice. Confounding treatment is the increased risks of contracting Mycobacterium tuberculosis, the mainstay treatment of which incorporates the potent CYP 2B6 inducer rifampicin. METHODS: This study applied pharmacokinetic modelling using virtual clinical trials, to pharmacokinetically quantify the extent and impact of rifampicin-mediated drug-drug interactions (DDI) on methadone plasma concentrations. An R-methadone model was developed and validated against 11 retrospective clinical studies prior to use in all subsequent studies. The aims were to investigate: (i) the impact of the DDI on daily methadone doses of 60 mg, 90 mg and 120 mg; (ii) dose escalation during rifampicin and (iii) dose reduction following rifampicin cessation. RESULTS: A dose increase to 160 mg daily during rifampicin treatment phases was required to maintain peak methadone plasma concentrations within a derived therapeutic window of 80-700 ng/mL. Dose escalation prior to rifampicin initiation was not required and resulted in an increase in subjects with supra-therapeutic concentrations. However, during rifampicin cessation, a dose reduction of 10 mg every 2 days commencing prior to rifampicin cessation, ensured that most patients possessed a peak methadone plasma concentration within an optimal therapeutic window. IMPLICATIONS: Rifampicin significantly alters methadone plasma concentrations and necessitates dose adjustments. Daily doses of almost double those used perhaps more commonly in clinical practice are required for optimal plasma concentration and careful consideration of dose reduction strategies would be required during the deinduction phase.


Assuntos
Analgésicos Opioides/farmacocinética , Metadona/farmacocinética , Modelos Biológicos , Rifampina/farmacocinética , Adulto , Analgésicos Opioides/administração & dosagem , Relação Dose-Resposta a Droga , Interações de Medicamentos/fisiologia , Quimioterapia Combinada , Feminino , Humanos , Masculino , Metadona/administração & dosagem , Pessoa de Meia-Idade , Inibidores da Síntese de Ácido Nucleico/administração & dosagem , Inibidores da Síntese de Ácido Nucleico/farmacocinética , Tratamento de Substituição de Opiáceos/métodos , Tratamento de Substituição de Opiáceos/normas , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/metabolismo , Estudos Retrospectivos , Rifampina/administração & dosagem
17.
J Pharm Biomed Anal ; 172: 206-213, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31060033

RESUMO

Overexpression of leucine-zipper and sterile-α motif kinase (ZAK) in heart has been closely associated with the development of hypertrophic cardiomyopathy (HCM). N-(3-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl) benzene-sulfonamides, novel highly selective ZAK inhibitors, had exhibited reasonable orally therapeutic effects on HCM in spontaneous hypertensive rat models. In the present study, a rapid and sensitive HPLC-MS/MS method for determining ZAK inhibitor 3h in beagle dog plasma was developed and validated. Meanwhile, the pharmacokinetics in beagle dog and drug-drug interaction potential of 3h had been conducted. The pharmacokinetic results showed that the absolute oral bioavailability for 3h in beagle dogs was determined to be 61.9%, which was significantly higher than that in the previous determination in Spragur-Dawley rats (F = 20%). The Cytochrome P450 enzymes and P-glycoprotein mediated drug-drug interactions by 3h were also investigated using dog and human liver microsomes and Caco-2 cells. The results demonstrated that only CYP2C9 was obviously inhibited (IC50 = 1.66 µM). Besides, 3h could significantly decrease digoxin efflux ratio in Caco-2 experiments in a dose-dependent manner (IC50 = 13.3 µM). Considering 3h strongly suppressed the ZAK kinase activity with an IC50 of 3.3 nM, there are significantly differences between this IC50 value for ZAK inhibition and the present determinations of IC50 values. In general, the clinical drug-drug interaction potential for 3h could be well monitored during the treatment of HCM.


Assuntos
Cardiomiopatia Hipertrófica/tratamento farmacológico , Cardiomiopatia Hipertrófica/metabolismo , Interações de Medicamentos/fisiologia , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/farmacocinética , Proteínas Quinases/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Disponibilidade Biológica , Células CACO-2 , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão/métodos , Sistema Enzimático do Citocromo P-450/metabolismo , Cães , Humanos , Masculino , Microssomos Hepáticos/metabolismo , Fosforilação/fisiologia , Ratos , Ratos Endogâmicos SHR , Ratos Sprague-Dawley , Sulfonamidas/farmacocinética , Espectrometria de Massas em Tandem/métodos
19.
Int J Cancer ; 145(9): 2450-2458, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30958892

RESUMO

Regorafenib 160 mg orally once daily (QD) 3 weeks on/1 week off is approved in colorectal cancer, gastrointestinal stromal tumors and hepatocellular carcinoma. We established the safety and pharmacokinetics (PK) of regorafenib combined with cetuximab in advanced refractory solid tumors. This was a phase 1, open-label, dose-escalation study (NCT01973868) in patients with advanced/metastatic solid tumors who progressed after standard therapy. Regorafenib was administered at various dose levels QD continuously or intermittently (3 weeks on/1 week off) combined with intravenous cetuximab 250 mg/m2 weekly. The primary objectives were safety, PK and maximum tolerated dose (MTD). The secondary objective was tumor response. Dose-limiting toxicities (DLTs) were evaluated in Cycle 1. Of 42 treated patients, 31 received regorafenib intermittently (120 mg, n = 8; 160 mg, n = 23) and 11 continuously (60 mg, n = 5; 100 mg, n = 6) plus cetuximab. The continuous arm was terminated due to low tolerable dose. In the intermittent arm, one DLT (grade 3 hand-foot skin reaction) was observed at 120 mg but none at 160 mg, therefore 160 mg/day was declared as the MTD in combination with cetuximab. The most common all-grade treatment-emergent adverse events were fatigue (52%), hypophosphatemia (48%) and diarrhea (40%). One grade 3 cetuximab-related dermatitis acneiform was observed. No clinically relevant drug-drug interactions were observed. Five patients (21%) had a partial response. Regorafenib 160 mg QD (3 weeks on/1 week off) plus standard dose of cetuximab was well tolerated with no unexpected toxicities and promising signs of efficacy.


Assuntos
Cetuximab/efeitos adversos , Cetuximab/farmacocinética , Neoplasias/tratamento farmacológico , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/farmacocinética , Piridinas/efeitos adversos , Piridinas/farmacocinética , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cetuximab/uso terapêutico , Interações de Medicamentos/fisiologia , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Compostos de Fenilureia/uso terapêutico , Piridinas/uso terapêutico , Resultado do Tratamento , Adulto Jovem
20.
Eur J Drug Metab Pharmacokinet ; 44(5): 713-717, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30993551

RESUMO

BACKGROUND AND OBJECTIVES: A recent report indicated that the pharmacodynamic interaction between clopidogrel and vonoprazan leading to attenuation of the anti-platelet effect of clopidogrel was unlikely to be caused by the inhibition of cytochrome P450 (CYP) 2B6, CYP2C19, or CYP3A4/5 by vonoprazan, based on in vitro CYP inhibition data. The current report investigates another important antiplatelet inhibitor, prasugrel, that is also activated through metabolism by CYP2B6, CYP2C19 and CYP3A4/5, for its CYP-based DDI potential with vonoprazan. The report describes in vitro metabolic inhibition assessments using radiolabeled prasugrel and human liver microsomes (HLMs). METHODS: Reversible and time-dependent inhibition studies of vonoprazan as well as esomeprazole on the formation of the active metabolite R-138727 of prasugrel were conducted using HLMs. RESULTS: Vonoprazan up to 10 µM, a concentration over 100-fold higher than the clinical maximum plasma concentration (Cmax) of 75.9 nM after 20 mg once daily for 7 days, did not significantly affect the formation of R-138727 from [14C]prasugrel via reversible or time-dependent inhibition. CONCLUSIONS: The in vitro data show that the pharmacodynamic interaction reported in the literature between vonoprazan and prasugrel is unlikely to be caused by CYP inhibition by vonoprazan. The results were similar to those obtained from the study with clopidogrel.


Assuntos
Interações de Medicamentos/fisiologia , Microssomos Hepáticos/metabolismo , Inibidores da Agregação de Plaquetas/metabolismo , Cloridrato de Prasugrel/metabolismo , Pirróis/farmacologia , Sulfonamidas/farmacologia , Clopidogrel/metabolismo , Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Humanos , Piperazinas/metabolismo , Agregação Plaquetária/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA