RESUMO
The method for the determination of primaquine (PQ) and 5,6-orthoquinone primaquine (5,6-PQ), the representative marker for PQ active metabolites, via CYP2D6 in human plasma and urine has been validated. All samples were extracted using acetonitrile for protein precipitation and analyzed using the ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) system. Chromatography separation was carried out using a Hypersil GOLDTM aQ C18 column (100 × 2.1 mm, particle size 1.9 µm) with a C18 guard column (4 × 3 mm) flowed with an isocratic mode of methanol, water, and acetonitrile in an optimal ratio at 0.4 mL/min. The retention times of 5,6-PQ and PQ in plasma and urine were 0.8 and 1.6 min, respectively. The method was validated according to the guideline. The linearity of the analytes was in the range of 25-1500 ng/mL. The matrix effect of PQ and 5,6-PQ ranged from 100% to 116% and from 87% to 104% for plasma, and from 87% to 89% and from 86% to 87% for urine, respectively. The recovery of PQ and 5,6-PQ ranged from 78% to 95% and form 80% to 98% for plasma, and from 102% to from 112% to 97% to 109% for urine, respectively. The accuracy and precision of PQ and 5,6-PQ in plasma and urine were within the acceptance criteria. The samples should be kept in the freezer (-80 °C) and analyzed within 7 days due to the metabolite stability. This validated UHPLC-MS/MS method was beneficial for a pharmacokinetic study in subjects receiving PQ.
Assuntos
Primaquina/análise , Primaquina/química , Primaquina/farmacocinética , Cromatografia Líquida de Alta Pressão , HumanosRESUMO
Drug dosing adjustment in sepsis-induced acute kidney injury (sepsis-AKI) is currently adjusted based on renal function. Sepsis is a multiorgan injury, and thus, drug metabolism in sepsis-AKI might be interfered by non-renal factors such as changes in functions of drug-metabolizing enzymes in the liver and functions of intestinal drug transporters. We compared the defect on mouse CYP3A11 (human CYP3A4 representative) in liver and intestine along with several intestinal drug transporters (MDR1a, MRP2, and OATP3) in three mouse models; chronic ischemic reperfusion injury (Chr I/R; 4-week), acute ischemic reperfusion injury (Acute I/R; 24-h), and cecal ligation and puncture (CLP; 24-h) as representative of sepsis-AKI. Decreased expression of CYP3A11 and drug transporters was demonstrated in all models. Among these models, sepsis-AKI had the least severe renal injury (increased BUN and Scr) with the most severe liver injury (increased ALT and changes in liver histopathology), the most severe intestinal leakage (increased serum (1â3)-ß-D-glucan) and the highest increase in serum IL-6. A reduced expression and activity of liver and intestinal CYP3A11 along with intestinal efflux-drug transporter expressions (MDR1a and MRP2), but not drug uptake transporter (OATP3), was predominant in sepsis-AKI compared with acute I/R. Additionally, a reduction of CYP3A4 expression with IL-6 was demonstrated on HepG2 cells implying a direct injury of IL-6 on human liver cells. Differences in drug metabolism were reported between sepsis-AKI and ischemic-AKI confirming that drug dosing adjustment in sepsis-AKI depends not just only on renal function but also on several non-renal factors. Further studies are warranted.
Assuntos
Injúria Renal Aguda/patologia , Insuficiência Renal Crônica/patologia , Traumatismo por Reperfusão/patologia , Sepse/complicações , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Injúria Renal Aguda/etiologia , Animais , Quimiocinas CC/metabolismo , Citocromo P-450 CYP3A/metabolismo , Modelos Animais de Doenças , Células Hep G2 , Humanos , Interleucina-6/metabolismo , Intestinos/patologia , Fígado/patologia , Proteínas Inflamatórias de Macrófagos/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Transportadores de Ânions Orgânicos/metabolismo , Insuficiência Renal Crônica/etiologia , Traumatismo por Reperfusão/etiologiaRESUMO
Clopidogrel is an antiplatelet drug, selectively binding to the platelet P2Y12 receptor of adenosine diphosphate. Clopidogrel is a prodrug modified through active metabolite in the liver by two steps of CYP enzyme. The active metabolite is responsible for inhibiting platelet aggregation. OBJECTIVE: The study aimed to assess the bioequivalence of clopidogrel 75 mg generic and reference drugs and to investigate the correlation between pharmacokinetics of active metabolites and its antiplatelet activities. MATERIALS AND METHODS: Determination of clopidogrel, carboxylic acid form, and active metabolite were done by liquid chromatography tandem mass spectrometry, and evaluation of platelet function was also investigated by light transmission aggregometer. 20 subjects were randomized and assigned in a crossover design to take a single 75-mg oral dose of clopidogrel generic and reference drugs in two periods with washout. Pharmacokinetic parameters Cmax, AUC0-t, and AUC0-inf of clopidogrel, carboxylic acid form, and active metabolite were analyzed. RESULTS: Bioequivalence could be shown when testing parameters with ANOVA, as 90% confidence intervals were found to be within the acceptance range of 80 - 125%. For the maximum of platelet aggregation after administration of both products, no significant differences were found. Significant correlation of Cmax of clopidogrel active metabolite and maximum platelet aggregation was found after receiving 0 - 6 hours of both formulations. CONCLUSION: The study found bioequivalence of clopidogrel generic and reference drugs. There were also significant correlations between Cmax of clopidogrel active metabolite and maximum platelet aggregation.â©.
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Inibidores da Agregação Plaquetária/farmacocinética , Ticlopidina/análogos & derivados , Adolescente , Adulto , Clopidogrel , Estudos Cross-Over , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Agregação Plaquetária/efeitos dos fármacos , Equivalência Terapêutica , Ticlopidina/farmacocinética , Ticlopidina/farmacologia , Adulto JovemRESUMO
OBJECTIVE: The purpose of the study was to evaluate the pharmacokinetics and bioequivalence of pregabalin following administration of a 150-mg capsule of test and reference products. METHOD: The study was designed as a randomized, two-treatment, two-period, two-sequence, single-dose crossover with 1-week washout period between period I and period II dosing. 20 healthy male and female Thai subjects were enrolled in the study. Each subject was in fasted state for ~ 10 hours prior to receiving a single oral 150-mg pregabalin capsule. Serial blood samples were collected at pre-dose until 32 hours after drug administration. Plasma samples were extracted by protein precipitation and derivatized with 4-chloro-7-nitrobenzofurazan. Pregabalin plasma concentrations were determined by HPLC method, and pharmacokinetic parameters were calculated. For bioequivalence assessment, the differences of Cmax, AUC0-t, and AUC0-inf means based on ln-transformed data were assessed by the 90% confidence interval (CI). RESULTS: Pharmacokinetic parameters were determined that test and reference products showed 0.96 ± 0.35 and 1.04 ± 0.96 hours for tmax, 4,594.217 ± 834.195 and 4,568.68 ± 573.963 ng/mL for Cmax, 30,048.150 ± 2,998.920 and 29,315.722 ± 2,747.396 ng×h/mL for AUC0-t, 30,594.210 ± 2,872.317 and 29,831.454 ± 2,688.020 ng×h/mL for AUC0-inf, respectively. The 90% CIs of Cmax, AUC0-t, and AUC0-inf for test and reference products were assessed at 95.356 - 104.630%, 99.303 - 105.751%, and 99.373 - 105.788%, respectively. The results were within the acceptance criteria of 80 - 125%. CONCLUSION: Pharmacokinetic parameters of a single oral 150-mg pregabalin capsule in healthy Thai subjects were evaluated and showed rapid absorption. 90% CI for the differences of Cmax, AUC0-t, and AUC0-inf were within the acceptable range of the criteria so that bioequivalence of the test and reference products of pregabalin 150-mg capsule could be concluded.â©.
Assuntos
Cápsulas/administração & dosagem , Cápsulas/farmacocinética , Pregabalina/administração & dosagem , Pregabalina/farmacocinética , Administração Oral , Adolescente , Adulto , Área Sob a Curva , Disponibilidade Biológica , Estudos Cross-Over , Feminino , Meia-Vida , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Comprimidos/administração & dosagem , Comprimidos/farmacocinética , Tailândia , Equivalência Terapêutica , Adulto JovemRESUMO
BACKGROUND: Rituximab is an anti-CD20 chimeric antibody widely used in combination with CHOP regimen for the treatment of diffuse large B-cell lymphoma (DLBCL). It is suggested that this antibody destroys B lymphoma cells mainly by antibody dependent cellular cytotoxicity (ADCC) mechanism via the binding of the drug to FC gamma IIIa receptor (FcγRIIIa) on natural killer (NK) cells, affected to kill cancer cells. The FcγRIIIa has genetic polymorphism at nucleotide position 559 (G559T or V158F or rs396991) have shown influence on the binding and efficacy of rituximab. OBJECTIVE: We identified the distribution of FcγRIIIa polymorphism in Thai patients with DLBCL and investigated the correlation between FcγRIIIa polymorphisms and the clinical outcomes in Thai DLBCL patients who were treated with rituximab plus CHOP chemotherapy regimen. MATERIAL AND METHOD: The Taqman SNP real-time PCR assay was used to identify the FcγRIIIa polymorphism in the present study and the clinical outcomes of these patients were evaluated and correlated between FcγRIIIa polymorphism. RESULTS: The distribution of FcγRIIIa genotype in patients were 54.17% homozygous V/V 10.41% homozygous F/F and 35.42% heterozygous V/F and there was no differences in clinical response among these patients (p-value = 0.31). Complete response was assessed in V/V 84.62%, V/F 88.24%, and F/F 80.00%. Partial response was in V/V 7.68% and F/F 20.00%. Stable disease was in V/F 11.76%, progressive disease in V/V 7.72%. CONCLUSION: The correlation could not be found between FcγRIIIa polymorphisms to the response of rituximab in Thai patients with diffuse large B-cell lymphoma.
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Linfoma Difuso de Grandes Células B , Receptores de IgG/genética , Rituximab/farmacologia , Citotoxicidade Celular Dependente de Anticorpos/genética , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Feminino , Genótipo , Humanos , Células Matadoras Naturais/imunologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Farmacogenética , Polimorfismo Genético , Estatística como AssuntoRESUMO
OBJECTIVE: Sirolimus may be of benefit in terms ofa reduction of cardiovascular disease in renal transplant recipients. The aim of the present study was to investigate cardiovascular risk markers in renal transplant recipients receiving calcineurin inhibitors (CNI-based regimen), as compared to those receiving sirolimus (SRL-based regimen). MATERIAL AND METHOD: 42 patients were recruited (21 patients for each regimen). Plasma concentrations of cardiovascular risk markers, including asymmetric dimethylarginine (ADMA), nitric oxide (NO), homocysteine (Hcy), and total antioxidant status (TAOS) were measured. RESULTS: Plasma ADMA concentrations were lower in patients with SRL-based regimen, as compared to those with CNI-based regimen (0.52 ± 0.02 and 0.60 ± 0.02 µmol/L, p = 0.027). There were no statistically significant differences seen in NO, Hcy, and TAOS between the two treatments. CONCLUSION: As compared to CNI-based regimen, cardiovascular risk marker (ADMA) levels are lower in patients with SRL-based regimen.
Assuntos
Arginina/análogos & derivados , Imunossupressores/uso terapêutico , Transplante de Rim/métodos , Sirolimo/uso terapêutico , Arginina/sangue , Inibidores de Calcineurina/uso terapêutico , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , TransplantadosRESUMO
OBJECTIVE: Pharmacokinetics and bioequivalence of 300 mg irbesartan tablets were studied in 26 healthy Thai male volunteers. METHODS: A single oral dose of one 300 mg tablet of the test product and the reference product was given to each volunteer according to a randomized two-way crossover design with 1-week wash out period. Blood samples were collected at predetermined time intervals until 72 hours post dose and irbesartan concentration was quantified with a validated HPLC method. Individual plasma irbesartan concentration-time profile was analyzed for pharmacokinetic parameters. RESULTS: Maximum plasma concentrations (Cmax) of 3,617.19 and 3,295.77 ng/mL for test and reference, respectively, were achieved. Areas under the plasma concentration-time curve; AUC0-t and AUC0-∞ were 15,304.65 and 15,638.90 ng×h/mL for test and 15,389.21 and 15,730.34 ng×h/mL for reference. The median tmax was 1.50 hours and 1.25 hours for test and reference, respectively. Plasma elimination half-lives (t1/2) were 7.35 hours and 8.09 hours for test and reference, respectively. Primary pharmacokinetic parameters Cmax, AUC0-t, and AUC0-∞ were tested parametrically by analysis of variance (ANOVA), and it revealed no statistically significant difference (defined as p < 0.05) between the corresponding Cmax, AUC0-t, and AUC0-∞ with respect to sequence, volunteers, period and formulation. The 90% confidence intervals for the ratio of test and reference product of the parameters Cmax, AUC0-t, and AUC0-∞ were within 80 - 125% (100.13 - 121.40% for Cmax, 90.83 - 106.86% for AUC0-t and 91.11 - 106.55% for AUC0-∞). CONCLUSION: The two products were bioequivalent in terms of both rate and extent of drug absorption into systemic circulation.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacocinética , Anti-Hipertensivos/farmacocinética , Compostos de Bifenilo/farmacocinética , Tetrazóis/farmacocinética , Administração Oral , Adolescente , Adulto , Análise de Variância , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Área Sob a Curva , Compostos de Bifenilo/administração & dosagem , Estudos Cross-Over , Meia-Vida , Voluntários Saudáveis , Humanos , Irbesartana , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Comprimidos , Tetrazóis/administração & dosagem , Tailândia , Equivalência Terapêutica , Adulto JovemRESUMO
Objectives: Primaquine is metabolized by the cytochrome P450-2D6 enzyme (CYP2D6) to an active primaquine-5,6-orthoquinone (POQ). No relationships of CYP2D6 polymorphisms with the pharmacokinetics of primaquine and POQ were reported in the Thai population. Methods: We evaluated the genetic distribution of CYP2D6 in 345 Thai army populations together with the pharmacokinetic profiles of primaquine and POQ in plasma and urine (n = 44, descriptive data are presented in median (range)). All dose-related pharmacokinetic parameters were normalized by primaquine dose per body weight before statistical analysis. Results: CYP2D6*10 was the allele observed with the highest frequency (56.62%) corresponding to CYP2D6*10/*10 (32.94%) and CYP2D6*1/*10 (27.94%) genotypes. CYP2D6 intermediate metabolizers (CYP2D6 IM) were found in 44.41% of the cohort and had an increase in the cumulative amount of primaquine excreted (CAE) in urine compared to normal metabolizers of CYP2D6 (CYP2D6 NM); (CYP2D6 IM vs. CYP2D6 NM: 2444 (1697-3564) vs. 1757 (1092-2185) µg/mg/kg, p = 0.039), a reduction in urine CAE of POQ (CYP2D6 IM vs CYP2D6 NM: 115 (46-297) vs. 318 (92-498) µg/mg/kg, p = 0.047) and a reduction in the POQ/primaquine CAE ratio in urine (CYP2D6 IM vs. CYP2D6 NM: 0.06 (0.01-0.11) vs. 0.16 (0.06-0.26), p = 0.009). No significant differences were found in the pharmacokinetic profiles of plasma primaquine and POQ. Conclusions: The CYP2D6 polymorphisms influenced the changes in primaquine and POQ that were noticeable in the urine, supporting the role of the CYP2D6 gene testing before drug administration.
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Sofosbuvir/Velpatasvir (SOF/VEL) is a combination drug used for chronic hepatitis C (HCV) infection. However, limited information exists regarding the pharmacokinetics of SOF/VEL and its metabolites in hemodialysis patients. We conducted a prospective investigation of the pharmacokinetic parameters of SOF/VEL after a single dose of SOF/VEL (400/100 mg) on days with and without dialysis in 12 Thai hemodialysis patients with chronic HCV infection, who had been undergoing hemodialysis for a duration of 0.5-20 years. Blood samples were collected before dose (0) and 0.5, 1.0, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 8.0, and 12.0 h after dose. Dialysate samples were also collected before dose (0) and 1.0, 2.0, 3.0, and 4.0 h after dose. Plasma and dialysate samples were quantified for SOF and its metabolite, GS-331007, and VEL concentrations using a fully validated LCMS technique. In addition, a preliminary efficacy study was conducted using the proposed SOF/VEL dose reduction regimen in all patients. No differences in SOF/VEL PK parameters between on- and off-dialysis studies. On the contrary, GS-331007 exhibited a 30% reduction in the area under the plasma concentration-time curve from time 0 to 24 h (AUC0-24h) on dialysis days compared with non-dialysis days (AUC0-24h ratio 0.68 vs. 1.04, respectively). The dialysis clearance of SOF and GS-331007 was 9.35 (8.72-15.11) and 8.89 (8.52-14.07) mL/min, respectively. Subsequently, an alternate-day regimen of SOF/VEL (400/100 mg) was administered for 12 weeks, resulting in an undetectable plasma HCV viral load without side effects. Further clinical studies are warranted to validate the efficacy and safety of our proposed dose reduction regimen.
Assuntos
Antivirais , Carbamatos , Esquema de Medicação , Combinação de Medicamentos , Hepatite C Crônica , Compostos Heterocíclicos de 4 ou mais Anéis , Diálise Renal , Sofosbuvir , Humanos , Sofosbuvir/farmacocinética , Sofosbuvir/administração & dosagem , Carbamatos/farmacocinética , Carbamatos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Hepatite C Crônica/tratamento farmacológico , Antivirais/farmacocinética , Antivirais/administração & dosagem , Estudos Prospectivos , Idoso , Adulto , Resultado do Tratamento , Hepacivirus/efeitos dos fármacos , Hepacivirus/isolamento & purificação , Benzimidazóis , BenzopiranosRESUMO
Chikungunya virus is a re-emerging arbovirus that has caused epidemic outbreaks in recent decades. Patients in older age groups with high viral load and severe immunologic response during acute infection are likely to develop chronic arthritis and severe joint pain. Currently, no antiviral drug is available. Previous studies suggested that a flavone derivative, 8-bromobaicalein, was a potential dengue and Zika replication inhibitor in a cell-based system targeting flaviviral polymerase. Here we characterized that 8-bromobaicalein inhibited chikungunya virus replication with EC50 of 0.49 ± 0.11â µM in Vero cells. The molecular target predicted at viral nsP1 methyltransferase using molecular binding and fragment molecular orbital calculation. Additionally, oral administration of 250â mg/kg twice daily treatment alleviated chikungunya-induced musculoskeletal inflammation and reduced viral load in healthy adult mice. Pharmacokinetic analysis indicated that the 250â mg/kg administration maintained the compound level above EC99.9 for 12â h. Therefore, 8-bromobaicalein should be a potential candidate for further development as a pan-arboviral drug.
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Arbovírus , Febre de Chikungunya , Vírus Chikungunya , Infecção por Zika virus , Zika virus , Chlorocebus aethiops , Humanos , Adulto , Animais , Camundongos , Idoso , Febre de Chikungunya/tratamento farmacológico , Células Vero , Carga Viral , Vírus Chikungunya/fisiologia , InflamaçãoRESUMO
Mid-dilution and mixed-dilution on-line hemodiafiltration (OL-HDF) techniques are innovated to overcome the limitations of two standard techniques including predilution and postdilution. Unfortunately, the head-to-head comparisons between these two novel techniques in the same study are still limited. Moreover, the original mid-dilution and mixed-dilution OL-HDF need special dialyzers and special machines. In the present study, simple mid-dilution and simple mixed-dilution OL-HDF were settled with the aim for clinical use in general hemodialysis (HD) centers. The efficacies of uremic toxins removal between both modalities were measured and compared. This prospective randomized crossover study was conducted on 12 stable HD patients undergoing simple mixed-dilution and simple mid-dilution OL-HDF techniques. HD prescriptions were similar in both techniques. The dialysis efficacies were determined by calculating small- (urea, creatinine, and phosphate) and middle-molecule (beta-2 microglobulin [ß2M]) removal. Moreover, potential complications such as high transmembrane pressure (TMP) and protein loss were also observed. Simple mixed-dilution OL-HDF provided significantly greater clearances of urea, creatinine, and ß2M when compared with the simple mid-dilution OL-HDF techniques. Phosphate clearances in both techniques were comparable. In addition, TMP and dialysate albumin loss were not different. There were no intradialytic complications in both techniques. Simple mixed-dilution OL-HDF could provide greater efficacy for small- and middle-molecule clearances and acceptable potential risks, while phosphate removal is comparable.
Assuntos
Hemodiafiltração/métodos , Falência Renal Crônica/terapia , Adulto , Idoso , Estudos Cross-Over , Feminino , Hemodiafiltração/efeitos adversos , Humanos , Falência Renal Crônica/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Gabapentin is an antiepileptic drug. It is structurally similar to yaminobutyric acid (GABA), which crosses the blood-brain barrier. Gabapentin is absorbed into the blood by the L-amino acid transport system. The oral bioavailability of gabapentin displays dose-dependence. Plasma concentrations ofgabapentin are not directly proportional to dose. Therefore, pharmacokinetic of gabapentin is essential for patients who have to receive gabapentin 600 mg. OBJECTIVE: To investigate the pharmacokinetic of gabapentin 600 mg in Thai healthy subjects. MATERIAL AND METHOD: The present study was performed on 24 healthy Thai male subjects who received a single oral dose of 600 mg gabapentin tablet. Serial blood samples were collected before and to 48 hours after drug administration. Plasma gabapentin concentrations were determined by automated High Performance Liquid Chromatography (HPLC) with UV detector after deproteinized with acetonitrile followed by derivatization with 1-fluoro-2,4-dinitrobenzene. The relevant pharmacokinetic parameters were determined. RESULTS: The mean values of pharmacokinetic parameters (mean +/- SD) were 3.17 +/- 0.80 hour (1.5 to 5.0 hour) for T; 4,853.58 +/- 1,369.67 ng/ml for Cm; 0.11 +/- 0.02 hour for Kel, 6.62 +/- 1.87 hour (4.89 to 11.41 hour) for T1/2; 47,712.88 +/- 12,853.61 ng.hour/ml for AUC0-t, 48,713.20 +/- 12,909.78 ng.hour/ml for AUC0-inf, 5.24 +/- 1.32 L/hour for CI, and 49.28 +/- 15.98 L for Vd. CONCLUSION: The data show the pharmacokinetic parameters of gabapentin 600 mg. These data should be used to support the assignment of therapeutic purposes for patients who have to receive gabapentin 600 mg.
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Aminas/farmacocinética , Anticonvulsivantes/farmacocinética , Ácidos Cicloexanocarboxílicos/farmacocinética , Ácido gama-Aminobutírico/farmacocinética , Administração Oral , Adulto , Aminas/administração & dosagem , Anticonvulsivantes/administração & dosagem , Área Sob a Curva , Disponibilidade Biológica , Ácidos Cicloexanocarboxílicos/administração & dosagem , Gabapentina , Humanos , Masculino , Valores de Referência , Comprimidos , Adulto Jovem , Ácido gama-Aminobutírico/administração & dosagemRESUMO
OBJECTIVES: This study investigated the steady-state pharmacokinetic profiles of 3-month weekly rifapentine plus isoniazid (3HP) in children with latent tuberculosisinfection (LTBI). We also assessed other factors, including tablet integrity, food, and pharmacogenetics. METHODS: During the 3HP treatment, blood and urine samples were collected in week 4. Isoniazid and rifapentine levels were measured using a high-performance liquid chromatography technique. The genetic variation of arylamine N-acetyltransferase 2 (NAT2) and arylacetamide deacetylase (AADAC) were assessed by the MassARRAY®. Safety and clinical outcomes at week 48 were monitored. RESULTS: A total of 12 children with LTBI (age 3.8 [range 2.1-4.9 years old]) completed the treatment (isoniazid and rifapentine dose 25.0 [range 21.7-26.8] and 25.7 [range 20.7-32.1] mg/kg, respectively). No serious adverse events or active TB occurred. Tablet integrity was associated with decreased area under the concentration-time curve (91 vs 73 mg.h/l, P= 0.026) and increased apparent oral clearance of isoniazid (0.27 vs 0.32 l/h/kg, P= 0.019) and decreased rifapentine's renal clearance (CLR, 0.005 vs 0.003 l/h, P= 0.014). Food was associated with increased CLR of isoniazid (3.45 vs 8.95 l/h, P= 0.006) but not rifapentine. Variability in NAT2 and AADAC did not affect the pharmacokinetics of both drugs. CONCLUSION: There is high variability in the pharmacokinetic profiles of isoniazid and rifapentine in young children with LTBI. The variability was partly influenced by tablet integrity and food, but not pharmacogenetics. Further study in a larger cohort is warranted to display the relationship of these factors to treatment outcomes.
Assuntos
Arilamina N-Acetiltransferase , Tuberculose Latente , Antituberculosos/efeitos adversos , Arilamina N-Acetiltransferase/genética , Criança , Pré-Escolar , Quimioterapia Combinada , Humanos , Isoniazida/efeitos adversos , Tuberculose Latente/tratamento farmacológico , Resultado do TratamentoRESUMO
Background and purpose: The study was aimed at validating a simple, rapid, and low-cost LC-MS/MS method for carvedilol and 4/-hydroxyphenyl carvedilol assay in human plasma. The validated method was applied to investigate the pharmacokinetics after a low dose of 6.25 mg. carvedilol. Experimental approach: In this study, the plasma was extracted by liquid-liquid extraction and evaporated the organic layer to dryness, then both analytes in the residue were reconstituted and detected by LC- MS/MS. The method was validated following the guideline on bioanalytical method validation. Thirty-one healthy volunteers participated in the pharmacokinetic study. After 10 h of fasting, each volunteer received one tablet of 6.25 mg carvedilol orally. Blood samples were collected at 16 prescheduled time points. The plasma samples were analyzed for pharmacokinetics. Findings/Results: The method was linear over a range of 0.050-50.049 ng/mL for carvedilol and 0.050- 10.017 ng/mL for 4/-hydroxyphenyl carvedilol. Crucial validated results reached the requirements of selectivity, accuracy, precision, and stability. Pharmacokinetics of carvedilol and 4/-hydroxyphenyl carvedilol were evaluated which showed Cmax at 21.26 ± 9.23 and 2.42 ± 2.07 ng/mL; AUC0-t 66.95 ± 29.45 and 5.93 ± 3.51 ng.h/mL; AUC0-inf 68.54 ± 30.11 and 6.78 ± 3.49 ng.h/mL; and T1/2 6.30 ± 1.95 and 6.31 ± 6.45 h, respectively. Conclusion and implications: The validated method was able to detect and quantify both analytes in plasma samples and can be applied to the pharmacokinetic study of carvedilol and 4/-hydroxyphenyl carvedilol after receiving carvedilol at 6.25 mg orally.
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PURPOSE: Plasma efavirenz (EFV) concentrations within therapeutic levels are essential to successfully treat patients suffering from human immunodeficiency virus (HIV) type 1. In addition to the drug-metabolizing enzyme CYP2B6, other phase II drug-metabolizing enzymes and transporters may have an important role in the pharmacokinetics of EFV. Thus, the influence of phase II drug-metabolizing enzymes and drug transporters on plasma EFV levels was investigated in Thai HIV patients receiving EFV. PATIENTS AND METHODS: Genotyping was performed by TaqMan® real-time PCR in 149 HIV-infected Thai adults, and plasma efavirenz concentration was measured by a validated high-performance liquid chromatography in 12 hours after dosing steady-state plasma samples at week 12 and 24. RESULTS: Patients with three or more copies of SULT1A1 had significantly lower median plasma EFV concentrations than those carrying two copies at week 12 (p=0.046) and SULT1A1*2 (c.638G>A) carriers had significantly lower median plasma EFV concentrations compared to those not carrying the variant at week 24 (p=0.048). However, no significant association was found after adjusting for CYP2B6 genotype. CONCLUSION: Genetic variation in a combination of SULT1A1*2 and SULT1A1 copy number may contribute to variability in EFV metabolism and thereby may impact drug response. The influence of a combination between the SULT1A1 and CYP2B6 genotype on EFV pharmacokinetics should be further investigated in a larger study population.
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Although high-volume postdilution online hemodiafiltration (ol-HDF) is superior to high-flux HD in removing all kinds of uremic toxins and improving survival, this treatment is not available in most HD centers. The present study was conducted to compare the effectiveness in removals of protein-bound (indoxyl sulfate [IS]), middle-molecule [beta-2 microglobulin (B2M) and alpha-1 microglobulin (A1MG)], and small-molecule uremic toxins between super high-flux HD (SHF-HD), HD with a novel SHF dialyzer and high-volume postdilution ol-HDF in a noninferiority fashion. Fifteen prevalent HD patients were randomly allocated into two sequences of 12-week treatment periods of SHF-HD treatment and later high-volume postdilution ol-HDF period or vice versa. Each treatment period was divided by a wash-out phase of 4-week high-flux HD. Twelve of 15 patients could complete the study. When compared with high-volume postdilution ol-HDF (convective volume of 24.4 ± 3.52 L), SHF-HD provided comparable reduction ratio values of IS, B2M, and A1MG with mean difference of 5.87 (95% confidence interval [CI] -1.63, 13.37), 1.98 (95% CI,-0.21, 4.18), and 22.96 (95% CI, -1.91, 47.83), respectively. The spKt/Vurea was not different. The predialysis levels of all uremic toxins at baseline and after 12-week treatment did not differ between both groups. Although albumin loss in dialysate in SHF-HD was greater than high-volume postdilution ol-HDF, the serum albumin levels after 12-week SHF-HD treatment were significantly higher than baseline. In conclusion, SHF-HD provides noninferior effectiveness to high-volume postdilution ol-HDF in removing various uremic toxins with significantly increased serum albumin levels despite higher albumin loss. SHF-HD might be an effectively alternative treatment when high-volume postdilution ol-HDF is not available.
Assuntos
Falência Renal Crônica/terapia , Diálise Renal/métodos , Uremia/terapia , Idoso , Estudos Cross-Over , Feminino , Hemodiafiltração/métodos , Humanos , Masculino , Estudos ProspectivosRESUMO
BACKGROUND: Rosiglitazone maleate is an antihyperglycemic agent in the thiazolidinedione class. It is indicated for the treatment of patients with type 2 diabetes mellitus. A new product of rosiglitazone has been developed. The pharmacokinetic in Thai subjects should be considered and the bioequivalent data of new generic product is required in order to assure the quality and performance. OBJECTIVE: To characterize the pharmacokinetics of rosiglitazone in Thai subjects and compare the bioequivalence of generic product of a single oral 8 mg rosiglitazone tablet with the innovator's product. MATERIAL AND METHOD: The present study was performed in 24 healthy Thai male volunteers. Each received a single oral dose of 8 mg rosiglitazone tablet. Double blind randomized two-way crossover design was used with two weeks washout period between treatments. After drug administration, a serial blood sample was collected over a period of 48 hours. Rosiglitazone plasma level was determined by HPLC with fluorescence detector. The pharmacokinetic parameters were determined by non compartment model. For bioequivalence determination, the difference of Cmax, AUC(0-t) and AUC(0-inf) were analyzed by ANOVA and 90% confidence interval. RESULTS: The mean +/- SD of pharmacokinetic parameters of generic product and the innovator's product were 0.82 +/- 0.52 vs. 1.02 +/- 1.50 hr of Tmax, 796.51 +/- 155.19 vs. 723.48 +/- 134.69 ng/ml of Cmax, 3.94 +/- 0.80 vs. 3.87 +/- 0.77 hr of T1/2, 4,308.43 +/- 1,006.28 vs. 4,135.66 +/- 1,061.96 ng x hr/ml of AUC(0-t), 4,384.65 +/- 1,035.15 vs. 4,183.87 +/- 1,075.39 ng x hr/ml of AUC(0-inf), respectively. The 90% confidence interval of mean difference of Cmax, AUC(0-t) and AUC(0-inf) (log transformed data) of generic product compared to the innovator's product were 98.42-122.18%, 97.28-109.66% and 97.79-110.30%, respectively. They were within the range of the acceptance criteria 80-125%. CONCLUSION: Pharmacokinetic parameters of a single oral dose of 8 mg rosiglitazone tablet were characterized in Thai healthy subjects. These parameters showed that rosiglitazone was rapidly absorbed with a short elimination half-life. The two formulations of rosiglitazone were bioequivalent.
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Hipoglicemiantes/farmacocinética , Tiazolidinedionas/farmacocinética , Administração Oral , Adolescente , Adulto , Análise de Variância , Área Sob a Curva , Povo Asiático , Estudos Cross-Over , Método Duplo-Cego , Fluorescência , Meia-Vida , Humanos , Hipoglicemiantes/sangue , Masculino , Pessoa de Meia-Idade , Rosiglitazona , Comprimidos , Tailândia , Equivalência Terapêutica , Tiazolidinedionas/sangue , Fatores de Tempo , Adulto JovemRESUMO
A reliable method has been validated using ultra-performance liquid chromatography mass spectrometry (MS)/MS for simultaneous evaluation of human plasma concentration of mycophenolic acid (MPA) and its major metabolites both total and free form. All analytes were extracted from plasma by simple protein precipitation procedure with methanol. Samples for determination of their free form concentration require a preanalytic spin through an ultrafiltration system. The chromatographic separation was completed using C18column at 0.3 ml/min with a gradient condition. Method validation was performed as the United State Food and Drug Administration guidelines for bio-analytical methods concerning precision, accuracy, linearity, selectivity, recovery, and matrix effect. Linearity was obtained over concentration of 0.05-4, 0.5-60, and 0.025-3 µg/ml for total MPA, mycophenolic acid glucuronide (MPAG) and mycophenolic acid acyl-glucuronide (AcMPAG), respectively. The linearity of the method for free form of analytes was confirmed in the range of 10-500, 125-10,000, and 0.5-300 ng/ml for MPA, MPAG, and AcMPAG, respectively. The intra- and interday accuracy ranged from 85.73%-102.01% for total form, and 87.23%-111.89% for free form, and the precisions of all analytes were lower than 15%. The mean recoveries of the analytes ranged from 85.54% to 94.76% and the matrix factor ranged from 0.88-1.06. The developed method is rapid, sensitive and convenient for pharmacokinetic study or therapeutic drug monitoring in patients after oral administration of enteric-coated mycophenolate sodium or mycophenolate mofetil.
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Use of colistin in children is rising in line with the increase of multidrug-resistant Gram-negative bacteria (MDR-GNB). In adults, a colistin loading dose is recommended to achieve therapeutic concentrations within 12-24 h. Here we aimed to describe the pharmacokinetic (PK) parameters of a loading dose versus a recommended initial dose of intravenous colistimethate sodium (CMS) in paediatric patients. A prospective, open-label, PK study was conducted in paediatric patients (age 2-18 years) with normal renal function. Patients (n = 20) were randomly assigned to receive either a CMS loading dose (LD group) of 4 mg of colistin base activity (CBA)/kg/dose or a standard initial dose (NLD group) of 2.5 mg (12-h interval) or 1.7 mg (8-h interval) of CBA/kg/dose. Serial blood samples were collected. Plasma concentrations of formed colistin were measured by LC-MS/MS. PK parameters were reported. Acute kidney injury (AKI) was monitored by serum creatinine and urine NGAL. The median (interquartile range) age and body weight were 8.5 (3.5-11.3) years and 21.5 (13.5-20.0) kg. The mean (standard deviation) of first-dose PK parameters of the LD group versus the NLD group were: Cmax, 6.1 (2.4) vs. 4.1 (1.3) mg/L; AUC0-t, 26.5 (12.5) vs. 13.5 (3.6) mg/L·h; Vd, 0.7 (0.4) vs. 0.6 (0.3) L/kg; and t1/2, 2.9 (0.6) vs. 2.6 (0.4) h. No patient developed AKI by serum creatinine criteria. A CMS loading dose is beneficial for improvement of colistin exposure without increased AKI. A higher daily dose of CMS should be considered, especially for MDR-GNB treatment.
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Antibacterianos/farmacocinética , Colistina/análogos & derivados , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Injúria Renal Aguda/induzido quimicamente , Administração Intravenosa , Adolescente , Antibacterianos/administração & dosagem , Biomarcadores/sangue , Biomarcadores/urina , Criança , Pré-Escolar , Colistina/administração & dosagem , Colistina/farmacocinética , Farmacorresistência Bacteriana Múltipla , Feminino , Bactérias Gram-Negativas/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/microbiologia , Humanos , Masculino , Estudos Prospectivos , Resultado do TratamentoRESUMO
PURPOSE: Donepezil, a drug frequently used to treat dementia, is mainly metabolized by cytochrome P450 2D6 (CYP2D6). This study investigated the relationships between CYP2D6 genotype and activity scores as well as predicted phenotype of plasma donepezil concentrations in 86 Thai dementia participants. MATERIALS AND METHODS: CYP2D6 was genotyped using bead-chip technology (Luminex xTAG® v.3). Steady-state trough plasma donepezil concentrations were measured using high-performance liquid chromatography. RESULTS: Sixteen genotypes were found but the most frequent genotypes detected among our participants were CYP2D6*10/*10 (27.9%) and *1/*10 (26.7%). One-third of the participants had an activity score of 1.25 which predicted that they were normal metabolizers. The overall median (interquartile range) of plasma donepezil concentration was 51.20 (32.59-87.24) ng/mL. Normal metabolizers (NMs) had lower plasma donepezil concentrations compared to intermediate metabolizers (IMs) (41.15 (28.44-67.65) ng/mL vs 61.95 (35.25-97.00) ng/mL). Multivariate analysis showed that CYP2D6 activity score (r2 = 0.50) and the predicted phenotype (independent of dose) could predict the plasma donepezil concentration (r2 = 0.49). CONCLUSION: Plasma donepezil concentration in NMs was lower compared to IMs. Additional studies with larger sample size and use of next-generation sequencing as well as its outcomes are warranted to confirm the benefit of using pharmacogenetic-guided treatment for donepezil.