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1.
Clin Pharmacol Drug Dev ; 12(12): 1185-1193, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37705424

RESUMO

Pompe disease is a rare, autosomal recessive, degenerative neuromuscular disease caused by deficiency of acid α-glucosidase, a lysosomal enzyme that degrades α-1,4 and α-1,6 linkages in glycogen. The objectives of this study (PAPAYA; NCT01410890) were to (1) characterize the pharmacokinetics of 20 mg/kg body weight alglucosidase alfa manufactured at the 4000-L scale following a single intravenous dose in participants aged less than 18 and 18 years or older with Pompe disease and (2) evaluate the relationship between anti-alglucosidase alfa antibody titers and the pharmacokinetics of alglucosidase alfa. Mean maximum plasma concentration and area under the concentration-time curve from time zero and extrapolated to infinite time were 204 µg/mL and 1110 µg â€¢ h/mL for participants aged less than 18 years (n = 10), respectively, and 307 µg/mL and 1890 µg â€¢ h/mL for participants aged 18 years or older (n = 10), respectively. Mean terminal half-life was 5.43 hours in participants aged less than 18 years with a high variability (70%) and 3.84 hours in participants aged 18 years or older with a low variability (21%). Mean maximum plasma concentration and area under the concentration-time curve from time zero and extrapolated to infinite time were 256 µg/mL and 1452 µg • h/mL, respectively, in anti-alglucosidase alfa-negative participants (n = 12) and 262 µg/mL and 1703 µg â€¢ h/mL, respectively, in anti-alglucosidase alfa-positive participants (n = 7). The study findings enrich available data from existing information on alglucosidase alfa without changing its known risks and benefits.


Assuntos
Doença de Depósito de Glicogênio Tipo II , alfa-Glucosidases , Humanos , alfa-Glucosidases/uso terapêutico , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Resultado do Tratamento , Administração Intravenosa
2.
Ther Drug Monit ; 45(5): 644-652, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-37556417

RESUMO

BACKGROUND: Pompe disease is a rare genetic disorder caused by a deficiency of a lysosomal enzyme called acid alpha-glucosidase and is classified into infantile and late-onset forms. Since 2006, an enzyme replacement therapy involving alglucosidase alfa has been available. In 2021, a new enzyme replacement therapy involving avalglucosidase alfa demonstrated improved clinical benefits. In this article, the authors describe the pharmacokinetics of avalglucosidase alfa using a population pharmacokinetic approach. METHODS: The population pharmacokinetic model was developed using a data set that included 75 patients and 2042 plasma drug concentrations determined through enzymatic activity assay from 3 studies (phases I/II and III) and involved 3 dose levels (5, 10, and 20 mg/kg). The analysis was performed using NONMEM software. RESULTS: Two sequences were observed in the plasma drug concentration profile: the first kinetic driving exposure, and after 12 hours postdose, a slight rebound addressing very low concentrations that lasted up to 2 weeks. Following model screening, a model with a central compartment with parallel linear and nonlinear elimination and 2 concatenated peripheral compartments was proposed. A putative back-redistribution of a marginal fraction of the drug from the second peripheral compartment to the central compartment may explain the slight rebound in concentration. The final model's mean bias and precision for individual predictions were -2.66% and 30.7%, respectively, and -0.433% and 38.9%, respectively, for population predictions. CONCLUSIONS: A concatenated 3-compartment model was developed to describe the avalglucosidase alfa concentrations in patients with late-onset Pompe disease. None of the covariates tested could explain the interindividual variability.


Assuntos
Doença de Depósito de Glicogênio Tipo II , Adolescente , Adulto , Humanos , Terapia de Reposição de Enzimas , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Doença de Depósito de Glicogênio Tipo II/etiologia , Cinética , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto
3.
J Pharmacokinet Pharmacodyn ; 50(6): 461-474, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37535240

RESUMO

Avalglucosidase alfa (AVAL) was approved in the United States (2021) for patients with late-onset Pompe disease (LOPD), aged ≥ 1 year. In the present study, pharmacokinetic (PK) simulations were conducted to propose alternative dosing regimens for pediatric LOPD patients based on a bodyweight cut-off. Population PK (PopPK) analysis was performed using nonlinear mixed effect modeling approach on pooled data from three clinical trials with LOPD patients, and a phase 2 study (NCT03019406) with infantile-onset Pompe disease (IOPD: 1-12 years) patients. A total of 2257 concentration-time points from 91 patients (LOPD, n = 75; IOPD, n = 16) were included in the analysis. The model was bodyweight dependent allometric scaling with time varying bodyweight included on clearance and distribution volume. Simulations were performed for two dosing regimens (20 mg/kg or 40 mg/kg) with different bodyweight cut-off (25, 30, 35 and 40 kg) by generating virtual pediatric (1-17 years) and adult patients. Corresponding simulated individual exposures (maximal concentration, Cmax and area under the curve in the 2-week dosing interval, AUC2W), and distributions were calculated. It was found that dosing of 40 mg/kg and 20 mg/kg in pediatric patients < 30 kg and ≥ 30 kg, respectively, achieved similar AVAL exposure (based on AUC2W) to adult patients receiving 20 mg/kg. PK simulations conducted on the basis of this model provided supporting data for the currently approved US labelling for dosing adapted bodyweight in LOPD patients ≥ 1 year by USFDA.


Assuntos
Doença de Depósito de Glicogênio Tipo II , Adulto , Humanos , Criança , Estados Unidos , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Doença de Depósito de Glicogênio Tipo II/induzido quimicamente , Doença de Depósito de Glicogênio Tipo II/epidemiologia , alfa-Glucosidases/efeitos adversos , alfa-Glucosidases/metabolismo , Peso Corporal , Cinética
4.
Br J Clin Pharmacol ; 87(2): 598-611, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32520410

RESUMO

AIMS: SAR247799 is a selective G-protein-biased sphingosine-1 phosphate receptor-1 (S1P1 ) agonist with potential to restore endothelial function in vascular pathologies. SAR247799, a first-in-class molecule differentiated from previous S1P1 -desensitizing molecules developed for multiple sclerosis, can activate S1P1 without desensitization and consequent lymphopenia. The aim was to characterize SAR247799 for its safety, tolerability, pharmacokinetics and pharmacodynamics (activation and desensitization). METHODS: SAR247799 was administered orally to healthy subjects in a double-blind, randomized, placebo-controlled study with single (2.5-37.5 mg) or 2-week once-daily (0.5-15 mg) doses. An open-label single dose pilot food-interaction arm with 10 mg SAR247799 in cross-over design was also performed. RESULTS: SAR247799 was well tolerated and, at the higher end of the dose ranges, caused the expected dose-dependent pharmacodynamics associated with S1P1 activation (heart rate reduction) and S1P1 desensitization (lymphocyte count reduction). SAR247799 demonstrated dose-proportional increases in exposure and was eliminated with an apparent terminal half-life of 31.2-33.1 hours. Food had a small effect on the pharmacokinetics of SAR247799. SAR247799 had a low volume of distribution (7-23 L), indicating a potential to achieve dose separation for endothelial vs cardiac S1P1 activation pharmacology. A supratherapeutic dose (10 mg) of SAR247799 produced sustained heart rate reduction over 14 days, demonstrating cardiac S1P1 activation without tachyphylaxis. Sub-lymphocyte-reducing doses (≤5 mg) of SAR247799, which, based on preclinical data, are projected to activate S1P1 and exhibit endothelial-protective properties, had minimal-to-no heart rate reduction and displayed no marked safety findings. CONCLUSION: SAR247799 is suitable for exploring the biological role of endothelial S1P1 activation without causing receptor desensitization.


Assuntos
Receptores de Lisoesfingolipídeo , Esfingosina , Relação Dose-Resposta a Droga , Método Duplo-Cego , Proteínas de Ligação ao GTP , Humanos , Fosfatos , Receptores de Lisoesfingolipídeo/metabolismo , Esfingosina/efeitos adversos
5.
Br J Clin Pharmacol ; 87(5): 2303-2320, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33125753

RESUMO

AIMS: SAR247799 is a G-protein-biased sphingosine-1 phosphate receptor-1 (S1P1 ) agonist designed to activate endothelial S1P1 and provide endothelial-protective properties, while limiting S1P1 desensitization and consequent lymphocyte-count reduction associated with higher doses. The aim was to show whether S1P1 activation can promote endothelial effects in patients and, if so, select SAR247799 doses for further clinical investigation. METHODS: Type-2 diabetes patients, enriched for endothelial dysfunction (flow-mediated dilation, FMD <7%; n = 54), were randomized, in 2 sequential cohorts, to 28-day once-daily treatment with SAR247799 (1 or 5 mg in ascending cohorts), placebo or 50 mg sildenafil (positive control) in a 5:2:2 ratio per cohort. Endothelial function was assessed by brachial artery FMD. Renal function, biomarkers and lymphocytes were measured following 5-week SAR247799 treatment (3 doses) to Zucker diabetic fatty rats and the data used to select the doses for human testing. RESULTS: The maximum FMD change from baseline vs placebo for all treatments was reached on day 35; mean differences vs placebo were 0.60% (95% confidence interval [CI] -0.34 to 1.53%; P = .203) for 1 mg SAR247799, 1.07% (95% CI 0.13 to 2.01%; P = .026) for 5 mg SAR247799 and 0.88% (95% CI -0.15 to 1.91%; P = .093) for 50 mg sildenafil. Both doses of SAR247799 were well tolerated, did not affect blood pressure, and were associated with minimal-to-no lymphocyte reduction and small-to-moderate heart rate decrease. CONCLUSION: These data provide the first human evidence suggesting endothelial-protective properties of S1P1 activation, with SAR247799 being as effective as the clinical benchmark, sildenafil. Further clinical testing of SAR247799, at sub-lymphocyte-reducing doses (≤5 mg), is warranted in vascular diseases associated with endothelial dysfunction.


Assuntos
Diabetes Mellitus Tipo 2 , Esfingosina , Animais , Artéria Braquial , Diabetes Mellitus Tipo 2/tratamento farmacológico , Endotélio Vascular , Proteínas de Ligação ao GTP , Humanos , Fosfatos , Ratos , Ratos Zucker , Vasodilatação
6.
Clin Pharmacokinet ; 58(1): 101-113, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29725996

RESUMO

BACKGROUND: Alirocumab, a human monoclonal antibody, inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) to significantly reduce low-density lipoprotein cholesterol levels; pharmacokinetics (PK) are governed by non-linear, target-mediated drug disposition (TMDD). OBJECTIVES: We aimed to develop and qualify a population PK (PopPK) model to characterize the PK profile of alirocumab, evaluate the impact of covariates on alirocumab PK and on individual patient exposures, and estimate individual predicted concentrations for a subsequent PK/pharmacodynamic (PD) analysis. METHODS: Data from 13 phase I-III trials of 2799 healthy volunteers or patients with hypercholesterolemia treated with intravenous or subcutaneous alirocumab (13,717 alirocumab concentrations) were included; a Michaelis-Menten approximation of the TMDD model was used to estimate PK parameters and exposures. The final model comprised two compartments with first-order absorption. Elimination from the central compartment was described by linear (CLL) and non-linear Michaelis-Menten clearance (Vm and Km). The model was validated using visual predictive check and bootstrap methods. Patient exposures to alirocumab were computed using individual PK parameters. RESULTS: The PopPK model was well-qualified, with the majority of observed alirocumab concentrations in the 2.5th-97.5th predicted percentiles. Covariates responsible for interindividual variability were identified. Body weight and concomitant statin administration impacted CLL, whereas time-varying free PCSK9 concentrations and age affected Km and peripheral distribution volume (V3), respectively. No covariates were clinically meaningful, therefore no dose adjustments were needed. CONCLUSIONS: The model explained the between-subject variability, quantified the impact of covariates, and, finally, predicted alirocumab concentrations (subsequently used in a PopPK/PD model, see Part II) and individual exposures.


Assuntos
Anticorpos Monoclonais Humanizados/farmacocinética , Anticolesterolemiantes/farmacocinética , Produtos Biológicos/farmacocinética , Hipercolesterolemia/metabolismo , Modelos Biológicos , Adulto , Idoso , Variação Biológica Individual , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade
7.
Clin Pharmacokinet ; 58(1): 115-130, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29725997

RESUMO

BACKGROUND: Alirocumab, a human monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly lowers low-density lipoprotein cholesterol levels. OBJECTIVE: This analysis aimed to develop and qualify a population pharmacokinetic/pharmacodynamic model for alirocumab based on pooled data obtained from 13 phase I/II/III clinical trials. METHODS: From a dataset of 2799 individuals (14,346 low-density lipoprotein-cholesterol values), individual pharmacokinetic parameters from the population pharmacokinetic model presented in Part I of this series were used to estimate alirocumab concentrations. As a second step, we then developed the current population pharmacokinetic/pharmacodynamic model using an indirect response model with a Hill coefficient, parameterized with increasing low-density lipoprotein cholesterol elimination, to relate alirocumab concentrations to low-density lipoprotein cholesterol values. RESULTS: The population pharmacokinetic/pharmacodynamic model allowed the characterization of the pharmacokinetic/pharmacodynamic properties of alirocumab in the target population and estimation of individual low-density lipoprotein cholesterol levels and derived pharmacodynamic parameters (the maximum decrease in low-density lipoprotein cholesterol values from baseline and the difference between baseline low-density lipoprotein cholesterol and the pre-dose value before the next alirocumab dose). Significant parameter-covariate relationships were retained in the model, with a total of ten covariates (sex, age, weight, free baseline PCSK9, total time-varying PCSK9, concomitant statin administration, total baseline PCSK9, co-administration of high-dose statins, disease status) included in the final population pharmacokinetic/pharmacodynamic model to explain between-subject variability. Nevertheless, the high number of covariates included in the model did not have a clinically meaningful impact on model-derived pharmacodynamic parameters. CONCLUSIONS: This model successfully allowed the characterization of the population pharmacokinetic/pharmacodynamic properties of alirocumab in its target population and the estimation of individual low-density lipoprotein cholesterol levels.


Assuntos
Anticorpos Monoclonais Humanizados/farmacocinética , Anticolesterolemiantes/farmacocinética , Produtos Biológicos/farmacocinética , Hipercolesterolemia/metabolismo , Modelos Biológicos , Adulto , Idoso , Anticorpos Monoclonais Humanizados/farmacologia , Anticolesterolemiantes/farmacologia , Produtos Biológicos/farmacologia , LDL-Colesterol/sangue , Feminino , Voluntários Saudáveis , Humanos , Hipercolesterolemia/sangue , Masculino , Pessoa de Meia-Idade
8.
Clin Pharmacokinet ; 56(10): 1155-1171, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28063030

RESUMO

BACKGROUND AND OBJECTIVE: Proprotein convertase subtilisin/kexin type 9 inhibition with monoclonal antibodies such as alirocumab significantly reduces low-density lipoprotein-cholesterol levels ± other lipid-lowering therapies. We aimed to develop and qualify a population pharmacokinetics (PopPK) model for alirocumab in healthy subjects and patients, taking into account the mechanistic target-mediated drug disposition (TMDD) process. METHODS: This TMDD model was developed using a subset of the alirocumab clinical trial database, including nine phase I/II/III studies (n = 527); the model was subsequently expanded to a larger data set of 13 studies (n = 2870). Potential model parameters and covariate relationships were explored, and predictive ability was qualified using a visual predictive check. RESULTS: The TMDD model was built using the quasi-steady-state approximation. The final TMDD-quasi-steady-state model included a significant relationship between distribution volume of the central compartment and disease state: distribution volume of the central compartment was 1.56-fold higher in patients vs. healthy subjects. Separately, application of the model to the expanded data set revealed a significant relationship between linear clearance and statin co-administration: linear clearance was 1.27-fold higher with statins. The good predictive performance of the TMDD model was assessed based on graphical and numerical quality criteria, together with the visual predictive check and comparison of the predictions to those from a PopPK model with parallel linear and Michaelis-Menten clearances (i.e., simplification of the TMDD PopPK model). CONCLUSIONS: This mechanistic TMDD PopPK model integrates the interaction of alirocumab with its target and accurately predicts both alirocumab and total proprotein convertase subtilisin/kexin type 9 concentrations in healthy subjects and patients.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Modelos Biológicos , Inibidores de PCSK9 , Pró-Proteína Convertase 9/sangue , Anticorpos Monoclonais Humanizados , Ensaios Clínicos Fase I como Assunto/métodos , Ensaios Clínicos Fase II como Assunto/métodos , Ensaios Clínicos Fase III como Assunto/métodos , Voluntários Saudáveis , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Distribuição Tecidual/efeitos dos fármacos , Distribuição Tecidual/fisiologia
9.
Drug Metab Dispos ; 43(4): 510-22, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25609219

RESUMO

Clopidogrel is a prodrug that needs to be converted to its active metabolite (clopi-H4) in two sequential cytochrome P450 (P450)-dependent steps. In the present study, a dynamic physiologically based pharmacokinetic (PBPK) model was developed in Simcyp for clopidogrel and clopi-H4 using a specific sequential metabolite module in four populations with phenotypically different CYP2C19 activity (poor, intermediate, extensive, and ultrarapid metabolizers) receiving a loading dose of 300 mg followed by a maintenance dose of 75 mg. This model was validated using several approaches. First, a comparison of predicted-to-observed area under the curve (AUC)0-24 obtained from a randomized crossover study conducted in four balanced CYP2C19-phenotype metabolizer groups was performed using a visual predictive check method. Second, the interindividual and intertrial variability (on the basis of AUC0-24 comparisons) between the predicted trials and the observed trial of individuals, for each phenotypic group, were compared. Finally, a further validation, on the basis of drug-drug-interaction prediction, was performed by comparing observed values of clopidogrel and clopi-H4 with or without dronedarone (moderate CYP3A4 inhibitor) coadministration using a previously developed and validated physiologically based PBPK dronedarone model. The PBPK model was well validated for both clopidogrel and its active metabolite clopi-H4, in each CYP2C19-phenotypic group, whatever the treatment period (300-mg loading dose and 75-mg last maintenance dose). This is the first study proposing a full dynamic PBPK model able to accurately predict simultaneously the pharmacokinetics of the parent drug and of its primary and secondary metabolites in populations with genetically different activity for a metabolizing enzyme.


Assuntos
Citocromo P-450 CYP2C19/genética , Modelos Biológicos , Polimorfismo de Nucleotídeo Único , Metabolismo Secundário/fisiologia , Ticlopidina/análogos & derivados , Adolescente , Adulto , Idoso , Amiodarona/administração & dosagem , Amiodarona/análogos & derivados , Amiodarona/farmacocinética , Área Sob a Curva , Biotransformação , Clopidogrel , Estudos Cross-Over , Citocromo P-450 CYP2C19/metabolismo , Inibidores do Citocromo P-450 CYP2C19/farmacologia , Método Duplo-Cego , Dronedarona , Interações Medicamentosas , Humanos , Absorção Intestinal , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Ticlopidina/administração & dosagem , Ticlopidina/metabolismo , Ticlopidina/farmacocinética , Distribuição Tecidual , Adulto Jovem
10.
Drug Metab Dispos ; 40(1): 187-97, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22004687

RESUMO

Clopidogrel is an antiplatelet agent widely used in cardiovascular diseases and an inactive prodrug that needs to be converted to an active metabolite in two sequential metabolic steps. Several CYP450 isoforms involved in these two steps have been described, although the relative contribution in vivo of each enzyme is still under debate. CYP2C19 is considered to be the major contributor to active metabolite formation. In the current study, net CYP2C19 contribution to the active metabolite formation was determined from exposure of the active metabolite in two clinical studies (one phase I study with well balanced genetic polymorphic populations and a meta-analysis with a total of 396 healthy volunteers) at different clopidogrel doses. CYP2C19 involvements were estimated to be from 58 to 67% in intermediate metabolizers (IMs), from 58 to 72% in extensive metabolizers (EMs), and from 56 to 74% in ultrarapid metabolizers (UMs), depending on the study and the dose. For this purpose, a static model was proposed to estimate the net contribution of a given enzyme to the secondary metabolite formation. This static model was compared with a dynamic approach (Simcyp model) and showed good consistency. In parallel, in vitro investigations showed that omeprazole is a mechanism-based inhibitor of CYP2C19 with K(I) of 8.56 µM and K(inact) of 0.156 min(-1). These values were combined with the net CYP2C19 contribution to the active metabolite formation, through a static approach, to predict the inhibitory effect at 80-mg omeprazole doses in EM, IM, and UM CYP2C19 populations, with good consistency, compared with observed clinical values.


Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Omeprazol/farmacologia , Polimorfismo Genético/fisiologia , Ticlopidina/análogos & derivados , Adolescente , Adulto , Idoso , Hidrocarboneto de Aril Hidroxilases/fisiologia , Clopidogrel , Estudos Cross-Over , Citocromo P-450 CYP2C19 , Feminino , Humanos , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/metabolismo , Pessoa de Meia-Idade , Ticlopidina/metabolismo
11.
J Clin Pharmacol ; 52(10): 1506-15, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22128201

RESUMO

Clopidogrel requires CYP450-mediated hepatic metabolism to form its active metabolite (clopi-H4). This randomized, placebo-controlled, crossover study was designed to characterize the effect of a high-fat or standard breakfast on adenosine diphosphate (ADP)-induced platelet aggregation and exposure to unchanged clopidogrel and clopi-H4 following clopidogrel (300-mg loading dose, 75 mg/d for 4 days) in 72 healthy men. At day 5 and as assessed by liquid chromatography-tandem mass spectrometry, unchanged clopidogrel area under the concentration- time curve from 0 to 24 hours (AUC(0-24)) increased 3.32-fold (90% confidence interval [CI], 2.88-3.84), and clopi-H4 AUC(0-24) decreased nonsignificantly by 12% (90% CI, 0.82-0.94) upon administration of clopidogrel with a standard breakfast. The estimated treatment difference in maximum platelet aggregation (MPA) induced by ADP 5 µM and assessed by light transmission aggregometry was 4.7%, with the 90% CI (0.9%-8.5%) contained within the prespecified equipotency range of ±15%. The mean ± standard deviation of day 5 inhibition of platelet aggregation was 49.7% ± 17.2% and 54.0% ± 13.3% in the fed and fasted states, respectively. Despite increased unchanged clopidogrel and slightly decreased clopi-H4 exposure following clopidogrel administration, the numerical increase in MPA in the fed versus fasted state was small and within the prespecified limit of equipotency. These findings confirm that clopidogrel can be taken with or without food.


Assuntos
Interações Alimento-Droga , Inibidores da Agregação Plaquetária/administração & dosagem , Agregação Plaquetária/efeitos dos fármacos , Ticlopidina/análogos & derivados , Difosfato de Adenosina , Adulto , Área Sob a Curva , Hidrocarboneto de Aril Hidroxilases/genética , Desjejum , Clopidogrel , Estudos Cross-Over , Citocromo P-450 CYP2C19 , Dieta Hiperlipídica , Genótipo , Humanos , Masculino , Inibidores da Agregação Plaquetária/sangue , Inibidores da Agregação Plaquetária/farmacocinética , Ticlopidina/administração & dosagem , Ticlopidina/sangue , Ticlopidina/farmacocinética , Adulto Jovem
12.
Thromb Haemost ; 105(4): 696-705, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21301779

RESUMO

Pharmacokinetic analyses of clopidogrel are hampered by the existence of multiple active metabolite isomers (H1 to H4) and their instability in blood. We sought to retest the pharmacodynamic activities of the four individual active metabolite isomers in vitro, with the ultimate aim of determining the isomers responsible for clopidogrel activity in vivo. In vitro activity was evaluated by measuring binding of [³³P]-2-methylthio-ADP on P2Y12-expressing Chinese hamster ovary (CHO) cells and human platelets in platelet-rich plasma (PRP). A stereoselective method that used reverse-phase ultra high-performance liquid chromatography (UHPLC) and tandem mass spectrometry (MS) was developed to measure individual concentrations of the stable 3'-methoxyacetophenone (MP) derivatives of H1-H4. The new method was used to analyze plasma samples from clopidogrel-treated subjects enrolled in a phase I clinical trial. In vitro binding assays confirmed the previously observed biological activity of H4 (IC50: CHO-P2Y12: 0.12 µM; PRP: 0.97 µM) and inactivity of H3, and demonstrated that H1 was also inactive. Furthermore, H2 demonstrated approximately half of the biological activity in vitro compared with H4. Optimisation of UHPLC conditions and MS collision parameters allowed the resolution and detection of the four derivatised active metabolite isomers (MP-H1 to MP-H4). The stereoselective assay was extensively validated, and was accurate and precise over the concentration range 0.5-250 ng/ml. Only MP-H3 and MP-H4 were quantifiable in incurred clinical samples. Based on in vitro pharmacodynamic data and found concentrations, the active metabolite isomer H4 is the only diastereoisomer of clinical relevance for documenting the pharmacokinetic profile of the active metabolite of clopidogrel.


Assuntos
Plaquetas/metabolismo , Plasma/citologia , Receptores Purinérgicos P2Y12/metabolismo , Ticlopidina/análogos & derivados , Difosfato de Adenosina/análogos & derivados , Difosfato de Adenosina/química , Difosfato de Adenosina/metabolismo , Animais , Plaquetas/citologia , Plaquetas/efeitos dos fármacos , Células CHO , Cromatografia Líquida de Alta Pressão , Clopidogrel , Cricetinae , Cricetulus , Humanos , Espectrometria de Massas , Isótopos de Fósforo/química , Plasma/química , Vigilância de Produtos Comercializados/métodos , Ligação Proteica/efeitos dos fármacos , Receptores Purinérgicos P2Y12/genética , Sensibilidade e Especificidade , Estereoisomerismo , Tionucleotídeos/química , Tionucleotídeos/metabolismo , Ticlopidina/análise , Ticlopidina/química , Ticlopidina/farmacologia , Transgenes/genética
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