RESUMEN
PURPOSE: The objective of this work was to systematically evaluate the effects of formulation composition on subcutaneous injection site pain (ISP) using matrices comprising of common pharmaceutical excipients. METHODS: Two randomized, blinded, crossover studies in healthy subjects were conducted at a single site, where subjects received 1 mL SC injections of the buffer matrices. ISP intensity was measured using a 100 mm visual analogue scale (VAS), which was then analyzed via heatmap, categorical grouping, subgroup analysis, and paired delta analysis. RESULTS: Buffer type, buffer concentration and tonicity agent showed a substantial impact on ISP. Citrate buffer demonstrated a higher ISP than acetate buffer or saline). The 20 mM citrate buffer was more painful than 10 or 5 mM citrate buffers. NaCl and propylene glycol were significantly more painful than sugar alcohols (mannitol, sucrose, trehalose or glycerol). Histidine buffers exhibited ISP in the descending order of 150 mM > 75 mM > 25 mM > 0 mM NaCl, while histidine buffers containing Arginine-HCl at 0, 50, or 150 mM all showed very low ISP. Histidine buffer at pH 6.5 showed a lower ISP than pH 5.7. CONCLUSIONS: This systematic study via orthogonal analyses demonstrated that subcutaneous ISP is significantly influenced by solution composition.
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Excipientes/efectos adversos , Reacción en el Punto de Inyección/etiología , Dolor/etiología , Soluciones/efectos adversos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Tampones (Química) , Estudios Cruzados , Excipientes/química , Femenino , Voluntarios Sanos , Humanos , Concentración de Iones de Hidrógeno , Reacción en el Punto de Inyección/diagnóstico , Reacción en el Punto de Inyección/prevención & control , Inyecciones Subcutáneas/efectos adversos , Masculino , Persona de Mediana Edad , Dolor/diagnóstico , Dolor/prevención & control , Dimensión del Dolor , Soluciones/administración & dosificación , Soluciones/química , Adulto JovenRESUMEN
The disposition and metabolism of prexasertib, a CHK-1 inhibitor was characterised over a 120 h period following a single 170-mg intravenous dose of [14C]prexasertib (50 µCi) to 6 patients with advanced/metastatic solid tumours.The prexasertib safety profile was consistent with prior studies. Plasma, urine, and faeces were analysed for radioactivity, prexasertib, and metabolites. Geometric mean t1/2 in plasma was 34.2 h for prexasertib and 73.8 h for total radioactivity. Unchanged prexasertib accounted for approximately 9% of plasma total radioactivity, indicating extensive metabolism by the presence of circulating metabolites. Both renal and faecal excretion were identified as important routes of elimination since 41.8% (±12.9%) of the total administered radioactivity was recovered in the renal excretions and 32.2% (±7.28%) in the faecal excretions. Mean renal clearance was approximately 15% of the total systemic clearance, while biliary clearance was also low. Prexasertib was cleared predominantly by metabolism with only 23% of the dose recovered in excreta as intact drug. Radioactivity was eliminated predominantly within 72 h in urine, but faecal elimination was protracted.The metabolism of prexasertib was complex while primary metabolic clearance pathways involved were oxidative deamination, O-dealkylation, mono-oxidation, and possibly direct glucuronide conjugation. Although prexasertib was the major component in plasma, up to 11 metabolites were observed. The most abundant metabolites identified in plasma were glucuronides and none of these are expected to contribute to the pharmacological activity or pose a safety concern.
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Neoplasias , Pirazinas/metabolismo , Pirazoles/metabolismo , Administración Intravenosa , Humanos , Tasa de Depuración Metabólica , Pirazinas/administración & dosificación , Pirazoles/administración & dosificaciónRESUMEN
Platelets of patients with sickle cell disease (SCD) show evidence of mild activation in the non-crisis steady state and greater activation during vaso-occlusive crises (VOC). Prasugrel, a potent inhibitor of ADP-mediated platelet activation and aggregation, may be useful in attenuating VOC. We compared platelet responses to ADP stimulation in patients with SCD and healthy subjects before and after treatment with prasugrel. In a phase 1 study, platelet biomarker levels were assessed in 12 adult patients with SCD and 13 healthy subjects before and after 12 ± 2 days of 5.0 or 7.5 mg/day prasugrel. The following were determined in whole blood samples stimulated with 20 µM ADP: (i) percentages of monocytes and neutrophils with adherent platelets (cell-platelet aggregates); (ii) the relative number (mass) of platelets associated with each monocyte and neutrophil as reported by CD61 mean fluorescence intensity (MFI) of the monocyte-platelet and neutrophil-platelet aggregates; (iii) the percentages of platelets positive for surface expression of CD40 ligand (CD40L), P-selectin (CD62p) and activated glycoprotein IIb-IIIa (GPIIb-IIIa); and (iv) the percentages of platelets and monocyte-platelet aggregates positive for surface tissue factor (TF) expression. At baseline, there were no significant differences between cohorts in the percentages of platelets expressing activation biomarkers. Following 12 days of prasugrel administration, the percentages of platelets expressing activation biomarkers following ADP stimulation were reduced in both cohorts, and there were no significant differences between groups. Both patients with SCD and healthy subjects had significant reductions in the monocyte-platelet and neutrophil-platelet aggregate MFI and the percentage of platelets expressing P-selectin and activated GPIIb-IIIa (all p < 0.05). Healthy subjects also had significant reductions in monocyte-platelet aggregate percentages (p = 0.004), neutrophil-platelet aggregate percentages (p = 0.011) and the percentage of CD40L-positive platelets (p = 0.044) that were not observed in patients with SCD. Prasugrel administration to SCD patients attenuates ex vivo ADP-stimulated platelet activation as measured by the percentage of platelets positive for P-selectin and GPIIb-IIIa, thus reducing the proportion of platelets that may participate in aggregates. Furthermore, prasugrel decreases ex vivo ADP-stimulated platelet aggregation with monocytes and neutrophils as measured by the monocyte-platelet and neutrophil-platelet aggregate MFI. This implies that in the presence of prasugrel, fewer platelets adhere to monocytes and neutrophils, which may result in reducing cell-platelet aggregate size. Therefore, reduced platelet reactivity and decreased size of leukocyte-platelet aggregates suggest additional mechanisms by which prasugrel may provide benefit to patients with SCD and support further investigation of possible therapeutic benefits of prasugrel in this population.
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Adenosina Difosfato/metabolismo , Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/tratamiento farmacológico , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Activación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Clorhidrato de Prasugrel/uso terapéutico , Adenosina Difosfato/farmacología , Adulto , Biomarcadores , Estudios de Casos y Controles , Femenino , Humanos , Leucocitos/efectos de los fármacos , Leucocitos/metabolismo , Masculino , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria/farmacología , Clorhidrato de Prasugrel/farmacología , Adulto JovenRESUMEN
AIM: The aim of this study was to assess the safety and tolerability, pharmacokinetics and pharmacodynamics of LY3000328 when administered as single escalating doses to healthy volunteers. METHODS: This was a phase 1, placebo-controlled, dose escalation study with LY3000328 in 21 healthy male volunteers. Subjects were administered escalating LY3000328 doses up to 300 mg with food in this single dose study. Blood samples were collected at set times post-dose for the assessment of LY3000328 pharmacokinetics and the measurement of cathepsin S (CatS) activity, CatS mass and calculated CatS specific activity. RESULTS: All doses of LY3000328 were well tolerated, with linear pharmacokinetics up to the 300 mg dose. The pharmacodynamic activity of LY3000328 was measured ex vivo showing a biphasic response to LY3000328, where CatS activity declines, then returns to baseline, and then increases to a level above baseline. CatS mass was also assessed post-dose which increased in a dose-dependent manner, and continued to increase after LY3000328 had been cleared from the body. CatS specific activity was additionally calculated to normalize CatS activity for changes in CatS mass. This demonstrated the increase in CatS activity was attributable to the increase in CatS mass detected in plasma. CONCLUSION: A specific inhibitor of CatS which is cleared quickly from plasma may produce a transient decrease in plasma CatS activity which is followed by a more prolonged increase in plasma CatS mass which may have implications for the future clinical development of inhibitors of CatS.
Asunto(s)
Benzopiranos/farmacocinética , Carbamatos/farmacocinética , Catepsinas/antagonistas & inhibidores , Inhibidores de Proteasas/farmacocinética , Adulto , Benzopiranos/farmacología , Carbamatos/farmacología , Catepsinas/metabolismo , Humanos , Masculino , Persona de Mediana EdadRESUMEN
AIMS: Prasugrel is a novel thienopyridine P2Y12 adenosine diphosphate (ADP) receptor antagonist that inhibits ADP-mediated platelet activation and aggregation. Accordingly, it may be useful in reducing platelet-related ischaemia in sickle cell disease (SCD). Exposure to prasugrel's active metabolite (Pras-AM) and its antiplatelet activity in SCD have not been investigated. METHODS: Thirteen adult patients with SCD and an equal number of matched healthy control subjects were studied before and after 12 days of 5.0 or 7.5 mg day(-1) prasugrel treatment. Platelet reactivity was assessed by light transmission aggregometry (LTA), impedance aggregometry (MEA), VerifyNow® P2Y12, vasodilator-stimulated phosphoprotein (VASP) phosphorylation and Plateletworks. Exposure to Pras-AM was also assessed. RESULTS: At baseline, patients with SCD showed increased platelet reactivity vs. healthy control subjects with VerifyNow (408 vs. 323 P2Y12 reaction units (PRU), respectively, P = 0.003) and MEA (106 vs. 77 area under the aggregation curve (AU.min), P = 0.002); lower platelet reactivity index with VASP flow cytometry (59 vs. 79% platelet reactivity index (PRI), P = 0.018); and no significant differences with LTA, VASP enzyme-linked immunosorbent assay or Plateletworks. Relative to baseline, prasugrel significantly reduced platelet reactivity by all assays in both populations (all P < 0.05). Prasugrel was well tolerated, with no bleeding-related events in patients with SCD. The mean concentration-time profiles of Pras-AM were comparable between healthy subjects and patients with SCD following a single 10 mg prasugrel dose and following the 12th dose of 7.5 or 5 mg prasugrel. CONCLUSIONS: Results demonstrate that in response to prasugrel, patients with SCD and healthy subjects have similar degrees of platelet inhibition and exposure to Pras-AM, and provide a basis for further study of prasugrel in patients with SCD.
Asunto(s)
Anemia de Células Falciformes/metabolismo , Plaquetas/efectos de los fármacos , Piperazinas/farmacocinética , Antagonistas del Receptor Purinérgico P2/farmacocinética , Tiofenos/farmacocinética , Adulto , Anemia de Células Falciformes/tratamiento farmacológico , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Humanos , Masculino , Piperazinas/efectos adversos , Piperazinas/farmacología , Pruebas de Función Plaquetaria , Clorhidrato de Prasugrel , Antagonistas del Receptor Purinérgico P2/efectos adversos , Antagonistas del Receptor Purinérgico P2/farmacología , Tiofenos/efectos adversos , Tiofenos/farmacología , Adulto JovenRESUMEN
INTRODUCTION: Subcutaneous (SC) injection is a common route of drug administration; however, injection site pain (ISP) might create a negative patient experience. We evaluated ISP, bioequivalence, and overall safety of the citrate-free (CF) formulation of ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin-17A. METHODS: Two phase 1, single-blind studies were conducted in healthy participants. The crossover study A (NCT03848403) evaluated pain intensity on injection as measured by visual analog scale of pain (VAS) scores. Subjects (N = 70) were randomized 1:1:1 at the beginning to three possible treatment sequences and received a 1 mL SC injection of the three formulations sequentially in the abdomen on days 1, 8, and 15, respectively. A mixed-effects repeated measures analysis model was used to analyze VAS score by time post-injection. Study B (NCT04259346) evaluated the bioequivalence of a single 80 mg dose of CF formulation compared to the original commercial formulation. Subjects (N = 245) were randomized 1:1 to either commercial or CF formulation and received a single SC injection into the abdomen, arm, or thigh. RESULTS: Primary endpoint was achieved in both studies. In study A, least-squares mean (LSM) difference of VAS scores immediately post injection between commercial (n = 61) and CF formulation (n = 63) was - 21.7 (p < 0.0001), indicating a lower degree of pain associated with CF formulation. In study B, bioequivalence of the CF formulation was established as 90% CIs for the ratio of geometric LSM AUC0-tlast, AUC0-∞, and Cmax between treatments were contained within the prespecified limits of 0.8 and 1.25. Except for less ISP in the CF formulation, overall safety profile was comparable. CONCLUSION: Ixekizumab CF formulation proved to be bioequivalent, was associated with less ISP, and had no other notable differences in the safety profile compared to the original commercial formulation. TRAIL REGISTRATION: ClinicalTrials.gov identifier NCT03848403, NCT04259346.
Asunto(s)
Ácido Cítrico , Reacción en el Punto de Inyección , Anticuerpos Monoclonales Humanizados , Área Bajo la Curva , Estudios Cruzados , Humanos , Dolor , Método Simple Ciego , Equivalencia TerapéuticaRESUMEN
We compared platelet function results obtained with the VerifyNow P2Y12 (VN-P2Y12) point-of-care device and the light transmission aggregometry (5 and 20 microM adenosine diphosphate) method using an integrated database of eight clinical trials with a total of 591 subjects. The study was performed in healthy subjects, patients with coronary artery disease, patients with end-stage renal disease, and patients with acute coronary syndrome after treatment with prasugrel or clopidogrel. Analyses focused on loading doses of 60 mg prasugrel or 600 mg clopidogrel and daily maintenance doses of 10 mg prasugrel or 75 or 150 mg clopidogrel. Similar patterns of platelet inhibition were observed for light transmission aggregometry versus VN-P2Y12 and assay results were well correlated (r approximately 0.7), although a sigmoidal model may more accurately represent the relationship between light transmission aggregometry and VN-P2Y12, because VN-P2Y12 was relatively less sensitive to low and high levels of inhibition. The percentage of poor responders was less with prasugrel compared with clopidogrel by both assays, but the percentages tended to differ between the assays. The VN-P2Y12 "BASE" channel appeared to be susceptible to high levels of P2Y12 blockade, which would underestimate the VN-P2Y12-reported percent inhibition in individuals who respond well to loading doses of thienopyridines. This integrated analysis supports the findings of earlier individual studies comparing these methodologies that assess platelet function.
Asunto(s)
Monitoreo de Drogas/métodos , Piperazinas/farmacología , Inhibidores de Agregación Plaquetaria/farmacología , Tiofenos/farmacología , Ticlopidina/análogos & derivados , Síndrome Coronario Agudo/tratamiento farmacológico , Adenosina Difosfato , Adulto , Anciano , Ensayos Clínicos como Asunto , Clopidogrel , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Bases de Datos Factuales , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Fallo Renal Crónico/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Piperazinas/administración & dosificación , Inhibidores de Agregación Plaquetaria/administración & dosificación , Pruebas de Función Plaquetaria/métodos , Sistemas de Atención de Punto , Clorhidrato de Prasugrel , Tiofenos/administración & dosificación , Ticlopidina/administración & dosificación , Ticlopidina/farmacologíaRESUMEN
PURPOSE: Prasugrel is a novel thienopyridine prodrug metabolised to an active metabolite that binds irreversibly to the platelet P2Y(12) receptor and inhibits adenosine diphosphate (ADP)-induced platelet aggregation. We compared prasugrel pharmacokinetics, pharmacodynamics, and tolerability in healthy Chinese, Japanese, Korean and Caucasian subjects. METHODS: In an open-label, single-centre, parallel-design study, 89 healthy subjects (25 Chinese, 20 Japanese, 22 Korean and 22 Caucasian) aged 20-65 years were given a prasugrel 60-mg loading dose (LD) followed by daily 10-mg maintenance doses (MD) for 7 days and then 5-mg MD for 10 days. Plasma concentrations of prasugrel's active metabolite and inhibition of ADP-induced platelet aggregation (IPA) were determined. RESULTS: Mean exposure to prasugrel's active metabolite in all treatment regimens was higher in each of the Asian groups than in the Caucasian group, although there was considerable overlap between individual exposure estimates in Asians and Caucasians. The mean IPA was also higher in Asians than in Caucasians following a prasugrel 60-mg LD, although the difference did not consistently achieve statistical significance. Prasugrel 10-mg or 5-mg MD produced statistically significantly higher IPA in each Asian group compared with that in the Caucasians. Prasugrel was well tolerated during the LD and MD regimens by all groups. CONCLUSIONS: Mean exposure to the prasugrel active metabolite following prasugrel 60-mg LD and during daily 10-mg or 5-mg MD was higher in each of the Asian groups than in the Caucasian group, which resulted in greater platelet inhibition.
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Piperazinas/farmacología , Piperazinas/farmacocinética , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/farmacocinética , Profármacos/farmacología , Profármacos/farmacocinética , Tiofenos/farmacología , Tiofenos/farmacocinética , Adenosina Difosfato/farmacología , Adulto , Anciano , Pueblo Asiatico , Índice de Masa Corporal , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Piperazinas/administración & dosificación , Piperazinas/efectos adversos , Piperazinas/sangre , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/efectos adversos , Clorhidrato de Prasugrel , Profármacos/administración & dosificación , Profármacos/efectos adversos , Estadística como Asunto , Tiofenos/administración & dosificación , Tiofenos/efectos adversos , Población Blanca , Adulto JovenRESUMEN
The objective of this phase 1 study was to evaluate the pharmacokinetics, safety, and tolerability of baricitinib after single and multiple doses in healthy Chinese adults. Eligible subjects received a once-daily dose of baricitinib 2, 4, or 10 mg or placebo on day 1 (single dose) and days 4 through 10 for 7 consecutive days (multiple doses). Plasma pharmacokinetic samples were collected up to 48 hours after dosing on days 1 and 10, with predose samples collected before dosing on day 1 and days 4 through 10. Safety and tolerability were also assessed. Baricitinib was rapidly absorbed, reaching peak plasma concentrations within 0.5 to 1 hour (median). Plasma concentrations declined rapidly following the attainment of peak concentrations, with a mean terminal half-life of 5.7 to 7.3 hours. Steady-state plasma concentrations of baricitinib were achieved after the second day of once-daily dosing, with minimal accumulation of baricitinib in plasma (up to 10% increase in area under the plasma concentration-time curve). Single- and multiple-dose mean values for area under the plasma concentration-time curve from time zero to infinity and maximum plasma concentration appeared to increase in an approximately dose-proportional manner across the dose range. Single and multiple oral doses of once-daily baricitinib up to 10 mg were well tolerated by healthy Chinese subjects.
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Artritis Reumatoide/tratamiento farmacológico , Azetidinas/farmacocinética , Voluntarios Sanos/estadística & datos numéricos , Oxazoles/farmacocinética , Purinas/farmacocinética , Pirazoles/farmacocinética , Sulfonamidas/farmacocinética , Administración Oral , Adulto , Área Bajo la Curva , Pueblo Asiatico/etnología , Azetidinas/administración & dosificación , Azetidinas/sangre , Estudios de Casos y Controles , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Tolerancia a Medicamentos , Femenino , Semivida , Humanos , Masculino , Persona de Mediana Edad , Oxazoles/administración & dosificación , Oxazoles/sangre , Placebos/administración & dosificación , Purinas/administración & dosificación , Purinas/sangre , Pirazoles/administración & dosificación , Pirazoles/sangre , Seguridad , Sulfonamidas/administración & dosificación , Sulfonamidas/sangreRESUMEN
This integrated analysis compared speed of onset, level of platelet inhibition, and response variability to prasugrel and clopidogrel in healthy subjects and in patients with stable coronary artery disease with data pooled from 24 clinical pharmacology studies. Data from subjects (N = 846) were categorized into the following treatment groups: prasugrel 60 mg loading dose (LD)/10 mg maintenance dose (MD), clopidogrel 300 mg LD/75 mg MD, or clopidogrel 600 mg LD/75 mg MDs. Maximum platelet aggregation (MPA) and inhibition of platelet aggregation (IPA) to 5 and 20 muM ADP were assessed by turbidimetric aggregometry. A linear mixed-effect model compared the MPA and IPA between treatments over time points evaluated in the integrated database, and covariates affecting platelet inhibition were identified. Prasugrel 60 mg LD resulted in faster onset, greater magnitude, and more consistent levels of inhibition of platelet function compared to either clopidogrel 300 mg or 600 mg LDs. Greater and more consistent levels of platelet inhibition were observed with the prasugrel 10 mg MD compared to the clopidogrel 75 mg MD. This integrated analysis confirms the findings of earlier individual studies, that prasugrel achieves faster onset of greater extent and more consistent platelet inhibition compared to the approved and higher loading doses of clopidogrel. Gender, race, body weight, and age were identified as statistically significant covariates impacting platelet inhibition.
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Piperazinas/farmacología , Agregación Plaquetaria/efectos de los fármacos , Tiofenos/farmacología , Ticlopidina/análogos & derivados , Adulto , Clopidogrel , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Recolección de Datos , Femenino , Humanos , Cinética , Masculino , Persona de Mediana Edad , Piperazinas/farmacocinética , Inhibidores de Agregación Plaquetaria/farmacología , Clorhidrato de Prasugrel , Tiofenos/farmacocinética , Ticlopidina/farmacocinética , Ticlopidina/farmacología , Adulto JovenRESUMEN
Platelet inhibition as measured by vasodilator-stimulated phosphoprotein (VASP) and light transmission aggregometry (LTA) have shown concordance following dosing of clopidogrel. No reports have directly compared the VASP assay and LTA at the levels of P2Y(12) blockade after loading doses (LDs) of prasugrel or high dose clopidogrel (600 and 900 mg). The aim was to compare the VASP assay and LTA during the loading dose phase of a comparative study of prasugrel and clopidogrel. Prasugrel 60 mg LD/10 mg maintenance dose (MD) and clopidogrel 300 mg/75 mg and 600 mg/75 mg LD/MD regimens were compared in a 3-way crossover study in 41 healthy, aspirin-free subjects. Each LD was followed by seven daily MDs and a 14-day washout period. P2Y(12) receptor blockade was estimated using the VASP assay, expressed as platelet reactivity index (VASP-PRI). Platelet aggregation was assessed by light transmission aggregometry (20 and 5 microM ADP). Twenty-four hours after prasgurel 60 mg or clopidogrel 300 mg and 600 mg, respectively, VASP-PRI decreased from approximately 80% to 8.9%, 54.7%, and 39.0%, and maximal platelet aggregation (MPA) decreased from approximately 79% to 10.8%, 42.7%, and 31.2%, with an overall VASP:MPA correlation of 0.88 (p < 0.01). VASP assay responses after the clopidogrel LDs showed a wider range of values (300 mg: 0-93%; 600 mg: 0-80%) than prasugrel (0-13%); MPA responses followed a similar trend. Pearson's correlation suggested a strong agreement between VASP and LTA (20 microM ADP) for MPA (r = 0.86, p < 0.0001). VASP and LTA demonstrated concordance across the response range of P2Y(12) receptor blockade following thienopyridine LDs.
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Plaquetas/efectos de los fármacos , Moléculas de Adhesión Celular/metabolismo , Luz , Proteínas de Microfilamentos/metabolismo , Fosfoproteínas/metabolismo , Piperazinas/administración & dosificación , Inhibidores de Agregación Plaquetaria/administración & dosificación , Agregación Plaquetaria/efectos de los fármacos , Pruebas de Función Plaquetaria/métodos , Tiofenos/administración & dosificación , Ticlopidina/análogos & derivados , Adenosina Difosfato/metabolismo , Adulto , Plaquetas/metabolismo , Clopidogrel , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Citometría de Flujo , Humanos , Masculino , Persona de Mediana Edad , Fosforilación , Clorhidrato de Prasugrel , Antagonistas del Receptor Purinérgico P2 , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2Y12 , Reproducibilidad de los Resultados , Ticlopidina/administración & dosificación , Factores de TiempoRESUMEN
Variability in response to antiplatelet agents has prompted the development of point-of-care (POC) technology. In this study, we compared the VerifyNow P2Y12 (VN-P2Y12) POC device with light transmission aggregometry (LTA) in subjects switched directly from clopidogrel to prasugrel. Healthy subjects on aspirin were administered a clopidogrel 600 mg loading dose (LD) followed by a 75 mg/d maintenance dose (MD) for 10 days. Subjects were then switched to a prasugrel 60 mg LD and then 10 mg/d MD for 10 days (n = 16), or to a prasugrel 10 mg/d MD for 11 days (n = 19). Platelet function was measured by LTA and VN-P2Y12 at baseline and after dosing. Clopidogrel 600 mg LD/75 mg MD treatment led to a reduction in P2Y(12) reaction units (PRU) from baseline. A switch from clopidogrel MD to prasugrel 60 mg LD/10 mg MD produced an immediate decrease in PRU, while a switch to prasugrel 10 mg MD resulted in a more gradual decline. Consistent with the reduction in PRU, device-reported percent inhibition increased during both clopidogrel and prasugrel regimens. Inhibition of platelet aggregation as measured by LTA showed a very similar pattern to that found with VN-P2Y12 measurement, irrespective of treatment regimens. The dynamic range of VN-P2Y12 appeared to be narrower than that of LTA. With two different thienopyridines, the VN-P2Y12 device, within a somewhat more limited range, reflected the overall magnitude of change in aggregation response determined by LTA. The determination of the clinical utility of such POC devices will require their use in clinical outcome studies.
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Pruebas de Coagulación Sanguínea/instrumentación , Plaquetas/efectos de los fármacos , Monitoreo de Drogas/instrumentación , Piperazinas/administración & dosificación , Inhibidores de Agregación Plaquetaria/administración & dosificación , Agregación Plaquetaria/efectos de los fármacos , Sistemas de Atención de Punto , Antagonistas del Receptor Purinérgico P2 , Tiofenos/administración & dosificación , Ticlopidina/análogos & derivados , Adulto , Aspirina/administración & dosificación , Pruebas de Coagulación Sanguínea/métodos , Plaquetas/metabolismo , Clopidogrel , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Monitoreo de Drogas/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Clorhidrato de Prasugrel , Receptores Purinérgicos P2/sangre , Receptores Purinérgicos P2Y12 , Valores de Referencia , Reproducibilidad de los Resultados , Ticlopidina/administración & dosificaciónRESUMEN
Prasugrel, a thienopyridine prodrug, is hydrolyzed in vivo by esterases to a thiolactone followed by a single cytochrome P450 (CYP)-dependent step to an active metabolite that is a potent inhibitor of adenosine diphosphate-induced platelet aggregation. This open-label, multiple-dose, 2-period, fixed-sequence study assessed CYP2B6 inhibition by prasugrel using bupropion as a probe substrate, where its active metabolite, hydroxybupropion, is almost exclusively formed by CYP2B6. Thirty healthy subjects received a single 150-mg oral dose of sustained-release bupropion. After a 7-day washout, a 60-mg prasugrel loading dose, followed by a 10-mg daily maintenance dose for 10 days, was administered. Bupropion (150 mg) was given with prasugrel on day 7 of this phase. Prasugrel weakly inhibited CYP2B6 activity as it increased bupropion Cmax and AUC0-infinity by 14% and 18%, respectively, and decreased hydroxybupropion Cmax and AUC0-infinity by 32% and 23%. These results are consistent with patients receiving prasugrel not requiring dose adjustments when treated with drugs primarily metabolized by CYP2B6.
Asunto(s)
Inhibidores Enzimáticos del Citocromo P-450 , Piperazinas/farmacología , Inhibidores de Agregación Plaquetaria/farmacología , Tiofenos/farmacología , Adolescente , Adulto , Área Bajo la Curva , Bupropión/análogos & derivados , Bupropión/metabolismo , Bupropión/farmacocinética , Cromatografía Liquida , Estudios Cruzados , Citocromo P-450 CYP2B6 , Sistema Enzimático del Citocromo P-450/metabolismo , Preparaciones de Acción Retardada/química , Interacciones Farmacológicas , Semivida , Humanos , Masculino , Persona de Mediana Edad , Estructura Molecular , Piperazinas/química , Inhibidores de Agregación Plaquetaria/química , Clorhidrato de Prasugrel , Profármacos/química , Profármacos/farmacología , Piridinas/química , Piridinas/farmacología , Espectrometría de Masas en Tándem , Tiofenos/química , Factores de TiempoRESUMEN
Prasugrel and clopidogrel, thienopyridine prodrugs, are each metabolized to an active metabolite that inhibits the platelet P2Y(12) ADP receptor. In this open-label, 4-period crossover study, the effects of the proton pump inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel were assessed in healthy subjects given single doses of prasugrel 60 mg and clopidogrel 300 mg with and without concurrent lansoprazole 30 mg qd. C(max) and AUC(0-tlast) of prasugrel's active metabolite, R-138727, and clopidogrel's inactive carboxylic acid metabolite, SR26334, were assessed. Inhibition of platelet aggregation (IPA) was measured by turbidimetric aggregometry 4 to 24 hours after each treatment. Lansoprazole (1) decreased R-138727 AUC(0-tlast) and C(max) by 13% and 29%, respectively, but did not affect IPA after the prasugrel dose, and (2) did not affect SR62334 exposure but tended to lower IPA after a clopidogrel dose. A retrospective tertile analysis showed in subjects with high IPA after a clopidogrel dose alone that lansoprazole decreased IPA, whereas IPA was unaffected in these same subjects after a prasugrel dose. The overall data suggest that a prasugrel dose adjustment is not likely warranted in an individual taking prasugrel with a proton pump inhibitor such as lansoprazole.
Asunto(s)
2-Piridinilmetilsulfinilbencimidazoles/farmacología , Piperazinas/farmacocinética , Inhibidores de Agregación Plaquetaria/farmacocinética , Inhibidores de la Bomba de Protones/farmacología , Tiofenos/farmacocinética , Ticlopidina/análogos & derivados , 2-Piridinilmetilsulfinilbencimidazoles/efectos adversos , Adenosina Difosfato/sangre , Adolescente , Adulto , Anciano , Área Bajo la Curva , Disponibilidad Biológica , Clopidogrel , Estudios Cruzados , Interacciones Farmacológicas , Femenino , Humanos , Lansoprazol , Masculino , Persona de Mediana Edad , Piperazinas/efectos adversos , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/efectos adversos , Clorhidrato de Prasugrel , Inhibidores de la Bomba de Protones/efectos adversos , Tiofenos/efectos adversos , Ticlopidina/efectos adversos , Ticlopidina/farmacocinéticaRESUMEN
STUDY OBJECTIVE: To investigate the potential effect of atorvastatin 80 mg/day on the pharmacokinetics and pharmacodynamics of the thienopyridines prasugrel and clopidogrel. DESIGN: Open-label, randomized, crossover, two-arm, parallel-group study. SETTING: Single clinical research center in the United Kingdom. PARTICIPANTS: Sixty-nine healthy men aged 18-60 years. Intervention. Subjects received either a loading dose of prasugrel 60 mg followed by a maintenance dose of 10 mg/day or a loading dose of clopidogrel 300 mg followed by 75 mg/day. The drug was given as monotherapy for 10 days, and after a 6-day run-in period with atorvastatin 80 mg/day, the same dosage of atorvastatin was continued with the respective thienopyridine for 10 days. A 14-day washout period separated the treatment regimens. MEASUREMENTS AND MAIN RESULTS: Blood samples were collected before and at various time points after dosing on days 1 and 11 for determination of plasma concentrations of metabolites and for measurement of platelet aggregation induced by adenosine 5'-diphosphate 20 microM and vasodilator-stimulated phosphoprotein (VASP). Coadministration of atorvastatin did not alter exposure to active metabolites of prasugrel or clopidogrel after the loading dose and thus did not alter inhibition of platelet aggregation (IPA). During maintenance dosing, atorvastatin administration resulted in 17% and 28% increases in the area under the plasma concentration-time curve (AUC) values of prasugrel's and clopidogrel's active metabolites, respectively. These small changes in AUC did not result in a significant change in IPA response to prasugrel but did result in a significant increase in IPA during clopidogrel maintenance dosing at some, but not all, of the time points on day 11. Coadministration of atorvastatin with either prasugrel or clopidogrel had no effect on VASP phosphorylation relative to the thienopyridine alone after the loading dose. CONCLUSION: Coadministration of atorvastatin 80 mg/day with prasugrel or clopidogrel did not negatively affect the antiplatelet response to either drug after a loading dose or during maintenance dosing. The lack of a clinically meaningful effect of high-dose atorvastatin on the pharmacodynamic response to prasugrel after the loading or maintenance dose indicates that no dosage adjustment should be necessary in patients receiving these drugs concomitantly.
Asunto(s)
Ácidos Heptanoicos/farmacología , Piperazinas/farmacocinética , Pirroles/farmacología , Tiofenos/farmacocinética , Ticlopidina/análogos & derivados , Adolescente , Adulto , Anticolesterolemiantes/efectos adversos , Anticolesterolemiantes/farmacología , Área Bajo la Curva , Atorvastatina , Cromatografía Liquida , Clopidogrel , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Epistaxis/inducido químicamente , Ácidos Heptanoicos/efectos adversos , Humanos , Hígado/efectos de los fármacos , Hígado/enzimología , Masculino , Tasa de Depuración Metabólica/efectos de los fármacos , Persona de Mediana Edad , Estructura Molecular , Piperazinas/sangre , Piperazinas/química , Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/farmacocinética , Clorhidrato de Prasugrel , Pirroles/efectos adversos , Espectrometría de Masas en Tándem , Tiofenos/sangre , Tiofenos/química , Ticlopidina/sangre , Ticlopidina/química , Ticlopidina/farmacocinética , Reino Unido , Adulto JovenRESUMEN
Prasugrel, a novel P2Y(12) antagonist, achieves faster onset and greater inhibition of platelet aggregation than clopidogrel 300 and 600 mg loading doses (LD). We studied the safety, time course, and level of platelet inhibition when switching directly from clopidogrel 75 mg maintenance dose (MD) to a prasugrel 60 mg LD/10 mg MD or 10 mg MD regimen. Healthy subjects (n = 39) on aspirin (81 mg/d) received a clopidogrel 600 mg LD followed by 10 days of clopidogrel MD (75 mg/d). Subjects were then randomized without a washout period to prasugrel 60 mg LD (n = 16) followed by 10 days of prasugrel MD (10 mg/d) or to prasugrel MD (10 mg/d, n = 19) for 11 days. Maximal platelet aggregation (MPA) to 20 microM ADP was measured by turbidimetric aggregometry. In subjects on clopidogrel 75 mg MD, mean MPA decreased from 39 to 12% by 30 minutes, and to 5% by 1 hour after a prasugrel 60 mg LD (p < 0.001 for both) and from 37 to 28% (p < 0.001) by 1 hour after a prasugrel 10 mg MD. During prasugrel MD, a new pharmacodynamic steady state MPA of approximately 24% (p < 0.01 vs. clopidogrel MD) occurred within four to five days of switching from clopidogrel. Changing from clopidogrel to prasugrel did not increase bleeding episodes or other adverse events. Switching directly from clopidogrel MD to either prasugrel LD or MD was well tolerated and resulted in significantly greater levels of platelet inhibition than a clopidogrel 75 mg MD.
Asunto(s)
Aspirina/uso terapéutico , Piperazinas/administración & dosificación , Tiofenos/administración & dosificación , Ticlopidina/análogos & derivados , Adenosina Difosfato/farmacología , Adulto , Clopidogrel , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Hemorragia/inducido químicamente , Humanos , Masculino , Persona de Mediana Edad , Piperazinas/farmacocinética , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/administración & dosificación , Pruebas de Función Plaquetaria , Clorhidrato de Prasugrel , Tiofenos/farmacocinética , Ticlopidina/administración & dosificación , Ticlopidina/farmacocinéticaRESUMEN
BACKGROUND: The aim of this study was to compare rate of onset, magnitude, and consistency of platelet inhibition after administration of prasugrel or clopidogrel and to relate platelet inhibition to systemic exposure to each active metabolite. Thienopyridines are prodrugs, metabolized in vivo to active metabolites that inhibit the platelet P2Y12 adenosine diphosphate (ADP) receptor. METHODS: This was an open-label, 2-way, crossover study that randomized healthy subjects (n = 68) to an oral loading dose (LD) of prasugrel 60 mg or clopidogrel 300 mg. Platelet aggregation response to 5 and 20 micromol/L of ADP was measured by turbidometric aggregometry. Plasma concentrations of the active metabolites of prasugrel and clopidogrel were quantified by liquid chromatography with tandem mass spectrometry detection methods. RESULTS: Inhibition of platelet aggregation (IPA) after prasugrel was significantly higher (P < .01) than that after clopidogrel from 15 minutes through 24 hours (5 micromol/L ADP) and from 30 minutes through 24 hours (20 micromol/L ADP). For 20 micromol/L ADP, the median time to reach > or = 20% IPA was 30 minutes for prasugrel and 1.5 hours for clopidogrel (P < .001). The maximum IPA was 84.1% +/- 9.5% with prasugrel versus 48.9% +/- 27.0% with clopidogrel for 5 micromol/L ADP and 78.8% +/- 9.2% versus 35.0% +/- 24.5%, respectively, for 20 micromol/L ADP (P < .001). Response to prasugrel was more consistent compared to clopidogrel (P < .01). The lower IPA response to clopidogrel was associated with lower plasma concentrations of its active metabolite (P < .001). CONCLUSIONS: Prasugrel 60 mg LD results in more rapid, potent, and consistent inhibition of platelet function than clopidogrel 300 mg LD. Lower IPA responses to clopidogrel were associated with lower concentrations of its active metabolite.
Asunto(s)
Plaquetas/efectos de los fármacos , Piperazinas/administración & dosificación , Inhibidores de Agregación Plaquetaria/administración & dosificación , Antagonistas del Receptor Purinérgico P2 , Tiofenos/administración & dosificación , Ticlopidina/análogos & derivados , Adulto , Área Bajo la Curva , Clopidogrel , Estudios Cruzados , Femenino , Humanos , Masculino , Persona de Mediana Edad , Piperazinas/metabolismo , Inhibidores de Agregación Plaquetaria/metabolismo , Clorhidrato de Prasugrel , Tiofenos/metabolismo , Ticlopidina/administración & dosificación , Ticlopidina/metabolismoRESUMEN
Failure to achieve an adequate level of platelet inhibition during percutaneous coronary intervention is associated with an increased risk for periprocedural myocardial injury. This study was conducted to compare the initial rate of platelet inhibition after a loading dose (LD) of prasugrel or clopidogrel and determine the association between the initial rate of inhibition and pharmacodynamic responder status. Data were pooled from 3 studies in which healthy subjects received LDs of prasugrel (60 mg; n = 76) or clopidogrel (300 mg; n = 87). Maximum platelet aggregation (MPA; 20 mumol/L adenosine diphosphate) was measured by turbidimetric aggregometry (0.25 to 24 hours after dosing). A mechanistic model was used to estimate the initial rate of decrease in MPA per hour (fast onset: MPA decrease >20%/hour). Subjects were defined as pharmacodynamic poor responders if the absolute decrease in MPA from baseline was <15% at either 4 to 5 or 24 hours after dosing. The median initial rate of decrease in MPA was greater after prasugrel (203%/hour) than with clopidogrel (23%/hour) (p <0.001). Overall, 76 subjects (100%) receiving prasugrel had fast onset of platelet inhibition compared with 47 subjects (54%) receiving clopidogrel. The initial rate of decrease in MPA was highly correlated with responder status (p <0.001). After prasugrel, subjects had a lower median MPA compared with clopidogrel (p <0.001; from >0.25 to 24 hours after dosing), and intersubject variability in MPA response was less after prasugrel compared with clopidogrel (p <0.001; from >1 to 24 hours after dosing). In conclusion, platelet inhibition after a 60-mg LD of prasugrel was more rapid in onset, less variable, and greater in magnitude than with a 300-mg LD of clopidogrel. After a thienopyridine LD, the initial rate of platelet inhibition was predictive of pharmacodynamic responder status.
Asunto(s)
Piperazinas/farmacología , Inhibidores de Agregación Plaquetaria/farmacología , Agregación Plaquetaria/efectos de los fármacos , Tiofenos/farmacología , Ticlopidina/análogos & derivados , Clopidogrel , Humanos , Nefelometría y Turbidimetría , Clorhidrato de Prasugrel , Ticlopidina/farmacología , Factores de TiempoRESUMEN
Multiple studies report response variability to a 300-mg clopidogrel loading dose (LD). Pooled platelet aggregometry data compared responses (change in maximal platelet aggregation [DeltaMPA] or inhibition of platelet aggregation [IPA]) to clopidogrel 300-mg (n = 131) or prasugrel 60-mg (n = 109) LDs. Poor responder rates were determined using empiric criteria (IPA < 10% and DeltaMPA < 10% for 20 microM and 5 microM adenosine diphosphate [ADP]) and Bayesian model-based criteria (IPA < 20% and DeltaMPA < 15% for 20 microM ADP; IPA < 25% and DeltaMPA < 20% for 5 microM ADP). Prasugrel achieved greater DeltaMPA and IPA from 2 to 24 hours post-LD (P < .001). For 20 microM ADP, poor responder rates for clopidogrel ranged from 17% to 43%; no prasugrel poor responders were observed. Regardless of the criterion, prasugrel 60 mg achieved greater IPA and fewer poor responders than the clopidogrel 300-mg LD.
Asunto(s)
Piperazinas/farmacología , Inhibidores de Agregación Plaquetaria/farmacología , Agregación Plaquetaria/efectos de los fármacos , Tiofenos/farmacología , Ticlopidina/análogos & derivados , Adenosina Difosfato , Adolescente , Adulto , Anciano , Teorema de Bayes , Ensayos Clínicos Fase I como Asunto , Clopidogrel , Bases de Datos Factuales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas de Función Plaquetaria , Clorhidrato de Prasugrel , Ticlopidina/farmacología , Resultado del TratamientoRESUMEN
Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, undergoes active renal tubular secretion. Baricitinib was not predicted to inhibit hepatic and renal uptake and efflux drug transporters, based on the ratio of the unbound maximum eliminating-organ inlet concentration and the in vitro half-maximal inhibitory concentrations (IC50 ). In vitro, baricitinib was a substrate for organic anion transporter (OAT)3, multidrug and toxin extrusion protein (MATE)2-K, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP). Probenecid, a strong OAT3 inhibitor, increased the area under the concentration-time curve from time zero to infinity (AUC[0-∞] ) of baricitinib by twofold and decreased renal clearance to 69% of control in healthy subjects. Physiologically based pharmacokinetic (PBPK) modeling reproduced the renal clearance of baricitinib and the inhibitory effect of probenecid using the in vitro IC50 value of 4.4 µM. Using ibuprofen and diclofenac in vitro IC50 values of 4.4 and 3.8 µM toward OAT3, 1.2 and 1.0 AUC(0-∞) ratios of baricitinib were predicted. These predictions suggest clinically relevant drug-drug interactions (DDIs) with ibuprofen and diclofenac are unlikely.