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1.
Pharm Dev Technol ; 26(9): 1021-1033, 2021 Nov.
Article in English | MEDLINE | ID: mdl-34435939

ABSTRACT

Prasugrel Hydrochloride (PHCl) is an antiplatelet drug. It is a class II drug with variable bioavailability. The objective of this work was to enhance the solubility and hence the bioavailability and efficacy of PHCl. A Self Nano-Emulsifying Drug Delivery System (SNEDDS) was prepared using Kolliphor El, Maisine 35-1, and Transcutol P as surfactant, oil, and co-surfactant, respectively in a ratio 10:72:18 v/v%. The SNEDDS was converted into solid by adsorption onto Neusilin. In vitro release of the drug from SNEDDS in (pH = 4) at 37 °C and 75 rpm for 45 min was studied. The results were compared to those from the unprocessed PHCl and Lexar® (the commercial drug). In-vivo studies (platelet Aggregation and bleeding time) were conducted using rats as animal models. It was found that the particle size of the SNEDDS ranged between 80 and 155 nm and EE% was in the range of 90.2% ± 0.4. The release from SNEDDS was about 84% compared to around 25% from unprocessed PHCl and 65% from Lexar® after 15 min. The platelet aggregation of the formula was lower than the PHCl, and Lexar® indicating higher bioavailability. In conclusion, SNEDDS with high EE% was prepared and was successful in enhancing the solubility, dissolution rate, and the bioavailability.


Subject(s)
Emulsifying Agents/pharmacokinetics , Platelet Aggregation Inhibitors/pharmacokinetics , Prasugrel Hydrochloride/pharmacokinetics , Animals , Biological Availability , Dose-Response Relationship, Drug , Emulsifying Agents/blood , Male , Platelet Aggregation Inhibitors/blood , Prasugrel Hydrochloride/blood , Rats , Rats, Sprague-Dawley , Solubility , X-Ray Diffraction/methods
2.
Circulation ; 142(5): 441-454, 2020 08 04.
Article in English | MEDLINE | ID: mdl-32795098

ABSTRACT

BACKGROUND: Standard administration of newer oral P2Y12 inhibitors, including prasugrel or ticagrelor, provides suboptimal early inhibition of platelet aggregation (IPA) in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention. We aimed to investigate the effects of cangrelor, tirofiban, and prasugrel, administered as chewed or integral loading dose, on IPA in patients undergoing primary percutaneous coronary intervention. METHODS: The FABOLUS-FASTER trial (Facilitation Through Aggrastat or Cangrelor Bolus and Infusion Over Prasugrel: A Multicenter Randomized Open-Label Trial in Patients with ST-Elevation Myocardial Infarction Referred for Primary Percutaneous Intervention) is an investigator-initiated, multicenter, open-label, randomized study. A total of 122 P2Y12-naive patients with ST-segment-elevation myocardial infarction were randomly allocated (1:1:1) to cangrelor (n=40), tirofiban (n=40) (both administered as bolus and 2-hour infusion followed by 60 mg of prasugrel), or 60-mg loading dose of prasugrel (n=42). The latter group underwent an immediate 1:1 subrandomization to chewed (n=21) or integral (n=21) tablets administration. The trial was powered to test 3 hypotheses (noninferiority of cangrelor compared with tirofiban using a noninferiority margin of 9%, superiority of both tirofiban and cangrelor compared with chewed prasugrel, and superiority of chewed prasugrel as compared with integral prasugrel, each with α=0.016 for the primary end point, which was 30-minute IPA at light transmittance aggregometry in response to 20 µmol/L adenosine diphosphate. RESULTS: At 30 minutes, cangrelor did not satisfy noninferiority compared with tirofiban, which yielded superior IPA over cangrelor (95.0±8.9 versus 34.1±22.5; P<0.001). Cangrelor or tirofiban were both superior to chewed prasugrel (IPA, 10.5±11.0; P<0.001 for both comparisons), which did not provide higher IPA over integral prasugrel (6.3±11.4; P=0.47), despite yielding higher prasugrel active metabolite concentration (ng/mL; 62.3±82.6 versus 17.1±43.5; P=0.016). CONCLUSIONS: Cangrelor provided inferior IPA compared with tirofiban; both treatments yielded greater IPA compared with chewed prasugrel, which led to higher active metabolite concentration but not greater IPA compared with integral prasugrel. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02978040; URL: https://www.clinicaltrialsregister.eu; EudraCT 2017-001065-24.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Platelet Aggregation/drug effects , Prasugrel Hydrochloride/therapeutic use , Purinergic P2Y Receptor Antagonists/therapeutic use , ST Elevation Myocardial Infarction/drug therapy , Tirofiban/therapeutic use , Adenosine Diphosphate/pharmacology , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/blood , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Administration, Oral , Aged , Aged, 80 and over , Area Under Curve , Aspirin/therapeutic use , Cardiac Catheterization , Comorbidity , Female , Heart/physiopathology , Humans , Infusions, Intravenous , Male , Mastication , Middle Aged , Percutaneous Coronary Intervention , Polypharmacy , Prasugrel Hydrochloride/administration & dosage , Prasugrel Hydrochloride/blood , Prasugrel Hydrochloride/pharmacology , Proportional Hazards Models , Purinergic P2Y Receptor Antagonists/administration & dosage , Purinergic P2Y Receptor Antagonists/blood , Purinergic P2Y Receptor Antagonists/pharmacology , ST Elevation Myocardial Infarction/therapy , Tablets , Tirofiban/administration & dosage , Tirofiban/blood , Tirofiban/pharmacology , Treatment Outcome
3.
Catheter Cardiovasc Interv ; 95(1): E8-E16, 2020 01.
Article in English | MEDLINE | ID: mdl-30983087

ABSTRACT

OBJECTIVE: The aim of this study was to compare how prasugrel and clopidogrel affect platelet aggregation reactivity, cardiac enzyme release, cardiac remodeling, and the formation of in-stent thrombi after primary percutaneous coronary intervention (PCI). BACKGROUND: The advantages of using prasugrel over clopidogrel in cardiac injury following acute coronary syndrome (ACS) remain unclear. METHODS: A total of 78 ACS patients were randomly allocated into clopidogrel (300 mg loading/75 mg maintenance) or prasugrel (20 mg loading/3.75 mg maintenance) treatment groups, followed by undergoing primary PCI. Platelet reactivity and cardiac enzymes were measured before and after primary PCI. Moreover, cardiac function was measured by ultrasound echocardiography and coronary angioscopic observation was after primary PCI up to 8 months later. RESULTS: Antiplatelet reactivity in the prasugrel treatment group reached optimal levels (P2Y12 reaction units [PRU] less than 262) immediately after the administration and was maintained even at 8 months, independently of the CYP2C19 genotype. Prasugrel treatment significantly suppressed creatine kinase elevation compared to clopidogrel treatment (median value 404 IU/L to 726 IU/L vs. 189 IU/L to 1,736 IU/L, p = 0.018 for maximum values) and reduced left ventricular mass (217.2-168.8 g in prasugrel, p = 0.045; 196.9-176.4 g in clopidogrel, p = 0.061). There were no significant differences in the incidence of in-stent attached thrombi between the two groups. CONCLUSIONS: Compared to clopidogrel, prasugrel produced a stable platelet aggregation inhibitory effect in patients with ACS regardless of CYP2C19 genotype, reduced cardiac enzyme release, and prevented cardiac remodeling after ACS.


Subject(s)
Acute Coronary Syndrome/therapy , Clopidogrel/administration & dosage , Coronary Thrombosis/prevention & control , Drug-Eluting Stents , Percutaneous Coronary Intervention/instrumentation , Platelet Aggregation Inhibitors/administration & dosage , Platelet Aggregation/drug effects , Prasugrel Hydrochloride/administration & dosage , Purinergic P2Y Receptor Antagonists/administration & dosage , Ventricular Function, Left/drug effects , Ventricular Remodeling/drug effects , Acute Coronary Syndrome/blood , Acute Coronary Syndrome/diagnostic imaging , Acute Coronary Syndrome/physiopathology , Aged , Clopidogrel/adverse effects , Clopidogrel/blood , Coronary Thrombosis/diagnostic imaging , Coronary Thrombosis/etiology , Cytochrome P-450 CYP2C19/genetics , Cytochrome P-450 CYP2C19/metabolism , Female , Humans , Male , Middle Aged , Percutaneous Coronary Intervention/adverse effects , Pharmacogenomic Variants , Platelet Aggregation Inhibitors/adverse effects , Platelet Aggregation Inhibitors/blood , Prasugrel Hydrochloride/adverse effects , Prasugrel Hydrochloride/blood , Prospective Studies , Purinergic P2Y Receptor Antagonists/adverse effects , Purinergic P2Y Receptor Antagonists/blood , Risk Factors , Time Factors , Tokyo , Treatment Outcome
4.
Clin Pharmacol Drug Dev ; 7(2): 143-150, 2018 02.
Article in English | MEDLINE | ID: mdl-28403576

ABSTRACT

Vorapaxar is a first-in-class antagonist of the protease-activated receptor-1, the primary thrombin receptor on human platelets, which mediates the downstream effects of thrombin in hemostasis and thrombosis. Prasugrel is a platelet inhibitor that acts as a P2Y12 receptor antagonist through an active metabolite, R-138727. This study investigated the interaction of these 2 platelet antagonists when coadministered. This was a randomized, open-label, multiple-dose study in 54 healthy volunteers consisting of a fixed-sequence crossover and a parallel group design. In sequence 1, 36 subjects received prasugrel 60 mg on day 1 and then prasugrel 10 mg once daily on days 2 to 7, followed by vorapaxar 40 mg and prasugrel 10 mg on day 8 and then vorapaxar 2.5 mg and prasugrel 10 mg orally once daily on days 9 to 28. In sequence 2, 18 subjects received vorapaxar 40 mg on day 1 and then vorapaxar 2.5 mg once daily on days 2 to 21. The geometric mean ratios (90% confidence intervals) for AUCτ and Cmax of coadministration/monotherapy for vorapaxar (0.93 ng·h/mL[0.85-1.02 ng·h/mL] and 0.95 ng/mL [0.86-1.05 ng/mL]) and R-138727 (0.91 ng·h/mL [0.85- 0.99 ng·h/mL] and 1.02 ng/mL [0.89-1.17 ng/mL]) were within prespecified bounds, demonstrating the absence of a pharmacokinetic interaction between vorapaxar and prasugrel. There was no specific safety or tolerability risk associated with multiple-dose coadministration of vorapaxar and prasugrel. In conclusion, in this study in healthy volunteers, there was no pharmacokinetic drug-drug interaction between vorapaxar and prasugrel. Multiple-dose coadministration of the 2 drugs was generally well tolerated.


Subject(s)
Lactones/pharmacokinetics , Platelet Aggregation Inhibitors/pharmacokinetics , Prasugrel Hydrochloride/pharmacokinetics , Pyridines/pharmacokinetics , Adult , Cross-Over Studies , Drug Administration Schedule , Drug Interactions , Female , Healthy Volunteers , Humans , Lactones/administration & dosage , Lactones/adverse effects , Lactones/blood , Male , Middle Aged , Platelet Aggregation Inhibitors/administration & dosage , Platelet Aggregation Inhibitors/adverse effects , Platelet Aggregation Inhibitors/blood , Prasugrel Hydrochloride/administration & dosage , Prasugrel Hydrochloride/adverse effects , Prasugrel Hydrochloride/blood , Pyridines/administration & dosage , Pyridines/adverse effects , Pyridines/blood , Young Adult
5.
Coron Artery Dis ; 28(6): 465-471, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28763341

ABSTRACT

OBJECTIVES: Patients with acute myocardial infarction pretreated with prasugrel or ticagrelor may require urgent coronary artery bypass grafting (CABG). However, prasugrel and ticagrelor withdrawal period is recommended for 5-7 days before planned CABG to enable full platelet recovery. We hypothesized that monitoring sequential platelet reactivity (PR) could identify patients with early platelet recovery who may benefit from earlier surgery before the guideline-recommended 5-7 day delay. PATIENTS AND METHODS: We performed preoperative PR assays in 35 patients with acute myocardial infarction who received prasugrel (60%) or ticagrelor (40%) and required an urgent CABG. When platelet inhibition levels were favorable, on the basis of the VerifyNow assay, surgery was endorsed. CABG-related bleeding parameters were collected and compared with two matched control groups composed of patients who received fewer potent antiplatelet regimens. RESULTS: On the basis of platelet function monitoring, we identified 21 (56.7%) patients with a relatively earlier platelet recovery who underwent CABG before the end of the conventional washout period (5-7 days). For these patients, the washout periods were shortened to an average time of 2.6±1.0 days for ticagrelor and 3.8±1.5 days for prasugrel. CABG-related bleeding parameters were comparable with the two matched control groups. CONCLUSION: A strategy of performing preoperative PR assays can identify patients who recover platelet function in less than 5-7 days after ticagrelor or prasugrel discontinuation. This strategy may provide the basis for performing urgent CABGs earlier than the currently recommended delay. Future, larger studies are required to establish these preliminary findings.


Subject(s)
Adenosine/analogs & derivatives , Coronary Artery Bypass , Coronary Artery Disease/surgery , Myocardial Infarction/surgery , Platelet Activation/drug effects , Platelet Aggregation Inhibitors/administration & dosage , Platelet Function Tests , Prasugrel Hydrochloride/administration & dosage , Time-to-Treatment , Adenosine/administration & dosage , Adenosine/adverse effects , Adenosine/blood , Aged , Blood Loss, Surgical/prevention & control , Coronary Artery Bypass/adverse effects , Coronary Artery Disease/blood , Coronary Artery Disease/diagnosis , Female , Humans , Male , Middle Aged , Myocardial Infarction/blood , Myocardial Infarction/diagnosis , Pilot Projects , Platelet Aggregation Inhibitors/adverse effects , Platelet Aggregation Inhibitors/blood , Point-of-Care Testing , Postoperative Hemorrhage/blood , Postoperative Hemorrhage/chemically induced , Postoperative Hemorrhage/prevention & control , Prasugrel Hydrochloride/adverse effects , Prasugrel Hydrochloride/blood , Predictive Value of Tests , Preoperative Period , Risk Factors , Ticagrelor , Time Factors , Treatment Outcome
6.
Thromb Haemost ; 117(8): 1582-1587, 2017 08 01.
Article in English | MEDLINE | ID: mdl-28692105

ABSTRACT

While prasugrel is indicated for the treatment of myocardial infarction, its effects in the most severely affected patients requiring intensive care is unknown, so that we measured the antiplatelet effects and sparse pharmacokinetics of prasugrel in critically ill patients. Twenty-three patients admitted to medical intensive care units, who were treated with 10 mg prasugrel once daily, were included in this prospective trial. Critically ill patients responded poorly to daily prasugrel treatment: adenosine diphosphate (ADP)-induced aggregation in whole blood classified 65 % (95 % confidence intervals (CI) 43-84 %) of patients as having high on treatment platelet reactivity, platelet function under high shear rates even 74 % (95 %CI 52-90 %). There was only limited additional inhibition provided 2 hours after the next dose of prasugrel. In contrast, insufficient inhibition of the target was only seen in 26 % (95 %CI 10-48 %) of patients as measured by the vasodilator-stimulated phosphoprotein phosphorylation (VASP-P) assay. Low effective plasma levels of prasugrel active metabolite were measured at trough [0.5 (quartiles 0.5-1.1) ng/ml at baseline], and 2 hours after intake [5.7 (3.8-9.8) ng/ml], but showed coefficients of variation of ~70 %. In sum, inhibition of platelet aggregation by prasugrel is not uniform but highly variable in critically ill patients, similar to clopidogrel in a general population. The pharmacokinetic measurements indicate that poor absorption/metabolism of prasugrel may partly contribute while inflammation induced heightened intrinsic platelet reactivity may also play a role.


Subject(s)
Blood Platelets/drug effects , Platelet Aggregation Inhibitors/administration & dosage , Platelet Aggregation/drug effects , Prasugrel Hydrochloride/administration & dosage , Activation, Metabolic , Austria , Biomarkers/blood , Blood Platelets/metabolism , Cell Adhesion Molecules/blood , Critical Illness , Drug Monitoring/methods , Drug Resistance , Female , Humans , Male , Microfilament Proteins/blood , Middle Aged , Phosphoproteins/blood , Platelet Aggregation Inhibitors/adverse effects , Platelet Aggregation Inhibitors/blood , Platelet Aggregation Inhibitors/pharmacokinetics , Platelet Function Tests , Prasugrel Hydrochloride/adverse effects , Prasugrel Hydrochloride/blood , Prasugrel Hydrochloride/pharmacokinetics , Treatment Outcome
7.
Article in English | MEDLINE | ID: mdl-27038402

ABSTRACT

A cost effective, sensitive, simple, and rapid high-performance liquid chromatography-tandem mass spectrometry method was developed and validated for the quantification of the prasugrel metabolite in human plasma. Following solid phase extraction, the analyte (prasugrel active metabolite; R-138727) and internal standard (emtricitabine) were separated using a mobile phase in an isocratic elution mode on a reverse phase C18 column and were analyzed by an LC-MS/MS in the multiple reaction monitoring mode using the respective [M+H](+) ions, m/z 498.3-206.0 for R-138727 and m/z 248.2-130.1 for the internal standard. The assay exhibited a linear dynamic range of 0.2-120 ng/mL. The lower limit of quantification was 0.2 ng/mL with a relative standard deviation of 5.0%. This LC-MS/MS method was validated with intra-batch and inter-batch precision and accuracy. Results for precision and accuracy are in range of 3.9-9.6% and 95.2-102.2% respectively. This validated method is simple and repeatable to use in bioequivalence/pharmacokinetic studies.


Subject(s)
Chromatography, Liquid/methods , Piperazines/blood , Prasugrel Hydrochloride/blood , Tandem Mass Spectrometry/methods , Humans , Linear Models , Reproducibility of Results , Sensitivity and Specificity
8.
Thromb Haemost ; 116(1): 96-102, 2016 07 04.
Article in English | MEDLINE | ID: mdl-27099137

ABSTRACT

Delays in the onset of action of prasugrel during primary percutaneous coronary intervention (PPCI) have been reported and could be related to the effects of morphine on gastric emptying and subsequent intestinal absorption. The study objective was to determine whether morphine delays the onset of action of prasugrel in patients with a prior history of ST-elevation myocardial infarction (STEMI) treated with PPCI. This was a crossover study of 11 aspirin-treated patients with prior history of STEMI treated with PPCI, for which prasugrel and morphine had been previously administered. Patients were randomised to receive either morphine (5 mg) or saline intravenously followed by 60 mg prasugrel. Blood samples were collected before randomised treatment and over 24 hours after prasugrel administration. The inhibitory effects of prasugrel on platelets were determined using the VerifyNow P2Y12 assay and light transmission aggregometry. Plasma levels of prasugrel and prasugrel active metabolite were measured. Platelet reactivity determined by VerifyNow PRU, VerifyNow % Inhibition and LTA was significantly higher at 30-120 minutes (min) when morphine had been co-administered compared to when saline had been co-administered. Morphine, compared to saline, significantly delayed adequate platelet inhibition after prasugrel administration (158 vs 68 min; p = 0.006). Patients with delayed onset of platelet inhibition also had evidence of delayed absorption of prasugrel. In conclusion, prior administration of intravenous morphine significantly delays the onset of action of prasugrel. Intravenous drugs may be necessary to reduce the risk of acute stent thrombosis in morphine-treated STEMI patients undergoing PPCI.


Subject(s)
Morphine/administration & dosage , Morphine/adverse effects , Platelet Aggregation Inhibitors/administration & dosage , Prasugrel Hydrochloride/administration & dosage , ST Elevation Myocardial Infarction/drug therapy , Aged , Cross-Over Studies , Humans , Intestinal Absorption/drug effects , Male , Middle Aged , Percutaneous Coronary Intervention , Platelet Aggregation/drug effects , Platelet Aggregation Inhibitors/blood , Platelet Aggregation Inhibitors/pharmacokinetics , Prasugrel Hydrochloride/blood , Prasugrel Hydrochloride/pharmacokinetics , ST Elevation Myocardial Infarction/blood , ST Elevation Myocardial Infarction/surgery , Time Factors
9.
J Am Coll Cardiol ; 67(17): 1994-2004, 2016 May 03.
Article in English | MEDLINE | ID: mdl-27012781

ABSTRACT

BACKGROUND: Platelet inhibitory effects induced by oral P2Y12 receptor antagonists are delayed in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI), which may be attributed to impaired absorption affecting drug pharmacokinetics (PK) and pharmacodynamics (PD). Crushing tablets has been suggested to lead to more favorable PK/PD profiles. To date, no studies have investigated the PK/PD effects of crushing prasugrel. OBJECTIVES: This study sought to determine whether crushing prasugrel is associated with more favorable drug bioavailability and platelet inhibitory effects compared with whole tablets in STEMI patients undergoing PPCI. METHODS: Our prospective, randomized, open-label study assessed STEMI patients undergoing PPCI (n = 52) who were treated with a prasugrel 60-mg loading dose (LD) either as whole or crushed tablets. PK/PD analyses were performed at 7 time points. PD effects were measured as P2Y12 reaction units and platelet reactivity index, and PK by plasma levels of prasugrel's active metabolite. RESULTS: Compared with whole tablets, crushed prasugrel led to reduced P2Y12 reaction units by 30 min post-LD, which persisted at 1, 2 (164 vs. 95; least square mean difference = 68; 95% confidence interval: 10 to 126; primary endpoint), and 4 h post-LD. Significant differences were no longer present at 6 h post-LD. Parallel findings were shown with platelet reactivity index. Accordingly, high on-treatment platelet reactivity rates were reduced with crushed prasugrel. PK analyses showed a >3-fold faster absorption with crushed compared with whole prasugrel. CONCLUSIONS: In STEMI patients undergoing PPCI, crushed prasugrel leads to faster drug absorption, and consequently, more prompt and potent antiplatelet effects compared with whole tablet ingestion. (Pharmacological Effects of Crushing Prasugrel in STEMI Patients; NCT02212028).


Subject(s)
Percutaneous Coronary Intervention , Platelet Aggregation Inhibitors/administration & dosage , Prasugrel Hydrochloride/administration & dosage , ST Elevation Myocardial Infarction/therapy , Female , Humans , Male , Middle Aged , Platelet Aggregation , Platelet Aggregation Inhibitors/blood , Platelet Aggregation Inhibitors/pharmacokinetics , Prasugrel Hydrochloride/blood , Prasugrel Hydrochloride/pharmacokinetics , Prospective Studies , Receptors, Purinergic P2Y12/blood , Tablets
10.
Langmuir ; 32(11): 2820-8, 2016 Mar 22.
Article in English | MEDLINE | ID: mdl-26910300

ABSTRACT

We report the development of a microfluidic device for the rapid assay in whole blood of interfacial platelet-protein interactions indicative of the efficacy of antiplatelet drugs, for example, aspirin and Plavix, two of the world's most widely used drugs, in patients with cardiovascular disease (CVD). Because platelet adhesion to surface-confined protein matrices is an interfacial phenomenon modulated by fluid shear rates at the blood/protein interface, and because such binding is a better indicator of platelet function than platelet self-aggregation, we designed, fabricated, and characterized the performance of a family of disposable, self-powered microfluidic chips with well-defined flow and interfacial shear rates suitable for small blood volumes (≤200 µL). This work demonstrates that accurate quantification of cell adhesion to protein matrices, an important interfacial biological phenomenon, can be used as a powerful diagnostic tool in those with CVD, the world's leading cause of death. To enable such measurements, we developed a simple technique to fabricate single-use self-powered chips incorporating shear control (SpearChips). These parallel-plate flow devices integrate on-chip vacuum-driven blood flow, using a predegassed elastomer component to obviate active pumping, with microcontact-printed arrays of 6-µm-diameter fluorescently labeled fibrinogen dots on a cyclic olefin polymer base plate as a means to quantitatively count platelet-protein binding events. The use of SpearChips to assess in whole blood samples the effects of GPIIb/IIIa and P2Y12 inhibitors, two important classes of "antiplatelet" drugs, is reported.


Subject(s)
Equipment Design/instrumentation , Lab-On-A-Chip Devices , Platelet Aggregation Inhibitors/blood , Abciximab , Adenosine/analogs & derivatives , Adenosine/blood , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/blood , Animals , Antibodies, Monoclonal/blood , Cattle , Clopidogrel , Dimethylpolysiloxanes , Fibrinogen , Humans , Immunoglobulin Fab Fragments/blood , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Powders , Prasugrel Hydrochloride/blood , Purinergic P2Y Receptor Antagonists/blood , Serum Albumin, Bovine , Ticagrelor , Ticlopidine/analogs & derivatives , Ticlopidine/blood
11.
Clin Res Cardiol ; 105(4): 349-55, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26493304

ABSTRACT

BACKGROUND: Morphine decreases the concentrations and effects of clopidogrel, which could lead to treatment failure in myocardial infarction. OBJECTIVES: To clarify whether more potent P2Y12-inhibitors may provide an effective alternative, we examined drug-drug interactions between morphine and prasugrel. METHODS: Twelve healthy volunteers received 60 mg prasugrel with placebo or 5 mg morphine intravenously in a randomized, double-blind, placebo-controlled, cross-over trial. Pharmacokinetics were determined by liquid chromatography tandem mass spectrometry, and prasugrel effects were measured by platelet function tests. RESULTS: Morphine neither diminished total drug exposure (AUC), which was the primary endpoint, nor significantly delayed drug absorption of prasugrel. However, morphine reduced maximal plasma concentrations (C max) of prasugrel active metabolite by 31 % (p = 0.019). Morphine slightly, but not significantly, delayed the onset of maximal inhibition of platelet plug formation under high shear rates (30 vs. 20 min). Whole blood aggregation was not influenced. CONCLUSIONS: Although morphine significantly decreases the maximal plasma concentrations of prasugrel active metabolite, it does not diminish its effects on platelets to a clinically relevant degree in healthy volunteers. However, it should be considered that the observed decrease in C max of prasugrel active metabolite caused by morphine co-administration may gain relevance in STEMI patients. CLINICAL TRIAL REGISTRATION: NCT01369186, EUDRA-CT#: 2010-023761-22.


Subject(s)
Analgesics, Opioid/administration & dosage , Morphine/administration & dosage , Platelet Aggregation Inhibitors/pharmacokinetics , Platelet Aggregation/drug effects , Prasugrel Hydrochloride/pharmacokinetics , Purinergic P2Y Receptor Antagonists/pharmacokinetics , Adult , Analgesics, Opioid/adverse effects , Austria , Biotransformation , Chromatography, Liquid , Cross-Over Studies , Double-Blind Method , Drug Interactions , Drug Monitoring/methods , Female , Healthy Volunteers , Humans , Male , Morphine/adverse effects , Platelet Aggregation Inhibitors/administration & dosage , Platelet Aggregation Inhibitors/adverse effects , Platelet Aggregation Inhibitors/blood , Platelet Function Tests , Prasugrel Hydrochloride/administration & dosage , Prasugrel Hydrochloride/adverse effects , Prasugrel Hydrochloride/blood , Purinergic P2Y Receptor Antagonists/administration & dosage , Purinergic P2Y Receptor Antagonists/adverse effects , Purinergic P2Y Receptor Antagonists/blood , Risk Assessment , Tandem Mass Spectrometry , Young Adult
12.
Platelets ; 26(4): 324-30, 2015.
Article in English | MEDLINE | ID: mdl-25905916

ABSTRACT

Managing bleeding in patients receiving P2Y12 inhibitors is challenging. Few data are available regarding the efficacy of platelet transfusion in patients treated with prasugrel or ticagrelor. The aim of this study was to evaluate the minimal amount of platelet supplementation (in terms of ratio of non-inhibited platelets to inhibited platelets) necessary to restore platelet reactivity in platelet-rich plasma (PRP) of patients treated with aspirin and a prasugrel or ticagrelor loading dose for an acute coronary syndrome. PRP samples from patients were mixed ex vivo with increasing proportions of pooled PRP from healthy volunteers. Platelet reactivity was challenged with adenosine diphosphate (ADP), arachidonic acid, collagen or thrombin receptor activating peptide using light transmission aggregometry. The primary endpoint was the proportion of patient samples recovering an ADP-induced maximal aggregation (ADP-Aggmax) value above 40%. In patients treated with prasugrel (n = 32), ADP-Aggmax increased progressively with supplements of pooled PRP, with an average increase of 7.9% (95% CI [7.1; 8.8], p < 0.001) per each 20% increase in the ratio of non-inhibited platelets to inhibited platelets. A ratio of 60% was associated with 90% of patients reaching the primary endpoint. In patients treated with ticagrelor (n = 15), ADP-Aggmax did not significantly increase with any level of supplements. In conclusions, ex vivo addition of non-inhibited platelets significantly improved ADP-Aggmax in patients treated with prasugrel with a dose-dependent effect. There was no evidence of such a reversal in patients treated with ticagrelor. These results suggest that platelet transfusion may be more effective in blunting bleeding in patients treated with prasugrel, than those treated with ticagrelor.


Subject(s)
Acute Coronary Syndrome/drug therapy , Adenosine/analogs & derivatives , Blood Platelets/drug effects , Platelet Aggregation Inhibitors/adverse effects , Platelet Transfusion/methods , Prasugrel Hydrochloride/blood , Purinergic P2Y Receptor Antagonists/adverse effects , Adenosine/adverse effects , Adenosine/blood , Female , Humans , Male , Middle Aged , Platelet Aggregation Inhibitors/blood , Prasugrel Hydrochloride/adverse effects , Prospective Studies , Purinergic P2Y Receptor Antagonists/blood , Ticagrelor
13.
Br J Clin Pharmacol ; 80(1): 139-45, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25557052

ABSTRACT

AIMS: The P2Y12 inhibitor prasugrel is a prodrug, which is activated after its initial hydrolysis partly by cytochrome P450 (CYP) 3A4. Grapefruit juice, a strong inactivator of intestinal CYP3A4, greatly reduces the activation and antiplatelet effects of clopidogrel. The aim of this study was to investigate the effects of grapefruit juice on prasugrel. METHODS: In a randomized crossover study, seven healthy volunteers ingested 200 ml of grapefruit juice or water three times daily for 4 days. On day 3, they ingested a single 10 mg dose of prasugrel with an additional 200 ml of grapefruit juice or water. Plasma concentrations of prasugrel metabolites and the antiplatelet effect were measured. RESULTS: Grapefruit juice increased the geometric mean area under the plasma concentration-time curve (AUC(0-∞)) of the primary, inactive metabolite of prasugrel to 164% of the control value (95% confidence interval 122-220%, P = 0.008), without a significant effect on its peak plasma concentration (C(max)). The C(max) and AUC(0-∞) of the secondary, active metabolite were decreased to 51% (95% confidence interval 32-84%, P = 0.017) and 74% of the control value (95% confidence interval 60-91%, P = 0.014) by grapefruit juice (P < 0.05). The average platelet inhibition, assessed with the VerifyNow® method at 0-24 h after prasugrel intake, was 5 percentage points (95% confidence interval 1-10 percentage points) lower in the grapefruit juice phase than in the water phase (P = 0.034). CONCLUSIONS: Grapefruit juice reduces the bioactivation of prasugrel, but this has only a limited effect on the antiplatelet effect of prasugrel.


Subject(s)
Beverages/adverse effects , Citrus paradisi/adverse effects , Food-Drug Interactions , Prasugrel Hydrochloride/pharmacokinetics , Prodrugs/metabolism , Activation, Metabolic/drug effects , Blood Platelets/drug effects , Cross-Over Studies , Female , Humans , Male , Platelet Aggregation Inhibitors/blood , Platelet Aggregation Inhibitors/metabolism , Platelet Aggregation Inhibitors/pharmacokinetics , Platelet Aggregation Inhibitors/pharmacology , Prasugrel Hydrochloride/blood , Prasugrel Hydrochloride/metabolism , Prasugrel Hydrochloride/pharmacology , Prodrugs/pharmacokinetics , Young Adult
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