Abciximab pharmacodynamic model with neural networks used to integrate sources of patient variability.

OBJECTIVE: Our objective was to develop a computational model for predicting abciximab-induced inhibition of ex vivo platelet aggregation from the administered dose and readily available patient clinical characteristics by use of a neural network approach. METHODS: A back-propagation neural network was designed to establish the relationship between abciximab dosing, patient clinical history, and effect (inhibition of 20 micromol/L adenosine diphosphate-induced ex vivo platelet aggregation). The neural network was trained by use of data from 8 (out of 47) patients undergoing coronary angioplasty and 30 healthy individuals. Final neuron connection weights were used to evaluate significant patient covariates. The final neural network was validated via (1) predicting the effects of the validation database (remaining 39 patients) and (2) predicting the individual patient doses to achieve 20% of baseline platelet aggregation. RESULTS: The trained neural network successfully captured the complex pharmacodynamic profiles of abciximab without specifying a structural model and identified several patient covariates that significantly contribute to establishing the abciximab dose-effect relationship, including stable angina with nitrate treatment, previous myocardial infarction, and smoking. A wide distribution of individual bolus doses of abciximab was predicted, suggesting the potential for dosing individualization while improving the risk of adverse drug events. The mean predicted dose (16.9 mg) was in agreement with the results from a previously published concentration-effect relationship for abciximab (18.9 +/- 2.0 mg). CONCLUSIONS: These findings suggest the usefulness of neural network methods to individualize dosing for drugs with a narrow therapeutic index when real-time measures of drug concentration and effect are unavailable, but future clinical studies are required for prospective validation.

Simultaneous modeling of abciximab plasma concentrations and ex vivo pharmacodynamics in patients undergoing coronary angioplasty.

An integrated structural pharmacokinetic/pharmacodynamic (PK/PD) model was developed for the glycoprotein IIb/IIIa antagonist abciximab administered to patients undergoing percutaneous transluminal coronary angioplasty. PK/PD data, in the form of plasma abciximab concentrations and ex vivo platelet aggregation in the presence of 20 microM adenosine diphosphate, were obtained from two previously conducted clinical studies. Study 1 consisted of patients who were given abciximab as a single intravenous injection of 0.25 mg/kg (n = 32). Patients in study 2 received an identical bolus dose, followed by a 36-h infusion at 0.125 microg/kg/min (n = 15). The PK component of the final model included drug-receptor binding, nonspecific distribution, and linear systemic clearance, whereas the PD module assumed that ex vivo dynamics were controlled by free plasma drug concentration. Mean PK/PD data from both studies were fitted simultaneously using nonlinear regression. PK profiles from both studies show rapidly decreasing plasma abciximab concentrations at early time points, but with extended terminal disposition phases. The maximum effect (Emax = 83.6%) was achieved rapidly and gradually returned to baseline values, although inhibition could be measured long after abciximab concentrations dropped below the detection limit. The final model well described the resulting PK/PD profiles and allowed for parameter estimation with relatively small coefficients of variation. Simulations were conducted to assess predicted receptor-occupancy and effects of selected parameters on PK/PD profiles. Models such as the one developed in this study demonstrate how drug binding to pharmacological targets may influence the PK of certain drugs and also provide a suitable paradigm for defining the PK/PD relationships of similar compounds.

An additional mechanism of action of abciximab: dispersal of newly formed platelet aggregates.

BACKGROUND: The ability of abciximab to prevent fibrinogen binding to activated platelets indicates it may also promote dissolution of platelet-rich thrombi. The present study examined the capacity of abciximab to reverse platelet aggregation in vitro. METHODS AND RESULTS: Experiments were performed on blood from healthy non-medicated donors. Platelet aggregate formation and disaggregation were monitored turbidimetrically. Platelet-bound fibrinogen was measured by flow cytometry. For disaggregation studies, platelets were first stimulated with either ADP or the 11-mer thrombin receptor activating peptide (TRAP), then varying amounts of abciximab were added at periodic intervals after agonist addition. Platelet disaggregation was detected by comparing the extent of light transmittance at 4 min after addition of either abciximab or saline to PRP. ATP release was simultaneously monitored by chemi-luminescence. When added 1 min after low concentrations of ADP, abciximab rapidly (< 1 min) dispersed platelet aggregates in a dose-dependent manner, with complete disaggregation observed with 6.25 microg/mL of the beta3 antagonist. In contrast, equivalent concentrations of abciximab did not induce appreciable disaggregation to platelets stimulated with TRAP (10 microM). Platelet counts of samples that had undergone complete disaggregation, as assessed by aggregometry, were equivalent to baseline, indicating dispersal of aggregates to single cells. Concentrations of abciximab that produced complete disaggregation induced partial displacement of platelet-bound fibrinogen (52 +/- 8% inhibition of fibrinogen binding at 12.5 microg/ml abciximab). The disaggregation effectiveness of abciximab decreased as the time between ADP and subsequent abciximab addition widened, and as the amount of both dense granule release and agonist stimulation increased. However, pre-treatment of platelets with acetylsalicylic acid (ASA) did not potentiate platelet disaggregation induced by abciximab. CONCLUSIONS: These data indicate that abciximab facilitates the dispersal of newly formed platelet aggregates in vitro, by partially displacing fibrinogen from activated GPIIb/IIIa receptors. In vivo, abciximab may destabilize coronary thrombi by preventing aggregate formation and dispersing mural thrombi.

Pharmacodynamics of abciximab during angioplasty: comparison to healthy subjects.

OBJECTIVES: Our objectives were to compare and contrast abciximab concentration-effect relationships in healthy volunteer participants with those in patients with coronary atherosclerosis undergoing elective coronary angioplasty. We also aimed to establish abciximab plasma concentrations associated with 80% inhibition of platelet aggregation. METHODS: Abciximab clearance and concentration-effect relationships were determined from two separate clinical studies, one in 30 healthy subjects aged 21 to 66 years and the other in 32 patients aged 44 to 74 years before they underwent elective coronary angioplasty. After abciximab administration, abciximab plasma concentrations, platelet glycoprotein IIb/IIIa (GP IIb/IIIa) receptor occupancy, and degree of inhibition of platelet aggregation in the presence of 5-micromol/L and 20-micromol/L adenosine diphosphate was determined. With an E(max) (receptor occupancy) or inhibitory E(max) (inhibition of platelet aggregation) model, abciximab concentrations required for 80% receptor occupancy and 80% inhibition of platelet aggregation were determined. RESULTS: Abciximab steady-state clearance in healthy participants was 183 +/- 72 ml/min (mean +/- SD), and single-dose clearance in patients undergoing angioplasty was 405 +/- 240 ml/min (mean +/- SD). Abciximab concentration required for 80% GP IIb/IIIa receptor occupancy was 35.2 +/- 2.4 versus 72.8 +/- 6.4 ng/ml in healthy participants versus patients (P <.01). Concentrations required for 80% inhibition of platelet aggregation stimulated by 5-micromol/L adenosine diphosphate were 25.6 +/- 1.6 versus 68.9 +/- 9.2 ng/ml (P <.01). Similarly, the concentrations required for 80% inhibition of platelet aggregation stimulated by 20-micromol/L adenosine diphosphate were 56.0 +/- 3.2 versus 141 +/- 16.8 ng/ml (P <.01). CONCLUSION: Approximately 2-fold greater abciximab exposure is required to achieve the same degree of GP IIb/IIIa occupancy and inhibition of platelet aggregation in patients undergoing angioplasty as compared with healthy participants. The difference between groups may be related either to different states of basal platelet activation or to the effect of heparin that patients received as part of the angioplasty procedure. A therapeutic concentration range for patients is 100 to 175 ng/ml, because this is the concentration consistent with >80% inhibition of platelet aggregation when 20-micromol/L adenosine diphosphate is used as the aggregating stimulus.

Pharmacodynamic profile of short-term readministration of abciximab in healthy subjects.

OBJECTIVE: The purpose of the study was to establish a rebolus regimen for abciximab that restores pharmacologic glycoprotein (GP) IIb/IIIa receptor blockade within a short time frame (up to 48 hours) after completion of an initial treatment. METHODS AND RESULTS: The study was a single-center, nonrandomized, open-label dose escalation trial in healthy volunteers (n = 30). Each subject received a 0.25 mg/kg bolus and a 0.125 microg/kg per minute infusion of abciximab, followed by incremental bolus doses of the agent at 15-minute intervals up to 48 hours (10 per group) after completion of the infusion, (maximal cumulative rebolus dose of 0.25 mg/kg). Pharmacodynamic measurements (GP IIb/IIIa receptor blockade, turbidimetric and whole blood platelet aggregation with use of a rapid platelet function assay [RPFA]) were obtained at periodic intervals during and after administration of the abciximab bolus and infusion. At the time of the first rebolus, pharmacodynamic measurements were attained immediately before administration of each rebolus and 15 minutes after the last rebolus dose. In subjects who received reboluses 12 hours after infusion, a cumulative dose of 0.05 mg/kg restored >80% blockade of GP IIb/IIIa receptors and >80% inhibition of turbidimetric (5 and 20 micromol/L adenosine diphosphate) and RPFA aggregation in 10 of 10 subjects. At 24 hours after treatment, a cumulative abciximab bolus dose of 0.1 mg/kg restored >80% blockade of all 4 pharmacodynamic measurements in 10 of 10 subjects. At 48 hours after treatment, a cumulative bolus dose of 0.15 mg/kg restored >80% blockade of all 4 pharmacodynamic measurements in 10 of 10 subjects. CONCLUSIONS: A fraction of the bolus of abciximab restored pharmacologic (>80%) GP IIb/IIIa receptor blockade when readministered at various postinfusion time points. These observations suggest that in the setting where acute readministration of abciximab is required less than a full bolus dose of the agent is warranted.