title: Mapping the dose-effect relationship of orbofiban from sparse data with an artificial neural network.
abstract: A neural network (NN) pharmacodynamic model was developed that correlates the inhibition of ex vivo platelet aggregation by orbofiban, an oral glycoprotein IIb/IIIa antagonist, with the administered dose and patient characteristics. Data were obtained from a Phase-II dose-finding study of orbofiban in patients presenting with acute coronary syndromes. A back-propagation NN was designed to predict drug effect measured at predose and 4 and 6 h on treatment days 1, 28, and 84 (nine responses/patient). The training set consisted of patients for whom complete response profiles were reported (n = 67), and remaining patients were included in the validation data set (n = 47). The concentration-effect relationship was described additionally using a population direct-effect inhibitory sigmoidal model, and a comparison of the predictive performances of both models was performed. The final NN reasonably described orbofiban pharmacodynamics from sparse data sets without specifying a structural model or drug concentrations. Despite considerable inter-patient variability in response-time profiles, the population model revealed a strong correlation between drug concentration and effect and exhibited greater precision than the NN model. Although the population model showed greater precision, these results suggest that NNs may be useful for individualizing pharmacotherapy when drug concentrations are relatively unpredictable or unavailable.
authors.affiliation: Laboratory of Clinical Investigation, National Institute on Aging, Gerontology Research Center, Baltimore, Maryland, USA.
authors.forename: Donald E
authors.initials: DE
authors.lastname: Mager
authors.forename: Jason D
authors.initials: JD
authors.lastname: Shirey
authors.forename: Dermot
authors.initials: D
authors.lastname: Cox
authors.forename: Desmond J
authors.initials: DJ
authors.lastname: Fitzgerald
authors.forename: Darrell R
authors.initials: DR
authors.lastname: Abernethy
mesh_terms: D000409:Alanine / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D000789:Angina, Unstable / Q000097:blood / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009203:Myocardial Infarction / Q000097:blood / Q000188:drug therapy; D016571:Neural Networks, Computer; D010975:Platelet Aggregation Inhibitors / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors; D011759:Pyrrolidines / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D015203:Reproducibility of Results
chemical_list: D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011759:Pyrrolidines; C120234:orbofiban; D000409:Alanine