title: Optimizing the concentration and bolus of a drug delivered by continuous infusion.
abstract: We consider treatment regimes in which an agent is administered continuously at a specified concentration until either a response is achieved or a predetermined maximum infusion time is reached. Response is an event defined to characterize therapeutic efficacy. A portion of the maximum planned total amount administered is given as an initial bolus. For such regimes, the amount of the agent received by the patient depends on the time to response. An additional complication when response is evaluated periodically rather than continuously is that the response time is interval censored. We address the problem of designing a clinical trial in which such response time data and a binary indicator of toxicity are used together to jointly optimize the concentration and the size of the bolus. We propose a sequentially adaptive Bayesian design that chooses the optimal treatment for successive patients by maximizing the posterior mean utility of the joint efficacy-toxicity outcome. The methodology is illustrated by a trial in which tissue plasminogen activator is infused intraarterially as rapid treatment for acute ischemic stroke.
authors.affiliation: Department of Biostatistics, M.D. Anderson Cancer Center, Houston, Texas 77030, USA. rex@mdanderson.org
authors.forename: Peter F
authors.initials: PF
authors.lastname: Thall
authors.forename: Aniko
authors.initials: A
authors.lastname: Szabo
authors.forename: Hoang Q
authors.initials: HQ
authors.lastname: Nguyen
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Amlie-Lefond
authors.forename: Osama O
authors.initials: OO
authors.lastname: Zaidat
mesh_terms: D002545:Brain Ischemia / Q000175:diagnosis* / Q000188:drug therapy* / Q000401:mortality; D002986:Clinical Trials as Topic / Q000379:methods*; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D004360:Drug Therapy, Computer-Assisted / Q000379:methods*; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D007261:Infusions, Intra-Arterial; D020521:Stroke / Q000175:diagnosis* / Q000188:drug therapy* / Q000401:mortality; D016019:Survival Analysis; D015996:Survival Rate; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator