Optimizing the Concentration and Bolus of a Drug Delivered by Continuous Infusion
Seminar Room 1, Newton Institute
AbstractWe consider treatment regimes in which an agent is administered continuously at a specified concentration until either a therapeutic response is achieved or a predetermined maximum infusion time is reached. Additionally, a portion of the planned maximum total amount of the agent is administered as an initial bolus. Efficacy is the time to response, and toxicity is a binary indicator of an adverse event that may occur after infusion. The amount of the agent received by the patient thus depends on the time to response, which in turn affect the probability of toxicity. An additional complication arises if response is evaluated periodically, since the response time is interval censored. We address the problem of designing a clinical trial in which such response time data and toxicity are used to jointly optimize the concentration and size of the initial bolus. We propose a sequentially adaptive Bayesian design that chooses the optimal treatment for each patient by maximizing the posterior mean utility of the joint efficacy-toxicity outcome. The methodology is illustrated by a clinical trial of tissue plasminogen activator (tPA) infused intra-arterially as rapid treatment for acute ischemic stroke. The fundamental problem is that too little tPA may not dissolve the clot that caused the stroke, but too much may cause a symptomatic intra-cranial hemorrhage, which often is fatal. A computer simulation study of the design in the context of the tPA trial is presented.
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