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1.
Figure 2

Figure 2. From: Pediatric Phase I Trial Design Using Maximum Target Inhibition as the Primary Endpoint.

Dose–effect curve and pharmacokinetic parameters for oral talabostat at doses ranging from 100 to 600 μg/m2. Talabostat effect is percent inhibition of serum dipeptidyl peptidase-4 (DPP-4) enzyme activity measured 24 hours after the first dose of talabostat. A maximum effect model, , where E(D) is the observed effect at a given dose D, Emax is the maximum effect (100% inhibition), ED50 is the dose achieving 50% of the Emax, and n is the slope, was fit to the dose–effect data with MLAB (Civilized Software, Silver Spring, MD; http://www.civilized.com/). A) The curve represents the fitted maximum effect model (n = 1.0, ED50 = 130 μg/m2). The maximum effect model predicts that the maximum target inhibition would be achieved at doses exceeding 1200 μg/m2. Each symbol represents an individual patient. B) Pharmacokinetic parameters for each patient and dose. Talabostat pharmacokinetic parameters include Cmax, maximum concentration; Tmax, time to peak concentration; AUC0–8, area under the concentration × time curve extrapolated to infinity; CL/F, apparent clearance.

Holly Meany, et al. J Natl Cancer Inst. 2010 June 16;102(12):909-912.
2.
Figure 1

Figure 1. From: Pediatric Phase I Trial Design Using Maximum Target Inhibition as the Primary Endpoint.

Trial schema. Algorithm of the adaptable trial design used to define an optimal dose of talabostat based on the degree of target (dipeptidyl peptidase-4 [DPP-4]) inhibition. Maximum target inhibition (MTI) is defined as a greater than 90% decrease in DPP-4 activity relative to baseline, 24 hours after the first dose of talabostat. Two patients are enrolled at the starting dose. If dose-limiting toxicity (DLT) is not observed (boxes with a single line border) and one or both do not achieve MTI, the dose would be escalated. If MTI is achieved in both, the dose level would be expanded to six patients. If fewer than five of the six have MTI, the dose would be escalated. If five or more achieve MTI, the dose would be escalated one additional dose level to ensure that the optimal dose is on the plateau of the dose–response curve. If DLT is observed in one patient at any point, the dose escalation would switch to a traditional phase I (3 + 3 design), and a more conservative 40% dose escalation would be used (boxes with double line border), but DPP-4 inhibition will continue to be monitored. If two or more patients at a dose level experience a DLT, a maximum tolerated dose (MTD) would be defined.

Holly Meany, et al. J Natl Cancer Inst. 2010 June 16;102(12):909-912.

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