Purpose:The purpose is to determine the maximumtolerated dose, assess the toxicities, characterize the pharmacokinetic behavior, and seek preliminary evidence of biological activity of cantuzumab mertansine when administered as a weekly i.v. infusion without interruption.Experimental Design: Patients with incurable solid tumors that expressed the target antigen for cantuzumab mertansine, CanAg, were treated with doses of cantuzumab mertansine ranging from 40 to 138 mg/m 2 . The maximumtolerated dose was defined as the highest dose at which no more than 1 of 6 patients experienced dose-limiting toxicity. Plasma concentrations of cantuzumab mertansine and total humanized antibody were determined, and area under the plasma concentration-time curve (to the last measured concentration) was calculated.Results: Thirty-nine patients received a total of 280 weekly doses of cantuzumab mertansine. Acute, transient elevation of the hepatic transaminases and reversible fatigue were identified as the dose-limiting toxicities at the highest dose level. The maximum-tolerated dose was determined to be 115 mg/m 2 /week. Evidence of clinical activity was noted in 3 patients. Pharmacokinetic analyses revealed that the pharmacokinetic variability was moderate, without evidence of dose dependency. Furthermore, the drug had a long terminal half-life (ϳ40 h).Conclusions: This study identified a safe and tolerable dose of the novel immunoconjugate prodrug cantuzumab mertansine. The evidence of antitumor activity suggests that additional clinical development is warranted, with a focus on tumors that express high levels of CanAg and which are known to be sensitive to antimicrotubule agents.
The pharmacokinetics and pharmacodynamics of remifentanil were not altered in patients with renal disease, but the elimination of its principal metabolite, GR90291, was markedly reduced. Based on simulations, the concentration of GR90291 at the end of a 12-h remifentanil infusion of 2 microg x kg(-1) x min(-1) is not likely to produce significant opioid effects.
Abstract. The purpose of this investigation is to evaluate the scientific benefits of a novel approach in using stable isotopes to reduce the number of subjects needed to perform relative bioavailability and bioequivalence pharmacokinetic studies for formulations that are qualitatively and quantitatively the same and quality by design (QbD) pharmacokinetic studies. The stable isotope approach was investigated using simulations to determine the impact this approach would have on the estimation of variability and, subsequently, the sample size for a bioequivalence study. A biostudy was conducted in dogs in a two period crossover to explore the viability of the stable isotope approach. For a drug product with within-subject variability (CV w ) of 50% and assuming a correlation of 0.95 between the enriched and non-enriched pharmacokinetics (PK), simulations showed that the variability can be reduced by 70% and the required sample size can be reduced by 90% while maintaining 90% power to demonstrate bioequivalence. The dog study showed a strong correlation (R 2 , >0.99) between the enriched and nonenriched area under the curve and maximum observed concentration, and a significant reduction in the variability (reduction in % coefficient of variation from 79.9% to 6.3%). Utilization of a stable isotope approach can markedly improve the efficiency and accuracy of bioavailability and bioequivalence studies particularly for highly variable drugs in formulations that are qualitatively and quantitatively the same and for studies designed for QbD investigations.
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