Assessing goodness-of-fit for evaluation of dose-proportionality.

For the clinical development of a new drug, the determination of dose-proportionality is an essential part of the pharmacokinetic evaluations, which may provide early indications of non-linear pharmacokinetics and may help to identify sub-populations with divergent clearances. Prior to making any conclusions regarding dose-proportionality, the goodness-of-fit of the model must be assessed to evaluate the model performance. We propose the use of simulation-based visual predictive checks to improve the validity of dose-proportionality conclusions for complex designs.

Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength.

The development of bone-rebuilding anabolic agents for treating bone-related conditions has been a long-standing goal. Genetic studies in humans and mice have shown that the secreted protein sclerostin is a key negative regulator of bone formation. More recently, administration of sclerostin-neutralizing monoclonal antibodies in rodent studies has shown that pharmacologic inhibition of sclerostin results in increased bone formation, bone mass, and bone strength.

Ectomycorrhizal community structure in a healthy and a Phytophthora-infected chestnut (Castanea sativa Mill.) stand in central Italy.

Ink disease caused by Phytophthora cambivora is a major disease of sweet chestnut (Castanea sativa). In two C. sativa stands in central Italy, one (Montesanti) that is infected with P.

Sample size calculation for the Power Model for dose proportionality studies.

There are several approaches to assess or demonstrate pharmacokinetic dose proportionality. One statistical method is the traditional ANOVA model, where dose proportionality is evaluated using the bioequivalence limits. A more informative method is the mixed effects Power Model, where dose proportionality is assessed using a decision rule for the estimated slope.

Combining estimates from multiple early studies to obtain estimates of response: using shrinkage estimates to obtain estimates of response.

Development of anti-cancer therapies usually involve small to moderate size studies to provide initial estimates of response rates before initiating larger studies to better quantify response. These early trials often each contain a single tumor type, possibly using other stratification factors. Response rate for a given tumor type is routinely reported as the percentage of patients meeting a clinical criteria (e.