TL34: Evaluating Effect of Intrinsic Factors on Pharmacokinetics
*Deborah Lorah Panebianco, Merck 

Keywords: pharmacokinetics, dosing recommendation, intrinsic factors, modeling

Common Technical Document Section 2.7.2. of a Worldwide Marketing Application includes evaluation of the effect of intrinsic and extrinsic factors on the drug’s PK. Dose adjustment or contraindication may be recommended based on the magnitude of these effects. Drug-drug interactions (extrinsic factors) are usually evaluated in dedicated studies in healthy subjects. Intrinsic factors such as age, gender or hepatic/renal impairment may also be evaluated in dedicated studies. However, addition information may be gained by pooling data across Phase I studies (and Phase II and III if PK data were collected). How do sponsors use these pooled data to quantify the effect of the intrinsic factors? If an adequate pop PK model has been developed, is this model used for the evaluation of intrinsic factors? Does the statistician evaluate the NCA (non-compartmental analysis) PK parameters in a linear model including categorical or continuous factors for the effects of interest? Is a graphical argument ever warranted – for example, data are limited, but all of the data points of the population being evaluated lie within the distribution of data points from the “reference” population?