Model biomarker-outcomes link

The exposure-response surface (see Chapters 8 and 32) is rarely mapped in children, thus limiting extrapolation of therapy from adults to children. Models linking biomarkers to patient outcomes—outcomes link models—are virtually absent in pediatric pharmacometries. There is no reason to believe that PK/PD-biomarker-surrogate-outcomes linkage in children should uniformly parallel adults therefore, this is an area where there is a great need for further model development. Population methods can play an important role for filling in these critical pieces to determine optimal pediatric therapy. 

Although in vitro models clearly show that MDR transporters can protect tumor cells, their relevance in clinical oncology remains controver sial. As is the case for most potentially useful cancer biomarkers, no universally embraced guidelines for analytical or clinical validation of MDR transporters exist. Evidence linking ABCB1 Pgp/MDRl expression with poor clinical outcome is most conclusive for breast cancer, sarcoma, and certain types of leukemia. The relevance of the other MDR transporters in clinical MDR is still unclear. The prognostic implication of ABCCl/ MRPl remains controversial and very little is known clinically about ABCG2. 

Chlorpyrifos provides an example of the utility of human pharmacokinetic models to estimate daily dose from biomonitoring data for a rapidly cleared pesticide. The urinary metabolite trichloro-2-pyridinol (TCP) is used in the NHANES study to monitor population exposure to chlorpyrifos (CDC 2005). Several epidemiologic studies have linked chlorpyrifos exposure to adverse birth outcomes through associations between urinary and blood biomarkers and have demonstrated maternal exposure and physiologic measurements in the neonate (Berkowitz et al. 2003, 2004 Whyatt et al. 2004 Needham 2005). 

For the purpose of the analysis, lactate concentrations were assumed be pseudosteady-state at the beginning of the first DCA dose, so that A i was set to equal the lactate concentration at time 0 multiplied by the estimated A out (A m= A out lactate). A link between the 24 hour post-trauma CSF lactate and 6 month postinjury Glasgow Coma Score (GCS) was also estimated by application of logistic regression to literature data (20). Thus, a PK-exposure-PD-CSF lactate-outcomes model was constructed with the biomarker, CSF lactate, in the center. It must be recognized that this modeling and evaluation of power and efficiency could not be executed without a biomarker. 

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