Subpopulation, defined

None of the tested covariates was identified as having a clinically relevant impact on the PK of cetuximab. Thus, changes in dose or dosing regimen do not appear to be necessary in any of the subpopulations defined by these covariates. However, it should be noted that the majority of the studied patients had adequate hepatic and renal function. Overall, more than 90 % of the patients included in the PK database had normal hepatic function, more than 60% had normal renal function, and a further 32% had only mild impairment (creatinine clearance 50-80 mL/min). Hence, the effect of more severe renal or hepatic impairment on cetuximab PK remains to be elucidated. 

Armitage RJ, Goff LK. Functional interaction between B cell subpopulations defined by CD23 expression. Eur J Immunol 1988 18(11) 1753-1760. 

Bucala R, Spiegel LA, Chesney J, Hogan M, Cerami A. Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Mol Med 1994 1(1) 71—81. 

Deficiency of thiopurine S-methyl transferase (TPMT) is another phenotype that exhibits inter-ethnic differences in frequency. TPMT is an enzyme that catalyzes methylation of therapeutic agents used in the treatment of acute lymphoblastic leukemia, rheumatoid arthritis, and autoimmune/inflammatory diseases, as well as in organ transplantation. Patients who have TPMT deficiency experience less efficient methylation and are at greater risk of fatal toxicity when treated with standard doses of fhiopurines. TPMT phenotype is defined by erythrocyte 6-mercapto-purine methylation. African American populations exhibit a 20% lower erythrocyte TPMT than Caucasian Americans, and persons of Chinese descent tend to exhibit greater activity than either of these other American subpopulations. 

NGF also has actions within the CNS, although it is not particularly abundant in the CNS. Its synthesis appears to be largely restricted to the hippocampus and neocortex, and even in these regions it is present at relatively low concentrations relative to the other neurotrophins. The most prominent population of NGF-responsive neurons expressing TrkA are the basal forebrain cholinergic neurons. The principal projections of these neurons are to the hippocampus and cortex, which conforms with the concept that NGF acts as a target-derived trophic factor in the CNS, just as it does in the peripheral nervous system (PNS). NGF also acts on a subpopulation of cholinergic neurons within the striatum. These interneurons express the NGF receptor, TrkA, and respond to NGF. However, they do not appear to rely entirely on NGF for their survival, and the specific actions of NGF on this neuronal population have not been clearly defined. NGF may also have autocrine actions in the CNS, as some neuronal populations have been identified that express both TrkA and NGF. 

In carrying out the exposure assessment the risk reduction/control measures that are already in place should be taken into account. Consideration should be given to the possibility that, for one or more of the defined populations, risk reduction/control measures which are required or appropriate in one use scenario may not be required or appropriate in another (i.e., there might be subpopulations legitimately using different patterns of control, which could lead to different exposure levels). 

The major elements to be considered in the risk characterization part include key information, context, sensitive subpopulations, scientific assumptions, policy choices, variability, uncertainty, bias and perspective, strengths and weaknesses, key conclusions, alternatives considered, and research needs. Whether every element is actually written into the risk characterization or not, depends upon the purpose of the risk assessment and the detail necessary to adequately characterize it. By the time the risk assessment is completed, the universe of policy choices, management decisions, and uncertainties should have been identified, as well as the conclusions of the risk assessment. Because key findings differ for each risk assessment, it is not possible to define exactly what they are genericaUy. Professional judgment is necessary to define them. 

The conservation equation for receptors defines the total number of receptors as the sum of bound and free receptors (Equation (6.3)). Although the receptor population is in fact made up of subpopulations of receptors in high- and low-affinity states, this is most relevant for modeling agonist interactions. Because most tracers are radiolabeled antagonists, this simplified model is sufficient for most tracer studies. The conservation and mass action equations (Equations (6.3) and (6.4)) can be rearranged to calculate the number of bound receptors ... 

Some subpopulation of the microorganisms is likely capable of taking advantage of this opportunity and growing on this chemical. This implies that as they metabolize PC, they will rapidly increase in number. You can estimate the critical bacterial cell abundance, [B]crit, by defining it as the cell density sufficient to consume all of the chemical during the next doubling interval ... 

---