Variability inter-individual

The statistical submodel characterizes the pharmacokinetic variability of the mAb and includes the influence of random - that is, not quantifiable or uncontrollable factors. If multiple doses of the antibody are administered, then three hierarchical components of random variability can be defined inter-individual variability inter-occasional variability and residual variability. Inter-individual variability quantifies the unexplained difference of the pharmacokinetic parameters between individuals. If data are available from different administrations to one patient, inter-occasional variability can be estimated as random variation of a pharmacokinetic parameter (for example, CL) between the different administration periods. For mAbs, this was first introduced in sibrotuzumab data analysis. In order to individualize therapy based on concentration measurements, it is a prerequisite that inter-occasional variability (variability within one patient at multiple administrations) is lower than inter-individual variability (variability between patients). Residual variability accounts for model misspecification, errors in documentation of the dosage regimen or blood sampling time points, assay variability, and other sources of error. 

PENG Y s, PENG Y M, MCGEE D L and ALBERTS D s (1994) Carotenoids, tocopherols and retinoids in human buccal mucosal cells intra- and inter-individual variability and storage stability. J Clin Nutr 59(3) 636-43. 

NOAEL (no-observed-adverse-effect level) is defined as the highest dose at which no adverse effects are observed in the most susceptible animal species. The NOAEL is used as a basis for setting human safety standards for acceptable daily intakes (ADIs), taking into account uncertainty factors for extrapolation from animals to humans and inter-individual variabilities of humans. The adequacy of any margin of safety or margin of exposure must consider the nature and quality of the available hazard identification and dose-response data and the reliability and relevance of the exposure estimations. In some cases, no adverse endpoint can be identified such as for many naturally occurring compounds that are widespread in foods. In that case, an ADI Not Specified is assigned. ... 

Heusler-Bitschv S, Knutti R, Schiatter C. 1988. Inter-individual variability of the kinetics of lead in man. In Braetter P, Schramel P, eds. Proceedings of the International Workshop Trace element analytical chemistry in medicine and biology. Vol. 5. April 1988, Neuherberg, West Germany, 627-634. 

It has now been established that genetic polymorphisms in drug metabolizing enzymes such as the cytochrome P450s (CYP) and the phase II enzyme, thiopu-rine methyltransferase, are responsible for inter-individual variability in response and adverse reactions [12, 13]. However, at the present time, the impact of poly-... 

The ratio, [Li ]/[Li+ut], in human erythrocytes ranges from 0.2-0.9, illustrating a large inter-individual variability however this ratio is relatively constant over long periods of time for individuals and there is evidence that this phenomena is under genetic control [62]. Higher ratios have been reported in patients with affective illnesses compared to healthy subjects [63] and in females compared to males [64]. There have been attempts to correlate the higher Li+ ratio to a better clinical response of patients to Li+ therapy [65]. 

Yang D, Pearce RE, Wang X, Gaedigk R, Wan YJ, Yan B (2009) Human carboxylesterases HCE1 and HCE2 ontogenic expression, inter-individual variability and differential hydrolysis of oseltamivir, aspirin, deltamethrin and permethrin. Biochem Pharmacol 77 238-247... 

Comment. The studies summarise intra- and inter- individual variability. 

UF2 = uncertainty factor to allow for inter-individual variability in humans. 

We will merely call attention here to the tremendous inter-individual human variability which exists in the anatomy of the endocrine glands. This variability is foreshadowed by the data already given with respect to rabbits and pigeons (pp. 2021). Since a separate chapter is devoted to these glands and their functioning, specific anatomical information with respect to the specific glands will be presented there. It is possible that these anatomical variations are more important from the standpoint of health and well-being than any we have so far discussed. 

Certainly these differences are far from trivial. Even to the author, who has been interested in variability for some years, the extent of the variability comes as a surprise. He, therefore, cannot blame his colleagues if they seem incredulous. We have included in our discussion every enzyme for which we have found substantial data, and the least inter-individual variation we know of appears to be about 2-fold. 

In concluding our discussion on inter-individual variability in hormone functions, we may well point out that with respect to hormone after hormone we have cited evidence of wide variability. Furthermore, the hormones for which the evidence is most convincing are those which have been studied in greatest detail and for the longest time. It may therefore be presumed that, as study of other individual hormone activities progresses, the role and importance of variation will become more widely evident. 

Pharmacokinetic concentration-time curves for a drug and ifs mefabolifes are used to identify primary exposure metrics such as AUC, or which are not time-dependent unlike the sequential measurements of concentration over time. A peak plasma concentration of a drug is often associated with a PD response, especially with an adverse event. There can be large inter-individual variability in the time-to-peak concentration, and closely spaced sampling times are often critical to determining the peak plasma concentration accurately in individual patients because of differences in demographics, disease states, and food effects, if any. All these elements are clearly spelled out in the protocols written to conduct these studies. 

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