Drug development toxicokinetics

Yacobi, A., Skelly, J.P. and Batra, VK. (1989). Toxicokinetics and New Drug Development. Pergamon Press, New York. 

J.G. Harter, G. Levy,T. Ludden, J.H. Rod-man, et al. 1994. Opportunities for integration of pharmacokinetics, pharmacodynamics, and toxicokinetics in rational drug development. J. Clin. Pharmacol. 34 111-119. 

Yacobi, A., J.P. Skelly, V.P. Shah, and L.Z. Benet. 1993. Integration of Pharmacokinetics, Pharmacodynamics, and Toxicokinetics in Rational Drug Development. New York Plenum Press. 

Yacobi A, Batra VK, Desjardins RE, Faulkner RD, Nicolau G, Pool WR, Shah A, Tonelli AP. Implementation of an effective pharmacokinetics research program in industry. In Yacobi A, Skelly JP, Shah VP, Benet LZ, eds. Integration of pharmacokinetics, pharmacodynamics, and toxicokinetics in rational drug development. New York Plenum 1993. p.125-35. 

Ings RMJ. Inter species scaling and comparisons in drug development and toxicokinetics. Xenobiotica 1990 20 1201-31. 

Should an early decision be made to develop the eutomer, then the drug development program would be the same as for conventional NCEs, with the possible exception that assessment of in vitro and/or in vivo chiral inversion may be desirable. However, if development continues with the racemate, time, cost, and staff resource commitments become magnified. For example, a very important variable to consider is spedes differences in enantiomer exposure. Appropriate toxicokinetic studies are advisable in order to assure that, at toxicological doses, the animal species tested have attained suffident plasma concentrations of each enantiomer to support clinical evaluation at therapeutic doses in humans. The enantiomeric ratio (based on maximum drug concentrations fCmax] and/or area under the plasma drug concentration-time curve [ALJC]) should be evaluated, and... 

Fig. 2 Tabular representation of preclinical and clinical testing phases of drug development at which new compounds have been showed to fail for toxicokinetic and safety reasons. The data show profiles between 1997 and 2001, and also indicate the proportional contribution of safety vs. efficacy testing during drug development.

Integration of Pharmacokinetics, Pharmacodynamics, and Toxicokinetics in Rational Drug Development. Plenum Press New York and London, 1993. 

Assays supporting pharmacokinetic and toxicokinetic studies involve the measurement of the specific test article. Pharmacokinetic and toxicokinetic measurements are an important part of the drug development process since it is important to correlate the levels of drug in biological fluid with the dose. 

Toxicokinetics has become a critically important component of any nonclinical program (see discussion in Section 14.10). Current ICH guidelines require the determination of animal pharmacokinetics at all dose levels administered on at least 2 days (beginning and end) during a nonclinical toxicology study.5 Similarly, this requires the development of a validated analytical method for the determination of parent drug (and possible major metabolites). 

Physiologically Based Toxicokinetic (PBTK) models are derived similarly to Physiologically Based Pharmacokinetic (PBPK) models, which have been used for a number of years in the development of medicinal drugs. They describe the rat or man as a set of tissue compartments, i.e., liver, adipose tissues, poorly perfused tissues, and richly perfused tissues along with a description of metabolism in the liver. In case of volatile organic compounds a description of gas exchange at the level of the lung is included, see also Section 4.3.6. 

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