Prediction of human pharmacokinetic parameters using animal data and principles of allometry. A case using bicifadine, a non-narcotic analgesic, as an example.

Allometry scaling of preclinical pharmacokinetic parameters for bicifadine (CAS 71195-57-8), a novel non-narcotic analgesic, was performed to predict the human pharmacokinetic parameters of clearance (CL(iv) and CL(oral)) and volume of distribution (Vz). The metabolism pattern, biotransformation pathways, and the predominant urinary excretion of the formed metabolites of bicifadine were found to be similar amongst mice, rats, monkeys and humans facilitating the scaling process. The availability of gender specific data in the preclinical species rendered the prediction of bicifadine parameters in gender specific groups.

Irinotecan and its active metabolite, SN-38: review of bioanalytical methods and recent update from clinical pharmacology perspectives.

The introduction of irinotecan has revolutionized the applicability of camptothecins as predominant topoisomerase I inhibitor for anti-cancer therapy. The potent anti-tumor activity of irinotecan is due to rapid formation of an in vivo active metabolite, SN-38. Therefore, irinotecan is considered as a pro-drug to generate SN-38.

Allometric scaling of a metabolically complex camptothecin analog: differences in scaling of irinotecan and its active metabolite, SN-38.

Allometry has been extensively used in the modern day drug development scenario to predict the human relevant parameters (clearance, Cl, and volume of distribution at steady state, Vss) from animal data. The applicability of allometry in the prediction of human parameters for irinotecan (CAS 97682-44-5), an important topoisomerase I inhibitor, has been retrospectively investigated. Literature pharmacokinetic data has been gathered for both irinotecan and its main metabolite, SN-38 (CAS 86639-52-3), from several animal species.

Use of bile correction factors for allometric prediction of human pharmacokinetic parameters of torcetrapib, a facile cholesteryl ester transfer protein inhibitor.

Torcetrapib was the lead candidate belonging to the class of cholesteryl ester transfer protein (CETP) inhibitor which was being developed for the management of cardiovascular risk factors by raising HDL. The availability of pharmacokinetic parameters (clearance: CL/F, volume of distribution: Vd/F, elimination rate constant: K(el) and elimination half-life: t(l/2)) in mice, rats and monkeys, enabled the prediction of human parameter values using the well accepted tool of allometry. Although allometry work has been largely restricted to intravenous drugs, the present case of torcetrapib showed that allometry may be equally applicable to oral route.

Allometric modeling of ciclesonide, a nonhalogenated glucocorticoid, and its active metabolite, desisobutyrylciclesonide, using animal-derived pharmacokinetic parameters.

Ciclesonide, a novel glucocorticosteroid, through a rapid metabolism to desisobutyryl-ciclesonide (des-ciclesonide), provides an effective treatment option for asthma episodes by the inhaled route of administration. The availability of pharmacokinetic parameters (clearance [CL/F]; volume of distribution [Vd/F]; elimination half-life [T(½)]; and elimination rate constant [Kel]) in mice, rats, rabbits, and dogs enabled the prediction of human parameter values for des-ciclesonide using the well-accepted tool of allometry after intravenous administration of ciclesonide. However, as a result of the rapid conversion of ciclesonide, it was possible to perform allometry for the CL parameter only.

Allometric prediction of the human pharmacokinetic parameters for naveglitazar.

Compounds that belong to the class known as dual (alpha,gamma) peroxisome proliferator-activated receptors (PPARs) show interesting pharmacological properties--regulation of blood glucose, fatty acids, and lipid parameters. Using the recently published preclinical data of naveglitazar, an allometric method was used to predict the human pharmacokinetic parameters (CL/F and Vss/F). The predicted parameters were compared to observed/predicted values of other important dual (a,y) PPAR compounds.