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. Simple allometry (CL = 4.781W°·7874; R² = 0.9968) appeared to predict the CL of ciclesonide in close proximity of the observed value (observed: 101.25 L/h versus predicted: 135.62 L/h). In a similar manner, simple allometry predicted the human pharmacokinetic parameters of des-ciclesonide (CL/F, Vd/F, T(½), and Kel) within a two- to threefold range of the observed values. The allometric equations for des-ciclesonide parameter values were: CL/F = 4.8166W°·49² (R² = 0.8598); Vd/F = 19.052W°·6³² (R² = 0.9049); T(½) = 3.7598W⁻°·¹6¹¹(R² = 0.8551); and Kel = 0.1832W°·¹596 (R² = 0.8632). In conclusion, the data suggested that allometry tool may be amenable for the prediction of the pharmacokinetic parameters of des-ciclesonide despite differences in the conversion rates and bioavailability of the active metabolite in various animal species.

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. Over the past decade, side-by-side with the clinical advancement of the use of irinotecan in the oncology field, a plethora of bioanalytical methods have been published to quantify irinotecan, SN-38 and other metabolites. Because of the availability of HPLC, LC-MS and LC-MS/MS methods, the pharmacokinetic profiling of irinotecan and its metabolites has been accomplished in multiple species, including cancer patients. The developed assays continue to find use in the optimization of newly designed delivery systems with regard to pharmacokinetics to promote safe and effective use of either irinotecan or SN-38. This review intends to: firstly, provide an exhaustive compilation of the published assays for irinotecan, SN-38 and other metabolite(s) of irinotecan, as applicable; secondly, to enumerate the validation parameters and applicable conclusions; and thirdly, provide some recent perspectives in the clinical pharmacology arena pertaining to efflux transporters, pediatric profiling, role of kidney function in defining toxicity, drug-drug interaction potential of irinotecan, etc.

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. The corresponding human parameters were predicted using allometry (Cl and Vss for irinotecan; Cl/F for SN-38). Although irinotecan has a complex metabolism and disposition profile, it appeared that simple allometry predicted satisfactorily the human values for Cl (1.7648W(0.669)) and Vss (3.1277W(0.9044)) for irinotecan. On the contrary, Cl/F for SN-38 was over predicted by simple allometry (53.389W(1.2773)); and the applicability of bile correction factor rendered Cl/F of SN-38 to be closer to the observed human value (8.9641W(1.3108)). The investigation suggests that prospective allometric approaches may aid in the development of future compounds in this important pharmacological and chemical class of cytotoxics.

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. Simple allometry appeared to markedly inflate the human parameters for CL/F, Vd/F, K(el), and t(1/2). However, the application of bile correction factors provided allometric equations of 0.2486W(0.877) (R2 = 0.9416), 1.4723W(1.8263) (R2 = 0.8873), 0.1685W(-095) (R2 = 0.828) and 4.1044W(0.493) (R2 = 0.9337) for CL/F, Vd/F, K(el) and t(1/2), rendering a closer prediction of human parameter values. Accordingly, the predicted (observed) values of torcetrapib were 10.3 L/h (15.8 L/h), 3449 L (4810 L), 0.00298 h(-1) (0.00328 h(-1)) and 211 h (231 h) for CL/F, Vd/F, K(el) and t(1/2), respectively. In summary, the data suggested that allometry tool with appropriate bile correction factors could be effectively used in a prospective manner for other orally administered CETP inhibitors.

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. The human parameters for CL(iv),Vz, and CL(oral) were predicted by allometric equations: 1.5252W(0.742) (R2 = 0.9989), 1.3489W(0.8484) (R2 = 0.9896), 3.2516W(0.7694) (R2 = 0.9875), respectively. The absolute bioavailability for bicifadine was estimated to be approximately 67%. The predicted CL(oral) (95 L/h) was within 45% of the human reported value (59 L/h). Overall, based on the closeness of allometric exponents (within 15% of suggested values), simple allometry approach could be used to prospectively predict the human pharmacokinetic parameters of bicifadine with confidence.

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. The allometry data suggested that naviglitazar (CL/F) was at least 4 times faster than that of ragaglitazar, while the Vss was either equal to or 40% lower as compared to that of ragaglitazar.