title: Prediction of human pharmacokinetic parameters using animal data and principles of allometry. A case using bicifadine, a non-narcotic analgesic, as an example.
abstract: 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.
authors.affiliation: Integrated Drug Development, Suramus Biopharm, Bangalore, India. srini.suramus@yahoo.com
authors.forename: Nuggehally R
authors.initials: NR
authors.lastname: Srinivas
authors.forename: Preeti
authors.initials: P
authors.lastname: Ahlawat
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000493:pharmacokinetics*; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics*; D005260:Female; D005544:Forecasting; D006207:Half-Life; D000882:Haplorhini; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism*; D010599:Pharmacokinetics; D051381:Rats; D012727:Sex Characteristics; D013045:Species Specificity
chemical_list: D000700:Analgesics; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004364:Pharmaceutical Preparations; C034438:bicifadine