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Population model for the pharmacokinetics of a series of compounds in human and monkey
Author(s) -
Chung John Inn,
ElKattan Ayman,
McKenzie Donald L,
Ware Joseph A,
Koup Jeffrey R
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1140-b
Subject(s) - nonmem , pharmacokinetics , volume of distribution , population , physiologically based pharmacokinetic modelling , distribution volume , distribution (mathematics) , dosing , chemistry , pharmacology , biology , medicine , mathematics , environmental health , mathematical analysis
A population pharmacokinetic (PK) model was developed to determine if monkeys could be used as an animal model to accurately predict human PK parameters (clearance, volume of distribution at steady state, and elimination half‐life) for a series of 10 structurally related, renally excreted, amino acid‐like compounds. Plasma concentration, time, and dosing data for six of the compounds were available for both monkeys and humans and were used to develop the model. Four of the compounds had this data for only monkeys and were included in the model development. The data was fitted with a standard 2‐compartment PK model with linear disposition using a mixed‐effects population PK model (NONMEM). Estimates of monkey and human clearance and volume of distribution were determined using allometric scaling based on body weight. Predicted human half‐lives were calculated with the clearance and volume distribution values estimated by the model and compared to those observed in humans. For three of the four compounds that had only monkey data, studies in humans were subsequently conducted to obtain human PK parameters and provided a test set for the PK model. The observed plasma levels in monkey and human versus time were well described by this model. Observed human half‐lives correlated well with predicted human values (r 2 = 0.9876). These results suggest that for the series of structurally related compounds studied, monkey is a useful animal model to predict human pharmacokinetic parameters and that renal active transport mechanisms are similar in monkeys and humans. This research was supported by Pfizer Global Research and Development.