Utility of preclinical species for uncertainty assessment and correction of prediction of human volume of distribution using the Rodgers-Lukacova model

• Published in: Xenobiotica Vol. 52; no. 7; pp. 661 - 668
• Main Authors: Sherbetjian, Eva, Peters, Sheila-Annie, Petersson, Carl
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 03-07-2022
• Subjects: human PK prediction; PBPK; preclinical; Rodgers-Lukacova model; Volume of distribution (VD; PBPK; Volume of distribution (VDss); human PK prediction; Rodgers-Lukacova model; preclinical
• ISSN: 0049-8254; 1366-5928
• DOI: 10.1080/00498254.2022.2132427

Prediction of rat, dog, monkey, and human volume of distribution (VD
ss
) by Rodgers-Lukacova model was evaluated using a data set of more than 100 compounds.
The prediction accuracy was best for humans followed by monkeys and dogs with 59, 52, and 41% of compounds within 2-fold, respectively.
The accuracy of predictions in preclinical species was indicative of the human situation. This was particularly true for monkeys, where 87% of the compounds that were predicted within 2-fold in monkeys were also predicted within 2-fold in humans.
The model's tendency to underestimate VD
ss
was higher in rats and dogs compared to humans and monkeys for all ion classes but zwitterions. Hence, correction of human predictions using prediction errors in rats and dogs resulted in overestimation of VD
ss
.
The model had a similar degree of underestimation in humans and monkeys. Correction using monkeys improved the accuracy of the human estimate, especially for basic and zwitterion compounds.
A strategy is proposed based on the accuracy of prediction in monkey and monkey scalars for prediction and prospective assessment of the accuracy of human VD
ss
.