PT  - JOURNAL ARTICLE
AU  - Yoko Franchetti
AU  - Thomas D Nolin
TI  - Simultaneous assessment of hepatic transport and metabolism pathways with a single probe using individualized PBPK modeling of <sup>14</sup>CO<sub>2</sub> production rate data
AID  - 10.1124/jpet.119.257212
DP  - 2019 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.119.257212
4099  - http://jpet.aspetjournals.org/content/early/2019/08/13/jpet.119.257212.short
4100  - http://jpet.aspetjournals.org/content/early/2019/08/13/jpet.119.257212.full
AB  - Erythromycin is a substrate of cytochrome P4503A4 (CYP3A4) and multiple drug transporters. Although clinical evidence suggests that uptake transport is likely to play a dominant role in erythromycin's disposition, the relative contributions of individual pathways are unclear. Phenotypic evaluation of multiple pathways generally requires a probe drug cocktail. This approach can result in ambiguous conclusions due to imprecision stemming from overlapping specificity of multiple drugs. We hypothesized that an individualized physiologically-based pharmacokinetic modeling approach incorporating 14CO2 production rates (iPBPK-R) of the erythromycin breath test (ERMBT) would enable us to differentiate the contribution of metabolic and transporter pathways to erythromycin disposition. A seven-compartmental PBPK model was built for 14C-erythromycin administered intravenously. Transporter and CYP3A4 clearance were embedded in hepatic compartments. 14CO2 production rates were simulated taking the first derivative of by-product 14CO2 concentrations. Parameters related non-renal elimination pathways were estimated by model fitting the ERMBT data of 12 healthy subjects individually. Optimized iPBPK-R models fit the individual rate data well. Using one probe, nine PBPK parameters were simultaneously estimated per individual. Maximum velocity of uptake transport, CYP3A4 clearance, total passive diffusion and others were found to collectively control 14CO2 production rates. The median CYP3A4 clearance was 12.2% of the input clearance. Males had lower CYP3A4 activity than females by 11.3%. We applied iPBPK-R to ERMBT data to distinguish and simultaneously estimate the activity of multiple non-renal elimination pathways in healthy subjects. The iPBPK-R framework is a novel tool for delineating rate-limiting and non-rate limiting elimination pathways using a single probe.SIGNIFICANCE STATEMENT Our developed individualized physiologically-based pharmacokinetic modeling approach incorporating rate data (iPBPK-R) enabled us to distinguish and simultaneously estimate the activity of multiple non-renal elimination pathways of erythromycin in healthy subjects. A new interpretation of ERMBT data was also obtained via iPBPK-R. We found that rate data has rich information allowing estimation of per-person PBPK parameters. This study serves as proof of principle that the iPBPK-R framework is a novel tool for delineating rate-limiting and non-rate limiting elimination pathways using a single probe. iPBPK-R can be applied to other rate-derived data beyond ERMBT. Potential areas of application include drug-drug interaction, pathophysiological effects on drug disposition, and the role of biomarkers on hemodialysis efficiency utilizing estimated adjustment factors with correlation analysis.