Plasma Carboxylesterase 1 Predicts Methylphenidate Exposure: A Proof-of-Concept Study Using Plasma Protein Biomarker for Hepatic Drug Metabolism

Abstract

Hepatic drug-metabolizing enzymes (DMEs) play critical roles in determining the pharmacokinetics and pharmacodynamics of numerous therapeutic agents. As such, noninvasive biomarkers capable of predicting DME expression in the liver have the potential to be used to personalize pharmacotherapy and improve drug treatment outcomes. In the present study, we quantified carboxylesterase 1 (CES1) protein concentrations in plasma samples collected during a methylphenidate pharmacokinetics study. CES1 is a prominent hepatic enzyme responsible for the metabolism of many medications containing small ester moieties, including methylphenidate. The results revealed a significant inverse correlation between plasma CES1 protein concentrations and the area under the concentration-time curves (AUCs) of plasma d-methylphenidate (P = 0.014, r = -0.617). In addition, when plasma CES1 protein levels were normalized to the plasma concentrations of 24 liver-enriched proteins to account for potential interindividual differences in hepatic protein release rate, the correlation was further improved (P = 0.003, r = -0.703), suggesting that plasma CES1 protein could explain ~ 50% of the variability in d-methylphenidate AUCs in the study participants. A physiologically-based pharmacokinetic modeling simulation revealed that the CES1-based individualized dosing strategy might significantly reduce d-methylphenidate exposure variability in pediatric patients relative to conventional trial and error fixed dosing regimens. This proof-of-concept study indicates that the plasma protein of a hepatic DME may serve as a biomarker for predicting its metabolic function and the pharmacokinetics of its substrate drugs.

Figure 1.

Overall study design. Plasma samples were collected from 15 healthy subjects who received a single dose of modified-release dl-MPH (40 mg). d-MPH PK analysis was performed in a previously published study. Plasma samples were subjected to the targeted quantification of CES1 proteins and global untargeted proteomics analysis. Plasma CES1 concentrations were furthered normalized by the plasma levels of liver-enriched proteins. The correlations between d-MPH AUCs and both unnormalized and normalized CES1 plasma concentrations were determined.

Figure 2.

Plasma concentrations of CES1 protein before (left panel) and after normalization (right panel) to the plasma concentrations of liver-enriched proteins.

Figure 3.

Heatmap of plasma concentrations of the 24 liver-enriched proteins used for CES1 plasma concentration normalization in individual subjects.

Figure 4.

Correlations between d-MPH AUCs and plasma CES1 protein concentrations (A) and plasma CES1 concentrations normalized to liver-enriched proteins (B) in subjects who received a single dose of modified-release dl-MPH (40 mg) (n = 15).

Figure 5.

PBPK modeling simulation of d-MPH plasma concentration-time profiles in pediatric patients who received a single oral fixed or individualized dose of immediate-release dl-MPH (20 mg). The solid lines and shaded areas represent the mean values and the 95% confidence intervals, respectively, of the simulated plasma concentrations in the virtual pediatric populations.