There is a growing
interest in using endogenous compounds as drug
transporter biomarkers to facilitate drug–drug interaction
(DDI) risk assessment in early phase I clinical trials. Compared to
other drug transporters, however, no valid biomarker for hepatic organic
cation transporter (OCT) 1 has been described to date. The present
work represents the first report of an endogenous compound, isobutyryl-l-carnitine (IBC), as a potential clinical OCT1 biomarker for
DDI assessment. A hydrophilic interaction chromatography (HILIC)-mass
spectrometry/high resolution mass spectrometry (MS/HRMS) assay with
a simple sample preparation method was developed. The assay is capable
of simultaneously quantifying multiple endogenous compounds, including
IBC, thiamine, N1-methylnicotinamide (1-NMN), creatinine,
carnitine, and metformin, which is a probe for OCT1 and OCT2 and MATE1
and MATE2K (multidrug and toxin extrusion proteins) in clinical studies.
The HRMS assay was fit-for-purpose validated in human plasma and demonstrated
good linearity, accuracy, and precision for all analytes. It was further
applied to two phase I clinical trials to evaluate potential biomarkers
for OCT1 and additional cation transporters (renal OCT2, MATE1, and
MATE2K). The clinical data demonstrated that plasma IBC changes correlated
well with in vitro data and supported its use as
a liver OCT1 biomarker. The described HILIC-MS/HRMS assay can be used
as a “biomarker cocktail” to simultaneously assess clinical
DDI risk for the inhibition of OCT1/2 and MATEs in clinical studies
with new drug candidates.
Endogenous biomarkers are emerging to advance clinical drug-drug interaction (DDI) risk assessment in drug development. Twelve healthy subjects received a multidrug and toxin exclusion protein (MATE) inhibitor (pyrimethamine, 10, 25, and 75 mg) in a crossover fashion to identify an appropriate endogenous biomarker to assess MATE1/2-K-mediated DDI in the kidneys. Metformin (500 mg) was also given as reference probe drug for MATE1/2-K. In addition to the previously reported endogenous biomarker candidates (creatinine and N 1methylnicotinamide (1-NMN)), N 1-methyladenosine (m 1 A) was included as novel biomarkers. 1-NMN and m 1 A presented as superior MATE1/2-K biomarkers since changes in their renal clearance (CL r) along with pyrimethamine dose were well-correlated with metformin CL r changes. The CL r of creatinine was reduced by pyrimethamine, however, its changes poorly correlated with metformin CL r changes. Nonlinear regression analysis (CL r vs. mean total concentration of pyrimethamine in plasma) yielded an estimate of the inhibition constant (K i) of pyrimethamine and the fraction of the clearance pathway sensitive to pyrimethamine. The in vivo K i value thus obtained was further converted to unbound Ki using plasma unbound fraction of pyrimethamine, which was comparable to the in vitro K i for MATE1 (1-NMN) and MATE2-K (1-NMN and m 1 A). It is concluded that 1-NMN and m 1 A CL r can be leveraged as quantitative MATE1/2-K biomarkers for DDI risk assessment in healthy volunteers.
Aim: Novel urinary biomarker evaluation approaches to support inhibition assessment for renal transporters (e.g., OCT2, multidrug and toxin extrusion proteins [MATEs]). Methods: Highly sensitive and robust hydrophilic interaction chromatography–MS/high-resolution MS assays, for urine and plasma, were developed and characterized to evaluate transporter biomarkers including N1-methyladenosine and N1-methylnicotinamide. Results: The assays were simple and reliable with good selectivity and sensitivity, and successfully supported a clinical drug–drug interaction study with a drug candidate that presented in vitro inhibition of OCT2 and MATEs. Conclusion: The multiplexed assays enable a performance comparison, including biomarker specificity and sensitivity, that should increase the confidence in early clinical OCT2/MATEs drug–drug interaction risk assessment.
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