Coproporphyrins in Plasma and Urine Can Be Appropriate Clinical Biomarkers to Recapitulate Drug-Drug Interactions Mediated by Organic Anion Transporting Polypeptide Inhibition

Abstract

In the present study, an open-label, three-treatment, threeperiod clinical study of rosuvastatin (RSV) and rifampicin (RIF) when administered alone and in combination was conducted in 12 male healthy subjects to determine if coproporphyrin I (CP-I) and coproporphyrin III (CP-III) could serve as clinical biomarkers for organic anion transporting polypeptide 1B1 (OATP1B1) and 1B3 that belong to the solute carrier organic anion gene subfamily. Genotyping of the human OATP1B1 gene was performed in all 12 subjects and confirmed absence of OATP1B1*5 and OATP1B1*15 mutations. Average plasma concentrations of CP-I and CP-III prior to drug administration were 0.91 6 0.21 and 0.15 6 0.04 nM, respectively, with minimum fluctuation over the three periods. CP-I was passively eliminated, whereas CP-III was actively secreted from urine. Administration of RSV caused no significant changes in the plasma and urinary profiles of CP-I and CP-III. RIF markedly increased the maximum plasma concentration (C max ) of CP-I and CP-III by 5.7-and 5.4-fold (RIF) or 5.7-and 6.5-fold (RIF1RSV), respectively, as compared with the predose values. The area under the plasma concentration curves from time 0 to 24 h (AUC 0-24h ) of CP-I and CP-III with RIF and RSV increased by 4.0-and 3.3-fold, respectively, when compared with RSV alone. In agreement with this finding, C max and AUC 0-24h of RSV increased by 13.2-and 5.0-fold, respectively, when RIF was coadministered. Collectively, we conclude that CP-I and CP-III in plasma and urine can be appropriate endogenous biomarkers specifically and reliably reflecting OATP inhibition, and thus the measurement of these molecules can serve as a useful tool to assess OATP drug-drug interaction liabilities in early clinical studies.

Effect of OATP1B1/1B3 Inhibitor GDC‐0810 on the Pharmacokinetics of Pravastatin and Coproporphyrin I/III in Healthy Female Subjects

“…Because there was another dose of GDC‐0810 at 24 hours in Figure , an increase of coproporphyrin I and III levels would have been observed at about 28 hours if evaluable. Interestingly, the time to reach the peak concentration of coproporphyrins was different from those reported in the presence of rifampin . This suggests that the biomarker kinetic profile is partly determined by the perpetrator kinetic profiles (such as GDC‐0810 vs rifampin).…”

“…Recently, endogenous biomarkers of drug transporters have gained more interest from both industry and academia with a potential to replace or assist in prioritization of a dedicated DDI study and thus offering cost and time effectiveness. Multiple endogenous biomarkers of OATP1B1/1B3 have been suggested/proposed, including coproporphyrin I and III, conjugated and unconjugated bilirubin, conjugated metabolites of steroids, conjugated and unconjugated bile acids, fatty acid dicarboxylates tetradecanedioate and hexadecanedioate, thyroid hormones and their metabolites, and so on . Coproporphyrin I and III, which are porphyrin metabolites arising from heme synthesis, were recently reported to be the reasonable endogenous biomarkers correlating with OATP1B function .…”

Quantitative Prediction of OATP‐Mediated Drug‐Drug Interactions With Model‐Based Analysis of Endogenous Biomarker Kinetics

“…Plasma concentration‐time profiles of CPI in the presence of rifampin or GDC‐0810 were used for model‐based analysis. General workflow of the model‐based analysis of CPI kinetics and the prediction of clinical DDIs is described in Figure .…”

“…These have been used as clinical diagnosis markers for Rotor syndrome, and a recent study demonstrated that genetic OATP1B deficiency causes Rotor syndrome . Lai et al . first demonstrated that CPI and CPIII showed comparable levels of increases in exposures as that of rosuvastatin, an OATP1B probe substrate, in the presence of OATP1B inhibitor rifampin in humans.…”

Transporter Role in Drug Efficacy and Organ Toxicity: Four Pillars of Clinical Trial Survival

“…Discovery of endogenous probes that could reflect the function of membrane transporters can greatly facilitate the understanding of transporter modulation in vivo [9]. The use of "omics" approaches, such as transcriptomics, proteomics or metabolomics becomes very popular tools to discover specific probes for monitoring transporter modulations or transporter related organ toxicity, despite very few endogenous probes for transporter function are available and data are controversial so far [10].…”