Coproporphyrins in Plasma and Urine Can Be Appropriate Clinical Biomarkers to Recapitulate Drug-Drug Interactions Mediated by Organic Anion Transporting Polypeptide Inhibition.
In the present study, an open-label, three-treatment, three-period 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 ± 0.21 and 0.15 ± 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 (Cmax) of CP-I and CP-III by 5.7- and 5.4-fold (RIF) or 5.7- and 6.5-fold (RIF+RSV), respectively, as compared with the predose values. The area under the plasma concentration curves from time 0 to 24 h (AUC0-24h) 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, Cmax and AUC0-24h 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.
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L., H.S., R.L., Y.C., P.S., J.D., W.G.H., P.M.); Bristol-Myers Squibb India Pvt. Ltd., Biocon Bristol-Myers Squibb Research and Development Center, Bangalore, India (Sa.M.); and Biocon BMS R&D Center, Syngene International Ltd., Bangalore, India (V.K.H., P.R., Se.M., N.G., S.S., O.D.) yurong.lai@bms.com.
Yurong
Y
Lai
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L., H.S., R.L., Y.C., P.S., J.D., W.G.H., P.M.); Bristol-Myers Squibb India Pvt. Ltd., Biocon Bristol-Myers Squibb Research and Development Center, Bangalore, India (Sa.M.); and Biocon BMS R&D Center, Syngene International Ltd., Bangalore, India (V.K.H., P.R., Se.M., N.G., S.S., O.D.).
Sandhya
S
Mandlekar
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L., H.S., R.L., Y.C., P.S., J.D., W.G.H., P.M.); Bristol-Myers Squibb India Pvt. Ltd., Biocon Bristol-Myers Squibb Research and Development Center, Bangalore, India (Sa.M.); and Biocon BMS R&D Center, Syngene International Ltd., Bangalore, India (V.K.H., P.R., Se.M., N.G., S.S., O.D.).
Hong
H
Shen
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L., H.S., R.L., Y.C., P.S., J.D., W.G.H., P.M.); Bristol-Myers Squibb India Pvt. Ltd., Biocon Bristol-Myers Squibb Research and Development Center, Bangalore, India (Sa.M.); and Biocon BMS R&D Center, Syngene International Ltd., Bangalore, India (V.K.H., P.R., Se.M., N.G., S.S., O.D.).
Vinay K
VK
Holenarsipur
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L., H.S., R.L., Y.C., P.S., J.D., W.G.H., P.M.); Bristol-Myers Squibb India Pvt. Ltd., Biocon Bristol-Myers Squibb Research and Development Center, Bangalore, India (Sa.M.); and Biocon BMS R&D Center, Syngene International Ltd., Bangalore, India (V.K.H., P.R., Se.M., N.G., S.S., O.D.).
Robert
R
Langish
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L., H.S., R.L., Y.C., P.S., J.D., W.G.H., P.M.); Bristol-Myers Squibb India Pvt. Ltd., Biocon Bristol-Myers Squibb Research and Development Center, Bangalore, India (Sa.M.); and Biocon BMS R&D Center, Syngene International Ltd., Bangalore, India (V.K.H., P.R., Se.M., N.G., S.S., O.D.).
Prabhakar
P
Rajanna
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L., H.S., R.L., Y.C., P.S., J.D., W.G.H., P.M.); Bristol-Myers Squibb India Pvt. Ltd., Biocon Bristol-Myers Squibb Research and Development Center, Bangalore, India (Sa.M.); and Biocon BMS R&D Center, Syngene International Ltd., Bangalore, India (V.K.H., P.R., Se.M., N.G., S.S., O.D.).
Senthilkumar
S
Murugesan
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L., H.S., R.L., Y.C., P.S., J.D., W.G.H., P.M.); Bristol-Myers Squibb India Pvt. Ltd., Biocon Bristol-Myers Squibb Research and Development Center, Bangalore, India (Sa.M.); and Biocon BMS R&D Center, Syngene International Ltd., Bangalore, India (V.K.H., P.R., Se.M., N.G., S.S., O.D.).
Nilesh
N
Gaud
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L., H.S., R.L., Y.C., P.S., J.D., W.G.H., P.M.); Bristol-Myers Squibb India Pvt. Ltd., Biocon Bristol-Myers Squibb Research and Development Center, Bangalore, India (Sa.M.); and Biocon BMS R&D Center, Syngene International Ltd., Bangalore, India (V.K.H., P.R., Se.M., N.G., S.S., O.D.).
Sabariya
S
Selvam
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L., H.S., R.L., Y.C., P.S., J.D., W.G.H., P.M.); Bristol-Myers Squibb India Pvt. Ltd., Biocon Bristol-Myers Squibb Research and Development Center, Bangalore, India (Sa.M.); and Biocon BMS R&D Center, Syngene International Ltd., Bangalore, India (V.K.H., P.R., Se.M., N.G., S.S., O.D.).
Onkar
O
Date
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L., H.S., R.L., Y.C., P.S., J.D., W.G.H., P.M.); Bristol-Myers Squibb India Pvt. Ltd., Biocon Bristol-Myers Squibb Research and Development Center, Bangalore, India (Sa.M.); and Biocon BMS R&D Center, Syngene International Ltd., Bangalore, India (V.K.H., P.R., Se.M., N.G., S.S., O.D.).
Yaofeng
Y
Cheng
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L., H.S., R.L., Y.C., P.S., J.D., W.G.H., P.M.); Bristol-Myers Squibb India Pvt. Ltd., Biocon Bristol-Myers Squibb Research and Development Center, Bangalore, India (Sa.M.); and Biocon BMS R&D Center, Syngene International Ltd., Bangalore, India (V.K.H., P.R., Se.M., N.G., S.S., O.D.).
Petia
P
Shipkova
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L., H.S., R.L., Y.C., P.S., J.D., W.G.H., P.M.); Bristol-Myers Squibb India Pvt. Ltd., Biocon Bristol-Myers Squibb Research and Development Center, Bangalore, India (Sa.M.); and Biocon BMS R&D Center, Syngene International Ltd., Bangalore, India (V.K.H., P.R., Se.M., N.G., S.S., O.D.).
Jun
J
Dai
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L., H.S., R.L., Y.C., P.S., J.D., W.G.H., P.M.); Bristol-Myers Squibb India Pvt. Ltd., Biocon Bristol-Myers Squibb Research and Development Center, Bangalore, India (Sa.M.); and Biocon BMS R&D Center, Syngene International Ltd., Bangalore, India (V.K.H., P.R., Se.M., N.G., S.S., O.D.).
William G
WG
Humphreys
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L., H.S., R.L., Y.C., P.S., J.D., W.G.H., P.M.); Bristol-Myers Squibb India Pvt. Ltd., Biocon Bristol-Myers Squibb Research and Development Center, Bangalore, India (Sa.M.); and Biocon BMS R&D Center, Syngene International Ltd., Bangalore, India (V.K.H., P.R., Se.M., N.G., S.S., O.D.).
Punit
P
Marathe
D000328:Adult; D015415:Biomarkers / Q000097:blood / Q000652:urine; D003306:Coproporphyrins / Q000097:blood* / Q000652:urine*; D004347:Drug Interactions; D006801:Humans; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors*; D012293:Rifampin / Q000493:pharmacokinetics / Q000494:pharmacology*; D000068718:Rosuvastatin Calcium / Q000493:pharmacokinetics / Q000494:pharmacology*; D055815:Young Adult
D015415:Biomarkers; D003306:Coproporphyrins; D027361:Organic Anion Transporters; C026971:coproporphyrin III; C031467:coproporphyrin I; D000068718:Rosuvastatin Calcium; D012293:Rifampin