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Research ArticleArticle

Prediction of Renal Transporter Mediated Drug-Drug Interactions for Pemetrexed Using Physiologically Based Pharmacokinetic Modeling

Maria M. Posada, James A. Bacon, Karen B. Schneck, Rommel G. Tirona, Richard B. Kim, J. William Higgins, Y. Anne Pak, Stephen D. Hall and Kathleen M. Hillgren
Drug Metabolism and Disposition March 2015, 43 (3) 325-334; DOI: https://doi.org/10.1124/dmd.114.059618
Maria M. Posada
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (M.M.P., J.A.B., K.B.S., J.W.H., Y.A.P., S.D.H., K.M.H.); and Division of Clinical Pharmacology, Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada (R.G.T., R.B.K.)
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James A. Bacon
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (M.M.P., J.A.B., K.B.S., J.W.H., Y.A.P., S.D.H., K.M.H.); and Division of Clinical Pharmacology, Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada (R.G.T., R.B.K.)
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Karen B. Schneck
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (M.M.P., J.A.B., K.B.S., J.W.H., Y.A.P., S.D.H., K.M.H.); and Division of Clinical Pharmacology, Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada (R.G.T., R.B.K.)
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Rommel G. Tirona
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (M.M.P., J.A.B., K.B.S., J.W.H., Y.A.P., S.D.H., K.M.H.); and Division of Clinical Pharmacology, Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada (R.G.T., R.B.K.)
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Richard B. Kim
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (M.M.P., J.A.B., K.B.S., J.W.H., Y.A.P., S.D.H., K.M.H.); and Division of Clinical Pharmacology, Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada (R.G.T., R.B.K.)
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J. William Higgins
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (M.M.P., J.A.B., K.B.S., J.W.H., Y.A.P., S.D.H., K.M.H.); and Division of Clinical Pharmacology, Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada (R.G.T., R.B.K.)
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Y. Anne Pak
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (M.M.P., J.A.B., K.B.S., J.W.H., Y.A.P., S.D.H., K.M.H.); and Division of Clinical Pharmacology, Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada (R.G.T., R.B.K.)
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Stephen D. Hall
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (M.M.P., J.A.B., K.B.S., J.W.H., Y.A.P., S.D.H., K.M.H.); and Division of Clinical Pharmacology, Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada (R.G.T., R.B.K.)
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Kathleen M. Hillgren
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (M.M.P., J.A.B., K.B.S., J.W.H., Y.A.P., S.D.H., K.M.H.); and Division of Clinical Pharmacology, Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada (R.G.T., R.B.K.)
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Abstract

Pemetrexed, an anionic anticancer drug with a narrow therapeutic index, is eliminated mainly by active renal tubular secretion. The in vitro to in vivo extrapolation approach used in this work was developed to predict possible drug-drug interactions (DDIs) that may occur after coadministration of pemetrexed and nonsteroidal anti-inflammatory drugs (NSAIDs), and it included in vitro assays, risk assessment models, and physiologically based pharmacokinetic (PBPK) models. The pemetrexed transport and its inhibition parameters by several NSAIDs were quantified using HEK-PEAK cells expressing organic anion transporter (OAT) 3 or OAT4. The NSAIDs were ranked according to their DDI index, calculated as the ratio of their maximum unbound concentration in plasma over the concentration inhibiting 50% (IC50) of active pemetrexed transport. A PBPK model for ibuprofen, the NSAID with the highest DDI index, was built incorporating active renal secretion in Simcyp Simulator. The bottom-up model for pemetrexed underpredicted the clearance by 2-fold. The model we built using a scaling factor of 5.3 for the maximal uptake rate (Vmax) of OAT3, which estimated using plasma concentration profiles from patients given a 10-minute infusion of 500 mg/m2 of pemetrexed supplemented with folic acid and vitamin B12, recovered the clinical data adequately. The observed/predicted increases in Cmax and the area under the plasma-concentration time curve (AUC0–inf) of pemetrexed when ibuprofen was coadministered were 1.1 and 1.0, respectively. The coadministration of all other NSAIDs was predicted to have no significant impact on the AUC0–inf based on their DDI indexes. The PBPK model reasonably reproduced pemetrexed concentration time profiles in cancer patients and its interaction with ibuprofen.

Footnotes

    • Received July 21, 2014.
    • Accepted December 12, 2014.
  • dx.doi.org/10.1124/dmd.114.059618.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (3)
Drug Metabolism and Disposition
Vol. 43, Issue 3
1 Mar 2015
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Research ArticleArticle

Predicting Renal OAT-Mediated DDIs for Pemetrexed

Maria M. Posada, James A. Bacon, Karen B. Schneck, Rommel G. Tirona, Richard B. Kim, J. William Higgins, Y. Anne Pak, Stephen D. Hall and Kathleen M. Hillgren
Drug Metabolism and Disposition March 1, 2015, 43 (3) 325-334; DOI: https://doi.org/10.1124/dmd.114.059618

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Research ArticleArticle

Predicting Renal OAT-Mediated DDIs for Pemetrexed

Maria M. Posada, James A. Bacon, Karen B. Schneck, Rommel G. Tirona, Richard B. Kim, J. William Higgins, Y. Anne Pak, Stephen D. Hall and Kathleen M. Hillgren
Drug Metabolism and Disposition March 1, 2015, 43 (3) 325-334; DOI: https://doi.org/10.1124/dmd.114.059618
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