title: Prediction of renal transporter mediated drug-drug interactions for pemetrexed using physiologically based pharmacokinetic modeling.
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/m(2) 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.
authors.affiliation: 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.) posada_maria_mercedes@lilly.com.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Posada
authors.affiliation: 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.).
authors.forename: James A
authors.initials: JA
authors.lastname: Bacon
authors.affiliation: 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.).
authors.forename: Karen B
authors.initials: KB
authors.lastname: Schneck
authors.affiliation: 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.).
authors.forename: Rommel G
authors.initials: RG
authors.lastname: Tirona
authors.affiliation: 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.).
authors.forename: Richard B
authors.initials: RB
authors.lastname: Kim
authors.affiliation: 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.).
authors.forename: J William
authors.initials: JW
authors.lastname: Higgins
authors.affiliation: 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.).
authors.forename: Y Anne
authors.initials: YA
authors.lastname: Pak
authors.affiliation: 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.).
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Hall
authors.affiliation: 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.).
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Hillgren
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism; D019540:Area Under Curve; D001692:Biological Transport / Q000502:physiology*; D045744:Cell Line, Tumor; D004347:Drug Interactions / Q000502:physiology*; D005260:Female; D005971:Glutamates / Q000378:metabolism* / Q000493:pharmacokinetics*; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D006367:HeLa Cells; D006801:Humans; D007052:Ibuprofen / Q000378:metabolism / Q000493:pharmacokinetics; D007668:Kidney / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism; D008875:Middle Aged; D008954:Models, Biological; D000068437:Pemetrexed
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D005971:Glutamates; D026901:Membrane Transport Proteins; D000068437:Pemetrexed; D006147:Guanine; D007052:Ibuprofen