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Predictive Value of Microdose Pharmacokinetics

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Abstract

Phase 0 microdose trials are exploratory studies to early assess human pharmacokinetics of new chemical entities, while limiting drug exposure and risks for participants. The microdose concept is based on the assumption that microdose pharmacokinetics can be extrapolated to pharmacokinetics of a therapeutic dose. However, it is unknown whether microdose pharmacokinetics are actually indicative of the pharmacokinetics at therapeutic dose. The aim of this review is to investigate the predictive value of microdose pharmacokinetics and to identify drug characteristics that may influence the scalability of these parameters. The predictive value of microdose pharmacokinetics was determined for 46 compounds and showed adequate predictability for 28 of 41 orally administered drugs (68%) and 15 of 16 intravenously administered drugs (94%). Microdose pharmacokinetics were considered predictive if the mean observed values of the microdose and the therapeutic dose were within twofold. Nonlinearity may be caused by saturation of enzyme and transporter systems, such as intestinal and hepatic efflux and uptake transporters. The high degree of success regarding linear pharmacokinetics shows that phase 0 microdose trials can be used as an early human model for determination of drug pharmacokinetics.

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References

  1. Dickson M, Gagnon JP. The cost of new drug discovery and development. Discov Med. 2004;4:172–9.

    PubMed  Google Scholar 

  2. Tonkens R. An overview of the drug development process. Physician Exec. 2005;31:48–52.

    PubMed  Google Scholar 

  3. Kola I, Landis J. Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov. 2004;3:711–5.

    CAS  PubMed  Google Scholar 

  4. Kola I. The state of innovation in drug development. Clin Pharmacol Ther. 2008;83:227–30.

    CAS  PubMed  Google Scholar 

  5. Rowland M, Benet LZ. Lead PK commentary: predicting human pharmacokinetics. J Pharm Sci. 2011;100:4047–9.

    CAS  PubMed  Google Scholar 

  6. Poulin P, Jones HM, Do Jones R, Yates JWT, Gibson CR, Chien JY, et al. PhRMA CPCDC initiative on predictive models of human pharmacokinetics, part 1: goals, properties of the PhRMA dataset, and comparison with literature datasets. J Pharm Sci. 2011;100:4050–73.

    CAS  PubMed  Google Scholar 

  7. Nair A, Morsy MA, Jacob S. Dose translation between laboratory animals and human in preclinical and clinical phases of drug development. Drug Dev Res. 2018. https://doi.org/10.1002/ddr.21461 (Epub 21 Oct 2018).

    Article  PubMed  Google Scholar 

  8. FDA/CDER. Guidance for industry, investigators, and reviewers: exploratory IND studies. Biotechnol Law Rep. 2006;25:167–74.

    Google Scholar 

  9. Lappin G, Noveck R, Burt T. Microdosing and drug development: past, present and future. Expert Opin Drug Metab Toxicol. 2013;9:817–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Benet LZ, Broccatelli F, Oprea TI. BDDCS applied to over 900 drugs. AAPS J. 2011;13:519–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Lappin G, Garner RC. The utility of microdosing over the past 5 years. Expert Opin Drug Metab Toxicol. 2008;4:1499–506.

    CAS  PubMed  Google Scholar 

  12. Rowland M. Commentary on ACCP position statement on the use of microdosing in the drug development process. J Clin Pharmacol. 2007;47:1595–6.

    PubMed  Google Scholar 

  13. Maeda K, Takano J, Ikeda Y, Fujita T, Oyama Y, Nozawa K, et al. Nonlinear pharmacokinetics of oral quinidine and verapamil in healthy subjects: a clinical microdosing study. Clin Pharmacol Ther. 2011;90:263–70.

    CAS  PubMed  Google Scholar 

  14. Ieiri I, Doi Y, Maeda K, Sasaki T, Kimura M, Hirota T, et al. Microdosing clinical study: pharmacokinetic, pharmacogenomic (SLCO2B1), and interaction (grapefruit juice) profiles of celiprolol following the oral microdose and therapeutic dose. J Clin Pharmacol. 2012;52:1078–89.

    CAS  PubMed  Google Scholar 

  15. Kajinami K, Takeda K, Maeda K, Sugiyama Y, Ieir I, Masaugi T, et al. SLCO1B1 polymorphisms affect atorvastatin pharmacokinetics and cholesterol-lowering effects in patients with hypercholesterolemia in a microdosing approach. Eur Heart. 2013;34:1.

    Google Scholar 

  16. Maeda K, Ikeda Y, Fujita T, Yoshida K, Azuma Y, Haruyama Y, et al. Identification of the rate-determining process in the hepatic clearance of atorvastatin in a clinical cassette microdosing study. Clin Pharmacol Ther. 2011;90:575–81.

    CAS  PubMed  Google Scholar 

  17. Lappin G, Shishikura Y, Jochemsen R, Weaver RJ, Gesson C, Brian Houston J, et al. Comparative pharmacokinetics between a microdose and therapeutic dose for clarithromycin, sumatriptan, propafenone, paracetamol (acetaminophen), and phenobarbital in human volunteers. Eur J Pharm Sci. 2011;43:141–50.

    CAS  PubMed  Google Scholar 

  18. Cho D-Y, Bae SHK, Shon J-H, Bae SHK. High-sensitive LC-MS/MS method for the simultaneous determination of mirodenafil and its major metabolite, SK-3541, in human plasma: application to microdose clinical trials of mirodenafil. J Sep Sci. 2013;362:840–8.

    Google Scholar 

  19. Ieiri I, Nishimura C, Maeda K, Sasaki T, Kimura M, Chiyoda T, et al. Pharmacokinetic and pharmacogenomic profiles of telmisartan after the oral microdose and therapeutic dose. Pharmacogenet Genom. 2011;21:495–505.

    CAS  Google Scholar 

  20. Yamashita S, Kataoka M, Suzaki Y, Imai H, Morimoto T, Ohashi K, et al. An assessment of the oral bioavailability of three Ca-channel blockers using a cassette-microdose study: a new strategy for streamlining oral drug development. J Pharm Sci. 2015;104:3154–61.

    CAS  PubMed  Google Scholar 

  21. Prueksaritanont T, Tatosian DA, Chu X, Railkar R, Evers R, Chavez-Eng C, et al. Validation of a microdose probe drug cocktail for clinical drug interaction assessments for drug transporters and CYP3A. Clin Pharmacol Ther. 2017;101:519–30.

    CAS  PubMed  Google Scholar 

  22. Park G-J, Bae SH, Park W-S, Han S, Park M-H, Shin S-H, et al. Drug–drug interaction of microdose and regular-dose omeprazole with a CYP2C19 inhibitor and inducer. Drug Des Dev Ther. 2017;11:1043–53.

    CAS  Google Scholar 

  23. Yamane N, Tozuka Z, Sugiyama Y, Tanimoto T, Yamazaki A, Kumagai Y. Microdose clinical trial: quantitative determination of nicardipine and prediction of metabolites in human plasma. Drug Metab Pharmacokinet. 2009;24:389–403.

    CAS  PubMed  Google Scholar 

  24. Lappin G, Kuhnz W, Jochemsen R, Kneer J, Chaudhary A, Oosterhuis B, et al. Use of microdosing to predict pharmacokinetics at the therapeutic dose: experience with 5 drugs. Clin Pharmacol Ther. 2006;80:203–15.

    CAS  PubMed  Google Scholar 

  25. Fujita K-I, Yoshino E, Kawara K, Maeda K, Kusuhara H, Sugiyama Y, et al. A clinical pharmacokinetic microdosing study of docetaxel with Japanese patients with cancer. Cancer Chemother Pharmacol. 2015;76:793–801.

    CAS  PubMed  Google Scholar 

  26. Ikeda T, Aoyama S, Tozuka Z, Nozawa K, Hamabe Y, Matsui T, et al. Microdose pharmacogenetic study of (14)C-tolbutamide in healthy subjects with accelerator mass spectrometry to examine the effects of CYP2C9*3 on its pharmacokinetics and metabolism. Eur J Pharm Sci. 2013;49:642–8.

    CAS  PubMed  Google Scholar 

  27. Chen J, Flexner C, Liberman RG, Skipper PL, Louissaint NA, Tannenbaum SR, et al. Biphasic elimination of tenofovir diphosphate and nonlinear pharmacokinetics of zidovudine triphosphate in a microdosing study. J Acquir Immune Defic Syndr. 2012;61:593–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Kusuhara H, Ito S, Kumagai Y, Jiang M, Shiroshita T, Moriyama Y, et al. Effects of a MATE protein inhibitor, pyrimethamine, on the renal elimination of metformin at oral microdose and at therapeutic dose in healthy subjects. Clin Pharmacol Ther. 2011;89:837–44.

    CAS  PubMed  Google Scholar 

  29. Harrison A, Gardner I, Hay T, Dickins M, Beaumont K, Phipps A, et al. Case studies addressing human pharmacokinetic uncertainty using a combination of pharmacokinetic simulation and alternative first in human paradigms. Xenobiotica. 2012;42:57–74.

    CAS  PubMed  Google Scholar 

  30. Seto C, Sakuma T, Ni J, Ouyang F, Lo L, Welty D, et al. Assessment of pharmacokinetic linearity of metabolites from a microdose to a normal dose. Drug Metab Rev. 2009;41:148–9.

    Google Scholar 

  31. Zhang L, Strong JM, Qiu W, Lesko LJ, Huang S-M. Scientific perspectives on drug transporters and their role in drug interactions. Mol Pharm. 2006;3:62–9.

    CAS  PubMed  Google Scholar 

  32. Kalliokoski A, Niemi M. Impact of OATP transporters on pharmacokinetics. Br J Pharmacol. 2009;158:693–705.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Do Jones R, Jones HM, Rowland M, Gibson CR, Yates JWT, Chien JY, et al. PhRMA CPCDC initiative on predictive models of human pharmacokinetics, part 2: comparative assessment of prediction methods of human volume of distribution. J Pharm Sci. 2011;100:4074–89.

    PubMed  Google Scholar 

  34. Ring BJ, Chien JY, Adkison KK, Jones HM, Rowland M, Do Jones R, et al. PhRMA CPCDC initiative on predictive models of human pharmacokinetics, part 3: comparative assessement of prediction methods of human clearance. J Pharm Sci. 2011;100:4090–110.

    CAS  PubMed  Google Scholar 

  35. Vuppugalla R, Marathe P, He H, Jones RDO, Yates JWT, Jones HM, et al. PhRMA CPCDC initiative on predictive models of human pharmacokinetics, part 4: prediction of plasma concentration-time profiles in human from in vivo preclinical data by using the Wajima approach. J Pharm Sci. 2011;100:4111–26.

    CAS  PubMed  Google Scholar 

  36. Poulin P, Jones RDO, Jones HM, Gibson CR, Rowland M, Chien JY, et al. PHRMA CPCDC initiative on predictive models of human pharmacokinetics, part 5: prediction of plasma concentration-time profiles in human by using the physiologically-based pharmacokinetic modeling approach. J Pharm Sci. 2011;100:4127–57.

    CAS  PubMed  Google Scholar 

  37. Vlaming MLH, van Duijn E, Dillingh MR, Brands R, Windhorst AD, Hendrikse NH, et al. Microdosing of a carbon-14 labeled protein in healthy volunteers accurately predicts its pharmacokinetics at therapeutic dosages. Clin Pharmacol Ther. 2015;98:196–204.

    CAS  PubMed  Google Scholar 

  38. Glassman PM, Balthasar JP. Mechanistic considerations for the use of monoclonal antibodies for cancer therapy. Cancer Biol Med. 2014;11:20–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Rowland M. Microdosing of protein drugs. Clin Pharmacol Ther. 2016;99:150–2.

    CAS  PubMed  Google Scholar 

  40. Dirks NL, Meibohm B. Population pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49:633–59.

    CAS  PubMed  Google Scholar 

  41. Smith DA, van Waterschoot RAB, Parrott NJ, Olivares-Morales A, Lave T, Rowland M. Importance of target-mediated drug disposition for small molecules. Drug Discov Today. 2018;23:2023–30.

    CAS  PubMed  Google Scholar 

  42. Bosgra S, Vlaming MLH, Vaes WHJ. To apply microdosing or not? Recommendations to single out compounds with non-linear pharmacokinetics. Clin Pharmacokinet. 2015;55:1–15.

    Google Scholar 

  43. Mahajan R, Parvez A, Gupta K. Microdosing vs. therapeutic dosing for evaluation of pharmacokinetic data: a comparative study. J Young Pharm. 2009;1:290.

    CAS  Google Scholar 

  44. Fujita K-I, Yoshino E, Kawara K, Maeda K, Kusuhara H, Sugiyama Y, et al. A clinical pharmacokinetic microdosing study of docetaxel with Japanese cancer patients. Eur J Cancer. 2015;51:S62.

    Google Scholar 

  45. Lappin G, Shishikura Y, Jochemsen R, Weaver RJ, Gesson C, Houston B, et al. Pharmacokinetics of fexofenadine: evaluation of a microdose and assessment of absolute oral bioavailability. Eur J Pharm Sci. 2010;40:125–31.

    CAS  PubMed  Google Scholar 

  46. Yamazaki A, Kumagai Y, Yamane N, Tozuka Z, Sugiyama Y, Fujita T, et al. Microdose study of a P-glycoprotein substrate, fexofenadine, using a non-radioisotope-labelled drug and LC/MS/MS. J Clin Pharm Ther. 2010;35:169–75.

    CAS  PubMed  Google Scholar 

  47. Hohmann N, Kocheise F, Carls A, Burhenne J, Haefeli W, Gerd M. Pharmacokinetics of an intravenous microgram dose of midazolam. Clin Pharmacol Ther. 2014;95:S45.

    Google Scholar 

  48. Hohmann N, Kocheise F, Carls A, Burhenne J, Haefeli WE, Mikus G. Midazolam microdose to determine systemic and pre-systemic metabolic CYP3A activity in humans. Br J Clin Pharmacol. 2015;79:278–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Halama B, Hohmann N, Burhenne J, Weiss J, Mikus G, Haefeli WE. A nanogram dose of the CYP3A probe substrate midazolam to evaluate drug interactions. Clin Pharmacol Ther. 2013;93:564–71.

    CAS  PubMed  Google Scholar 

  50. Madan A, O’Brien Z, Wen J, O’Brien C, Farber RH, Beaton G, et al. A pharmacokinetic evaluation of five H1 antagonists after an oral and intravenous microdose to human subjects. Br J Clin Pharmacol. 2009;67:288–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Garner CR, Park KB, French NS, Earnshaw C, Schipani A, Selby AM, et al. Observational infant exploratory [(14)C]-paracetamol pharmacokinetic microdose/therapeutic dose study with accelerator mass spectrometry bioanalysis. Br J Clin Pharmacol. 2015;80:157–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Jones HM, Butt RP, Webster RW, Gurrell I, Dzygiel P, Flanagan N, et al. Clinical micro-dose studies to explore the human pharmacokinetics of four selective inhibitors of human Nav1.7 voltage-dependent sodium channels. Clin Pharmacokinet. 2016;55:875–87.

    CAS  PubMed  Google Scholar 

  53. Stevens L, Evans P, Dueker S, Lostroh P, Giacomo J, Yeh L, et al. Microdose and microtracer intravenous pharmacokinetics of RDEA806 in healthy subjects. Clin Pharmacol Ther. 2009;85:S24–5.

    Google Scholar 

  54. Sun L, Li H, Willson K, Breidinger S, Rizk ML, Wenning L, et al. Ultrasensitive liquid chromatography−tandem mass spectrometric methodologies for quantification of five HIV-1 integrase inhibitors in plasma for a microdose clinical trial. Anal Chem. 2012;84:8614–21.

    CAS  PubMed  Google Scholar 

  55. Wagner CC, Simpson M, Zeitlinger M, Bauer M, Karch R, Abrahim A, et al. A combined accelerator mass spectrometry-positron emission tomography human microdose study with 14C- and 11C-labelled verapamil. Clin Pharmacokinet. 2011;50:111–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Kaplan N, Garner C, Hafkin B. AFN-1252 in vitro absorption studies and pharmacokinetics following microdosing in healthy subjects. Eur J Pharm Sci. 2013;50:440–6.

    CAS  PubMed  Google Scholar 

  57. Hafkin B, Kaplan N, Hunt TL. Safety, tolerability and pharmacokinetics of AFN-1252 administered as immediate release tablets in healthy subjects. Future Microbiol. 2015;10:1805–13.

    CAS  PubMed  Google Scholar 

  58. Kusuhara H, Takashima T, Fujii H, Takashima T, Tanaka M, Ishii A, et al. Comparison of pharmacokinetics of newly discovered aromatase inhibitors by a cassette microdosing approach in healthy Japanese subjects. Drug Metab Pharmacokinet. 2017;32:293–300.

    CAS  PubMed  Google Scholar 

  59. Nomura Y, Koyama H, Ohashi Y, Watanabe H. Clinical dosage determination of a new aromatase inhibitor, anastrozole, in postmenopausal Japanese women with advanced breast cancer. Clin Drug Investig. 2000;20:357–69.

    CAS  Google Scholar 

  60. Lau YY, Huang Y, Frassetto L, Benet LZ. Effect of OATP1B transporter inhibition on the pharmacokinetics of atorvastatin in healthy volunteers. Clin Pharmacol Ther. 2007;81:194–204.

    CAS  PubMed  Google Scholar 

  61. Croft M, Keely B, Morris I, Tann L, Lappin G, et al. Predicting drug candidate victims of drug–drug interactions, using microdosing. Clin Pharmacokinet. 2012;51:237–46.

    CAS  PubMed  Google Scholar 

  62. Culm-Merdek KE, von Moltke LL, Harmatz JS, Greenblatt DJ. Fluvoxamine impairs single-dose caffeine clearance without altering caffeine pharmacodynamics. Br J Clin Pharmacol. 2005;60:486–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Perera V, Gross AS, Xu H, McLachlan AJ. Pharmacokinetics of caffeine in plasma and saliva, and the influence of caffeine abstinence on CYP1A2 metrics. J Pharm Pharmacol. 2011;63:1161–8.

    CAS  PubMed  Google Scholar 

  64. Amchin J, Zarycranski W, Taylor KP, Albano D, Klockowski PM. Effect of venlafaxine on CYP1A2-dependent pharmacokinetics and metabolism of caffeine. J Clin Pharmacol. 1999;39:252–9.

    CAS  PubMed  Google Scholar 

  65. Friedman H, Greenblatt DJ, Peters GR, Metzler CM, Charlton MD, Harmatz JS, et al. Pharmacokinetics and pharmacodynamics of oral diazepam: effect of dose, plasma concentration, and time. Clin Pharmacol Ther. 1992;52:139–50.

    CAS  PubMed  Google Scholar 

  66. Spector R, Choudhury AK, Chiang CK, Goldberg MJ, Ghoneim MM. Diphenhydramine in orientals and caucasians. Clin Pharmacol Ther. 1980;28:229–34.

    CAS  PubMed  Google Scholar 

  67. Blyden GT, Greenblatt DJ, Scavone JM, Shader RI. Pharmacokinetics of diphenhydramine and a demethylated metabolite following intravenous and oral administration. J Clin Pharmacol. 1986;26:529–33.

    CAS  PubMed  Google Scholar 

  68. Scavone JM, Luna BG, Harmatz JS, von Moltke L, Greenblatt DJ. Diphenhydramine kinetics following intravenous, oral, and sublingual dimenhydrinate administration. Biopharm Drug Dispos. 1990;11:185–9.

    CAS  PubMed  Google Scholar 

  69. Simons KJ, Watson WT, Martin TJ, Chen XY, Simons FE. Diphenhydramine: pharmacokinetics and pharmacodynamics in elderly adults, young adults, and children. J Clin Pharmacol. 1990;30:665–71.

    CAS  PubMed  Google Scholar 

  70. Meredith CG, Christian CDJ, Johnson RF, Madhavan SV, Schenker S. Diphenhydramine disposition in chronic liver disease. Clin Pharmacol Ther. 1984;35:474–9.

    CAS  PubMed  Google Scholar 

  71. Zhou X-J, Garner RC, Nicholson S, Kissling CJ, Mayers D. Microdose pharmacokinetics of IDX899 and IDX989, candidate HIV-1 non-nucleoside reverse transcriptase inhibitors, following oral and intravenous administration in healthy male subjects. J Clin Pharmacol. 2009;49:1408–16.

    CAS  PubMed  Google Scholar 

  72. Zhou X-J, Pietropaolo K, Damphousse D, Belanger B, Chen J, Sullivan-Bolyai J, et al. Single-dose escalation and multiple-dose safety, tolerability, and pharmacokinetics of IDX899, a candidate human immunodeficiency virus type 1 nonnucleoside reverse transcriptase inhibitor, in healthy subjects. Antimicrob Agents Chemother. 2009;53:1739–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Nguyen MA, Staubach P, Wolffram S, Langguth P. The influence of single-dose and short-term administration of quercetin on the pharmacokinetics of midazolam in humans. J Pharm Sci. 2015;104:3199–207.

    CAS  PubMed  Google Scholar 

  74. Kuwano K, Hashino A, Asaki T, Hamamoto T, Yamada T, Okubo K, et al. 2-{4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl) acetamide (NS-304), an orally available and long-acting prostacyclin receptor agonist prodrug. J Pharmacol Exp Ther. 2007;322:1181–8.

    CAS  PubMed  Google Scholar 

  75. Kaufmann P, Okubo K, Bruderer S, Mant T, Yamada T, Dingemanse J, et al. Pharmacokinetics and tolerability of the novel oral prostacyclin IP receptor agonist selexipag. Am J Cardiovasc Drugs. 2015;15:195–203.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Tozuka Z, Kusuhara H, Nozawa K, Hamabe Y, Ikushima I, Ikeda T, et al. Microdose study of 14C-acetaminophen with accelerator mass spectrometry to examine pharmacokinetics of parent drug and metabolites in healthy subjects. Clin Pharmacol Ther. 2010;88:824–30.

    CAS  PubMed  Google Scholar 

  77. Kapitza C, Zdravkovic M, Hindsberger C, Flint A. The effect of the once-daily human glucagon-like peptide 1 analog liraglutide on the pharmacokinetics of acetaminophen. Adv Ther. 2011;28:650–60.

    CAS  PubMed  Google Scholar 

  78. Shinoda S, Aoyama T, Aoyama Y, Tomioka S, Matsumoto Y, Ohe Y. Pharmacokinetics/pharmacodynamics of acetaminophen analgesia in Japanese patients with chronic pain. Biol Pharm Bull. 2007;30:157–61.

    CAS  PubMed  Google Scholar 

  79. Stangier J, Su CA, Fraunhofer A, Tetzloff W. Pharmacokinetics of acetaminophen and ibuprofen when coadministered with telmisartan in healthy volunteers. J Clin Pharmacol. 2000;40:1338–46.

    CAS  PubMed  Google Scholar 

  80. Rawlins MD, Henderson DB, Hijab AR. Pharmacokinetics of paracetamol (acetaminophen) after intravenous and oral administration. Eur J Clin Pharmacol. 1977;11:283–6.

    CAS  PubMed  Google Scholar 

  81. Albert KS, Sedman AJ, Wilkinson P, Stoll RG, Murray WJ, Wagner JG. Bioavailability studies of acetaminophen and nitrofurantoin. J Clin Pharmacol. 1974;14:264–70.

    CAS  PubMed  Google Scholar 

  82. Viswanathan CT, Booker HE, Welling PG. Pharmacokinetics of phenobarbital following single and repeated doses. J Clin Pharmacol. 1979;19:282–9.

    CAS  PubMed  Google Scholar 

  83. Prueksaritanont T, Chu X, Evers R, Klopfer SO, Caro L, Kothare PA, et al. Pitavastatin is a more sensitive and selective organic anion-transporting polypeptide 1B clinical probe than rosuvastatin. Br J Clin Pharmacol. 2014;78:587–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Deng S, Chen X-P, Cao D, Yin T, Dai Z-Y, Luo J, et al. Effects of a concomitant single oral dose of rifampicin on the pharmacokinetics of pravastatin in a two-phase, randomized, single-blind, placebo-controlled, crossover study in healthy Chinese male subjects. Clin Ther. 2009;31:1256–63.

    CAS  PubMed  Google Scholar 

  85. Fukazawa I, Uchida N, Uchida E, Yasuhara H. Effects of grapefruit juice on pharmacokinetics of atorvastatin and pravastatin in Japanese. Br J Clin Pharmacol. 2004;57:448–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Ogawa K, Hasegawa S, Udaka Y, Nara K, Iwai S, Oguchi K. Individual difference in the pharmacokinetics of a drug, pravastatin, in healthy subjects. J Clin Pharmacol. 2003;43:1268–73.

    CAS  PubMed  Google Scholar 

  87. Sugimoto K, Ohmori M, Tsuruoka S, Nishiki K, Kawaguchi A, Harada K, et al. Different effects of St John’s wort on the pharmacokinetics of simvastatin and pravastatin. Clin Pharmacol Ther. 2001;70:518–24.

    CAS  PubMed  Google Scholar 

  88. Iwamoto M, Wenning LA, Petry AS, Laethem M, De Smet M, Kost JT, et al. Safety, tolerability, and pharmacokinetics of raltegravir after single and multiple doses in healthy subjects. Clin Pharmacol Ther. 2008;83:293–9.

    CAS  PubMed  Google Scholar 

  89. Kirchheiner J, Bauer S, Meineke I, Rohde W, Prang V, Meisel C, et al. Impact of CYP2C9 and CYP2C19 polymorphisms on tolbutamide kinetics and the insulin and glucose response in healthy volunteers. Pharmacogenetics. 2002;12:101–9.

    CAS  PubMed  Google Scholar 

  90. Chen K, Wang R, Wen S-Y, Li J, Wang S-Q. Relationship of P450 2C9 genetic polymorphisms in Chinese and the pharmacokinetics of tolbutamide. J Clin Pharm Ther. 2005;30:241–9.

    CAS  PubMed  Google Scholar 

  91. Jetter A, Kinzig-Schippers M, Skott A, Lazar A, Tomalik-Scharte D, Kirchheiner J, et al. Cytochrome P450 2C9 phenotyping using low-dose tolbutamide. Eur J Clin Pharmacol. 2004;60:165–71.

    CAS  PubMed  Google Scholar 

  92. Uchida S, Yamada H, Li XD, Maruyama S, Ohmori Y, Oki T, et al. Effects of Ginkgo biloba extract on pharmacokinetics and pharmacodynamics of tolbutamide and midazolam in healthy volunteers. J Clin Pharmacol. 2006;46:1290–8.

    CAS  PubMed  Google Scholar 

  93. Chan E, McLachlan AJ, Pegg M, MacKay AD, Cole RB, Rowland M. Disposition of warfarin enantiomers and metabolites in patients during multiple dosing with rac-warfarin. Br J Clin Pharmacol. 1994;37:563–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Chen J, Garner RC, Lee LS, Seymour M, Fuchs EJ, Hubbard WC, et al. Accelerator mass spectrometry measurement of intracellular concentrations of active drug metabolites in human target cells in vivo. Clin Pharmacol Ther. 2010;88:796–800.

    CAS  PubMed  Google Scholar 

  95. Vuong LT, Ruckle JL, Blood AB, Reid MJ, Wasnich RD, Synal H-A, et al. Use of accelerator mass spectrometry to measure the pharmacokinetics and peripheral blood mononuclear cell concentrations of zidovudine. J Pharm Sci. 2008;97:2833–43.

    CAS  Google Scholar 

  96. Drugbank: AFN-1252. 2018 [cited 7 Jan 2019]. https://www.drugbank.ca/drugs/DB12658. Accessed 07 Jan 2019.

  97. Kamdem LK, Liu Y, Stearns V, Kadlubar SA, Ramirez J, Jeter S, et al. In vitro and in vivo oxidative metabolism and glucuronidation of anastrozole. Br J Clin Pharmacol. 2010;70:854–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Lazarus P, Sun D. Potential role of UGT pharmacogenetics in cancer treatment and prevention: focus on tamoxifen and aromatase inhibitors. Drug Metab Rev. 2010;42:182–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Miyajima M, Kusuhara H, Takahashi K, Takashima T, Hosoya T, Watanabe Y, et al. Investigation of the effect of active efflux at the blood–brain barrier on the distribution of nonsteroidal aromatase inhibitors in the central nervous system. J Pharm Sci. 2013;102:3309–19.

    CAS  PubMed  Google Scholar 

  100. Reeves PR, McAinsh J, McIntosh DA, Winrow MJ. Metabolism of atenolol in man. Xenobiotica. 1978;8:313–20.

    CAS  PubMed  Google Scholar 

  101. Yu J, Zhou Z, Tay-Sontheimer J, Levy RH, Ragueneau-Majlessi I. Intestinal drug interactions mediated by OATPs: a systematic review of preclinical and clinical findings. J Pharm Sci. 2017;106:2312–25.

    CAS  PubMed  Google Scholar 

  102. Arnaud MJ. Pharmacokinetics and metabolism of natural methylxanthines in animal and man. Handb Exp Pharmacol. 2011;200:33–91.

    CAS  Google Scholar 

  103. Nehlig A. Interindividual differences in caffeine metabolism and factors driving caffeine consumption. Pharmacol Rev. 2018;70:384–411.

    CAS  PubMed  Google Scholar 

  104. Rodrigues AD, Roberts EM, Mulford DJ, Yao Y, Ouellet D. Oxidative metabolism of clarithromycin in the presence of human liver microsomes. Major role for the cytochrome P4503A (CYP3A) subfamily. Drug Metab Dispos. 1997;25:623–30.

    CAS  PubMed  Google Scholar 

  105. Togami K, Chono S, Morimoto K. Transport characteristics of clarithromycin, azithromycin and telithromycin, antibiotics applied for treatment of respiratory infections, in Calu-3 cell monolayers as model lung epithelial cells. Pharmazie. 2012;67:389–93.

    CAS  PubMed  Google Scholar 

  106. Wessler JD, Grip LT, Mendell J, Giugliano RP. The P-glycoprotein transport system and cardiovascular drugs. J Am Coll Cardiol. 2013;61:2495–502.

    CAS  PubMed  Google Scholar 

  107. US Food and Drug Administration (FDA). FDA label: Cardizem (diltiazem). 2010 [cited 7 Jan 2019]. p. 9. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/018602s063lbl.pdf. Accessed 07 Jan 2019.

  108. Yamamoto T, Kubota T, Ozeki T, Sawada M, Yokota S, Yamada Y, et al. Effects of the CYP3A5 genetic polymorphism on the pharmacokinetics of diltiazem. Clin Chim Acta. 2005;362:147–54.

    CAS  PubMed  Google Scholar 

  109. Akutsu T, Kobayashi K, Sakurada K, Ikegaya H, Furihata T, Chiba K. Identification of human cytochrome p450 isozymes involved in diphenhydramine N-demethylation. Drug Metab Dispos. 2007;35:72–8.

    CAS  PubMed  Google Scholar 

  110. MacFadyen RJ, Meredith PA, Elliott HL. Enalapril clinical pharmacokinetics and pharmacokinetic-pharmacodynamic relationships. An overview. Clin Pharmacokinet. 1993;25:274–82.

    CAS  PubMed  Google Scholar 

  111. Liu L, Cui Y, Chung AY, Shitara Y, Sugiyama Y, Keppler D, et al. Vectorial transport of enalapril by Oatp1a1/Mrp2 and OATP1B1 and OATP1B3/MRP2 in rat and human livers. J Pharmacol Exp Ther. 2006;318:395–402.

    CAS  PubMed  Google Scholar 

  112. US Food and Drug Administration (FDA). Prescribing information: Allegra (fexofenadine). 1996 [cited 7 Jan 2019]. p. 7. https://www.accessdata.fda.gov/drugsatfda_docs/label/2001/20625lbl.pdf. Accessed 07 Jan 2019.

  113. Shimizu M, Fuse K, Okudaira K, Nishigaki R, Maeda K, Kusuhara H, et al. Contribution of OATP (organic anion-transporting polypeptide) family transporters to the hepatic uptake of fexofenadine in humans. Drug Metab Dispos. 2005;33:1477–81.

    CAS  PubMed  Google Scholar 

  114. Drugbank: Fosdevirine (IDX-899). 2018 [cited 7 Jan 2019]. https://www.drugbank.ca/drugs/DB06166. Accessed 07 Jan 2019.

  115. Sica DA, Gehr TWB, Ghosh S. Clinical pharmacokinetics of losartan. Clin Pharmacokinet. 2005;44:797–814.

    CAS  PubMed  Google Scholar 

  116. Stearns RA, Chakravarty PK, Chen R, Chiu SH. Biotransformation of losartan to its active carboxylic acid metabolite in human liver microsomes. Role of cytochrome P4502C and 3A subfamily members. Drug Metab Dispos. 1995;23:207–15.

    CAS  PubMed  Google Scholar 

  117. Soldner A, Benet LZ, Mutschler E, Christians U. Active transport of the angiotensin-II antagonist losartan and its main metabolite EXP 3174 across MDCK-MDR1 and caco-2 cell monolayers. Br J Pharmacol. 2000;129:1235–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. US Food and Drug Administration (FDA). FDA label: Glucophage (metformin). 1997 [cited 7 Jan 2019]. p. 23. https://www.accessdata.fda.gov/drugsatfda_docs/nda/97/020357a_s006.pdf. Accessed 07 Jan 2019.

  119. Graham GG, Punt J, Arora M, Day RO, Doogue MP, Duong JK, et al. Clinical pharmacokinetics of metformin. Clin Pharmacokinet. 2011;50:81–98.

    CAS  PubMed  Google Scholar 

  120. Pentikainen PJ, Neuvonen PJ, Penttila A. Pharmacokinetics of metformin after intravenous and oral administration to man. Eur J Clin Pharmacol. 1979;16:195–202.

    CAS  PubMed  Google Scholar 

  121. Liang X, Giacomini KM. Transporters involved in metformin pharmacokinetics and treatment response. J Pharm Sci. 2017;106:2245–50.

    CAS  PubMed  Google Scholar 

  122. Kimura N, Masuda S, Tanihara Y, Ueo H, Okuda M, Katsura T, et al. Metformin is a superior substrate for renal organic cation transporter OCT2 rather than hepatic OCT1. Drug Metab Pharmacokinet. 2005;20:379–86.

    CAS  PubMed  Google Scholar 

  123. US Food and Drug Administration (FDA). FDA label: Versed (midazolam). 1996 [cited 7 Jan 2019]. p. 79. https://www.accessdata.fda.gov/drugsatfda_docs/nda/97/018654ap.pdf. Accessed 07 Jan 2019.

  124. Heizmann P, Ziegler WH. Excretion and metabolism of 14C-midazolam in humans following oral dosing. Arzneimittelforschung Ger. 1981;31:2220–3.

    CAS  Google Scholar 

  125. Wrighton SA, Stevens JC. The human hepatic cytochromes P450 involved in drug metabolism. Crit Rev Toxicol. 1992;22:1–21.

    CAS  PubMed  Google Scholar 

  126. US Food and Drug Administration (FDA). Clinical pharmacology and biopharmaceutics review: Uptravi (selexipag). 2014 [cited 7 Jan 2019]. p. 31. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207947Orig1s000ClinPharmR.pdf. Accessed 07 Jan 2019.

  127. Mazaleuskaya LL, Sangkuhl K, Thorn CF, FitzGerald GA, Altman RB, Klein TE. PharmGKB summary: pathways of acetaminophen metabolism at the therapeutic versus toxic doses. Pharmacogenet Genom. 2015;25:416–26.

    CAS  Google Scholar 

  128. Zhang C, Kwan P, Zuo Z, Baum L. In vitro concentration dependent transport of phenytoin and phenobarbital, but not ethosuximide, by human P-glycoprotein. Life Sci. 2010;86:899–905.

    CAS  PubMed  Google Scholar 

  129. US Food and Drug Administration (FDA). FDA label: Pravachol (pravastatin). 2012 [cited 7 Jan 2019]. p. 111. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/019898s062.pdf. Accessed 07 Jan 2019.

  130. Nishizato Y, Ieiri I, Suzuki H, Kimura M, Kawabata K, Hirota T, et al. Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics. Clin Pharmacol Ther. 2003;73:554–65.

    CAS  PubMed  Google Scholar 

  131. US Food and Drug Administration (FDA). Clinical pharmacology and biopharmaceutics review: Isentress (raltegravir). 2011 [cited 7 Jan 2019]. p. 58. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/203045Orig1s000ClinPharmR.pdf. Accessed 07 Jan 2019.

  132. Hashiguchi Y, Hamada A, Shinohara T, Tsuchiya K, Jono H, Saito H. Role of P-glycoprotein in the efflux of raltegravir from human intestinal cells and CD4+ T-cells as an interaction target for anti-HIV agents. Biochem Biophys Res Commun. 2013;439:221–7.

    CAS  PubMed  Google Scholar 

  133. US Food and Drug Administration (FDA). Clinical pharmacology and biopharmaceutics review: Viread (tenofovir). 2001 [cited 7 Jan 2019]. p. 53. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/21-356_Viread_biopharmr.pdf. Accessed 07 Jan 2019.

  134. Miners JO, Birkett DJ. Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br J Clin Pharmacol. 1998;45:525–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Bi Y-A, Mathialagan S, Tylaska L, Fu M, Keefer J, Vildhede A, et al. Organic anion transporter 2 mediates hepatic uptake of tolbutamide, a CYP2C9 probe drug. J Pharmacol Exp Ther. 2018;364:390–8.

    CAS  PubMed  Google Scholar 

  136. Cload PA. A review of the pharmacokinetics of zidovudine in man. J Infect. 1989;18(Suppl 1):15–21.

    PubMed  Google Scholar 

  137. Errasti-Murugarren E, Pastor-Anglada M. Drug transporter pharmacogenetics in nucleoside-based therapies. Pharmacogenomics. 2010;11:809–41.

    CAS  PubMed  Google Scholar 

  138. VanWert AL, Gionfriddo MR, Sweet DH. Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology. Biopharm Drug Dispos. 2010;31:1–71.

    CAS  PubMed  Google Scholar 

  139. US Food and Drug Administration (FDA). FDA label: Lipitor (atorvastatin). 2009 [cited 7 Oct 2018]. p. 48. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/020702Orig1s056.pdf. Accessed 07 Jan 2019.

  140. Caruso FS, Doshan HD, Hernandez PH, Costello R, Applin W, Neiss ES. Celiprolol: pharmacokinetics and duration of pharmacodynamic activity. Br J Clin Pract Suppl. 1985;40:12–6.

    CAS  PubMed  Google Scholar 

  141. Drugbank: Mirodenafil. 2018. https://www.drugbank.ca/drugs/DB11792. Accessed 07 Jan 2019.

  142. Lee HS, Park EJ, Ji HY, Kim SY, Im G-J, Lee SM, et al. Identification of cytochrome P450 enzymes responsible for N-dealkylation of a new oral erectogenic, mirodenafil. Xenobiotica. 2008;38:21–33.

    CAS  PubMed  Google Scholar 

  143. Shin K-H, Kim B-H, Kim T-E, Kim JW, Yi S, Yoon S-H, et al. The effects of ketoconazole and rifampicin on the pharmacokinetics of mirodenafil in healthy Korean male volunteers: an open-label, one-sequence, three-period, three-treatment crossover study. Clin Ther. 2009;31:3009–20.

    CAS  PubMed  Google Scholar 

  144. Guengerich FP, Brian WR, Iwasaki M, Sari MA, Baarnhielm C, Berntsson P. Oxidation of dihydropyridine calcium channel blockers and analogues by human liver cytochrome P-450 IIIA4. J Med Chem. 1991;34:1838–44.

    CAS  PubMed  Google Scholar 

  145. Andersson T. Pharmacokinetics, metabolism and interactions of acid pump inhibitors. Focus on omeprazole, lansoprazole and pantoprazole. Clin Pharmacokinet. 1996;31:9–28.

    CAS  PubMed  Google Scholar 

  146. US Food and Drug Administration (FDA). Prescribing information: Livalo (pitavastatin). 2009 [cited 7 Jan 2019]. p. 15. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022363s000lbl.pdf. Accessed 07 Jan 2019.

  147. US Food and Drug Administration (FDA). Clinical pharmacology and biopharmaceutics review: Zypitamag (pitavastatin). 2015 [cited 7 Jan 2019]. p. 35. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208379Orig1s000ClinPharmR.pdf. Accessed 07 Jan 2019.

  148. Clinical pharmacology and biopharmaceutics review: Rytmonorm (propafenone). 2003 [cited 7 Jan 2019]. p. 91. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-416_RythmolSR_BioPharmr.pdf. Accessed 07 Jan 2019.

  149. Botsch S, Gautier JC, Beaune P, Eichelbaum M, Kroemer HK. Identification and characterization of the cytochrome P450 enzymes involved in N-dealkylation of propafenone: molecular base for interaction potential and variable disposition of active metabolites. Mol Pharmacol. 1993;43:120–6.

    CAS  PubMed  Google Scholar 

  150. Guengerich FP, Muller-Enoch D, Blair IA. Oxidation of quinidine by human liver cytochrome P-450. Mol Pharmacol. 1986;30:287–95.

    CAS  PubMed  Google Scholar 

  151. US Food and Drug Administration (FDA). Prescribing information: Crestor (rosuvastatin). 2003 [cited 7 Jan 2019]. p. 43. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021366s016lbl.pdf. Accessed 07 Jan 2019.

  152. US Food and Drug Administration (FDA). Clinical pharmacology and biopharmaceutics review: Crestor (rosuvastatin). 2003 [cited 10 Jan 2019]. p. 86. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-366_Crestor_BioPharmr.pdf. Accessed 07 Jan 2019.

  153. Wu H-F, Hristeva N, Chang J, Liang X, Li R, Frassetto L, et al. Rosuvastatin pharmacokinetics in Asian and white subjects wild type for both OATP1B1 and BCRP under control and inhibited conditions. J Pharm Sci. 2017;106:2751–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Matthaei J, Kuron D, Faltraco F, Knoch T, Dos Santos Pereira JN, Abu Abed M, et al. OCT1 mediates hepatic uptake of sumatriptan and loss-of-function OCT1 polymorphisms affect sumatriptan pharmacokinetics. Clin Pharmacol Ther. 2016;99:633–41.

    CAS  PubMed  Google Scholar 

  155. US Food and Drug Administration (FDA). Prescribing information: Micardis (telmisartan). 1998 [cited 7 Jan 2019]. p. 13. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020850s032lbl.pdf. Accessed 07 Jan 2019.

  156. Ishiguro N, Maeda K, Kishimoto W, Saito A, Harada A, Ebner T, et al. Predominant contribution of OATP1B3 to the hepatic uptake of telmisartan, an angiotensin II receptor antagonist, in humans. Drug Metab Dispos. 2006;34:1109–15.

    CAS  PubMed  Google Scholar 

  157. Ishiguro N, Maeda K, Saito A, Kishimoto W, Matsushima S, Ebner T, et al. Establishment of a set of double transfectants coexpressing organic anion transporting polypeptide 1B3 and hepatic efflux transporters for the characterization of the hepatobiliary transport of telmisartan acylglucuronide. Drug Metab Dispos. 2008;36:796–805.

    CAS  PubMed  Google Scholar 

  158. Kroemer HK, Gautier JC, Beaune P, Henderson C, Wolf CR, Eichelbaum M. Identification of P450 enzymes involved in metabolism of verapamil in humans. Naunyn Schmiedebergs Arch Pharmacol. 1993;348:332–7.

    CAS  PubMed  Google Scholar 

  159. Yang M-S, Yu C-P, Chao P-DL, Lin S-P, Hou Y-C. R- and S-warfarin were transported by breast cancer resistance protein: from in vitro to pharmacokinetic-pharmacodynamic studies. J Pharm Sci. 2017;106:1419–25.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek-The Netherlands Cancer Institute, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands

    Merel van Nuland, Hilde Rosing, Alwin D. R. Huitema & Jos H. Beijnen

  2. Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Merel van Nuland, Alwin D. R. Huitema & Jos H. Beijnen

  3. Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands

    Alwin D. R. Huitema

  4. Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

    Jos H. Beijnen

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Jos H. Beijnen is a part-time employee, stock holder, and patent holder for Modra Pharmaceuticals B.V. (a spin-out company developing oral taxane formulations). However, this activity is not related to the content of the current manuscript. Merel van Nuland, H. Rosing, and A. D. R. Huitema have no conflicts of interest to declare.

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van Nuland, M., Rosing, H., Huitema, A.D.R. et al. Predictive Value of Microdose Pharmacokinetics. Clin Pharmacokinet 58, 1221–1236 (2019). https://doi.org/10.1007/s40262-019-00769-x

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