Design and Data Analysis in Drug Interaction Studies

  • David E. Nix
  • Keith Gallicano
Part of the Infectious Disease book series (ID)


This chapter covers basic concepts pertaining to designing drug-drug interaction studies and interpreting results. Planning a drug-drug interaction study should encompass a statement of the rationale for doing the study. The basic design involves a two-period randomized crossover study with two treatment sequences; however, more complex and alternative study designs are discussed. Considerations include dose and duration of precipitant drug administration, washout period between treatments, and whether the potential interaction that results will affect the pharmacokinetic assessment plan. Existing information available for the test agents should be reviewed to formulate expected outcomes. The expected outcomes should be considered to ensure that the proper pharmacokinetic and sometimes pharmacodynamic information is collected for all treatments. All drug-drug interaction studies should be planned to incorporate equivalence testing and to present mean ratio of treatment/reference and corresponding 90% confidence intervals. The “no-effect” bounds, typically 80.00–125.00%, should be stated in the plan and based on consideration of the therapeutic index and pharmacokinetic variability of the object drug.


Drug interactions Pharmacokinetics Pharmacodynamics Study design Data analysis Regulatory guidance Crossover design Parallel design Absorption Distribution Metabolism Renal excretion Transporters Pharmacogenomics Statistics 


  1. 1.
    Ekins S (1996) Past, present, and future applications of precision-cut liver slices for in vitro xenobiotic metabolism. Drug Metab Rev 28(4):591–623CrossRefGoogle Scholar
  2. 2.
    Decker CJ, Laitinen LM, Bridson GW et al (1998) Metabolism of amprenavir in liver microsomes: role of CYP3A4 inhibition for drug interactions. J Pharm Sci 87(7):803–807CrossRefGoogle Scholar
  3. 3.
    Bonnabry P, Sievering J, Leemann T et al (2001) Quantitative drug interactions prediction system (Q-DIPS): a dynamic computer-based method to assist in the choice of clinically relevant in vivo studies. Clin Pharmacokinet 40(9):631–640Google Scholar
  4. 4.
    Rodrigues AD, Wong SL (1997) Application of human liver microsomes in metabolism-based drug-drug interactions: in vitro-in vivo correlations and the Abbott Laboratories experience. Adv Pharmacol 43:65–101Google Scholar
  5. 5.
    Koudriakova T, Iatsimirskaia E, Utkin I et al (1998) Metabolism of the human immunodeficiency virus protease inhibitors indinavir and ritonavir by human intestinal microsomes and expressed cytochrome P4503A4/3A5: mechanism-based inactivation of cytochrome P4503A by ritonavir. Drug Metab Dispos 26(6):552–561Google Scholar
  6. 6.
    Hochman JH, Yamazaki M, Ohe T et al (2002) Evaluation of drug interactions with p-glycoprotein in drug discovery: in vitro assessment of the potential for drug-drug interactions with p-glycoprotein. Curr Drug Metab 3(3):257–273CrossRefGoogle Scholar
  7. 7.
    Benet LZ, Cummins CL, Wu CY (2003) Transporter-enzyme interactions: implications for predicting drug-drug interactions from in vitro data. Curr Drug Metab 4(5):393–398CrossRefGoogle Scholar
  8. 8.
    Rolan PE (1994) Plasma protein binding displacement interactions--why are they still regarded as clinically important? Br J Clin Pharmacol 37(2):125–128CrossRefGoogle Scholar
  9. 9.
    Sansom LN, Evans AM (1995) What is the true clinical significance of plasma protein binding displacement interactions? Drug Saf 12(4):227–233CrossRefGoogle Scholar
  10. 10.
    FDA US (2012) Guidance for industry: drug interaction studies – study design, data analysis, implications for dosing and labeling recommendations; draft guidance. February 2012, Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, 1–79Google Scholar
  11. 11.
    EMA (2012) Guideline on the investigation of drug interactions. Committee for Human Medicinal Products, European Medicines Agency, June 21, 1–59Google Scholar
  12. 12.
    Bjornsson TD, Callaghan JT, Einolf HJ et al (2003) The conduct of in vitro and in vivo drug-drug interaction studies: a Pharmaceutical Research and Manufacturers of America (PHARMA) perspective. Drug Metab Dispos 31(7):815–832Google Scholar
  13. 13.
    Gallicano KD, Sahai J, Shukla VK et al (1999) Induction of zidovudine glucuronidation and amination pathways by rifampicin in HIV-infected patients. Br J Clin Pharmacol 48(2):168–179CrossRefGoogle Scholar
  14. 14.
    Ormsby E (1994) Statistical methods in bioequivalence. CRC Press, Boca RatonGoogle Scholar
  15. 15.
    Wang BS, Wang XJ, Gong LK (2009) The construction of a williams design and randomization in cross-over clinical trials using SAS. J Stat Softw 29(1):1–10Google Scholar
  16. 16.
    Fleiss JL (1989) A critique of recent research on the two-treatment crossover design. Control Clin Trials 10(3):237–243CrossRefGoogle Scholar
  17. 17.
    Vuorinen J (1997) A practical approach for the assessment of bioequivalence under selected higher-order cross-over designs. Stat Med 16(19):2229–2243CrossRefGoogle Scholar
  18. 18.
    Chow SC, Liu JP (1992) On assessment of bioequivalence under a higher-order crossover design. J Biopharm Stat 2(2):239–256CrossRefGoogle Scholar
  19. 19.
    Nix DE, Di Cicco RA, Miller AK et al (1999) The effect of low-dose cimetidine (200 mg twice daily) on the pharmacokinetics of theophylline. J Clin Pharmacol 39(8):855–865CrossRefGoogle Scholar
  20. 20.
    Grasela TH Jr, Antal EJ, Ereshefsky L et al (1987) An evaluation of population pharmacokinetics in therapeutic trials. Part ii. Detection of a drug-drug interaction. Clini Pharmacol Ther 42(4):433–441CrossRefGoogle Scholar
  21. 21.
    Purkins L, Wood N, Kleinermans D et al (2003) No clinically significant pharmacokinetic interactions between voriconazole and indinavir in healthy volunteers. Br J Clin Pharmacol 56(Suppl 1):62–68CrossRefGoogle Scholar
  22. 22.
    Cato A 3rd, Cavanaugh J, Shi H et al (1998) The effect of multiple doses of ritonavir on the pharmacokinetics of rifabutin. Clini Pharmacol Ther 63(4):414–421CrossRefGoogle Scholar
  23. 23.
    Romero AJ, Le Pogamp P, Nilsson LG et al (2002) Effect of voriconazole on the pharmacokinetics of cyclosporine in renal transplant patients. Clini Pharmacol Ther 71(4):226–234CrossRefGoogle Scholar
  24. 24.
    Cadieux RJ (1989) Drug interactions in the elderly. How multiple drug use increases risk exponentially. Postgrad Med 86(8):179–186CrossRefGoogle Scholar
  25. 25.
    Ragueneau I, Poirier JM, Radembino N et al (1999) Pharmacokinetic and pharmacodynamic drug interactions between digoxin and macrogol 4000, a laxative polymer, in healthy volunteers. Br J Clin Pharmacol 48(3):453–456CrossRefGoogle Scholar
  26. 26.
    Piscitelli SC, Goss TF, Wilton JH et al (1991) Effects of ranitidine and sucralfate on ketoconazole bioavailability. Antimicrob Agents Chemother 35(9):1765–1771CrossRefGoogle Scholar
  27. 27.
    Blum RA, D’Andrea DT, Florentino BM et al (1991) Increased gastric pH and the bioavailability of fluconazole and ketoconazole. Ann Intern Med 114(9):755–757Google Scholar
  28. 28.
    Lebsack ME, Nix D, Ryerson B et al (1992) Effect of gastric acidity on enoxacin absorption. Clini Pharmacol Ther 52(3):252–256CrossRefGoogle Scholar
  29. 29.
    Lehto P, Kivisto KT, Neuvonen PJ (1994) The effect of ferrous sulphate on the absorption of norfloxacin, ciprofloxacin and ofloxacin. Br J Clin Pharmacol 37(1):82–85CrossRefGoogle Scholar
  30. 30.
    Nix DE, Watson WA, Lener ME et al (1989) Effects of aluminum and magnesium antacids and ranitidine on the absorption of ciprofloxacin. Clin Pharmacol Ther 46(6):700–705CrossRefGoogle Scholar
  31. 31.
    Parpia SH, Nix DE, Hejmanowski LG et al (1989) Sucralfate reduces the gastrointestinal absorption of norfloxacin. Antimicrob Agents Chemother 33(1):99–102CrossRefGoogle Scholar
  32. 32.
    Muller J, Keiser M, Drozdzik M et al (2017) Expression, regulation and function of intestinal drug transporters: an update. Biol Chem 398(2):175–192CrossRefGoogle Scholar
  33. 33.
    Arakawa H, Kamioka H, Kanagawa M et al (2016) Possible interaction of quinolone antibiotics with peptide transporter 1 in oral absorption of peptide-mimetic drugs. Biopharm Drug Dispos 37(1):39–45CrossRefGoogle Scholar
  34. 34.
    Shugarts S, Benet LZ (2009) The role of transporters in the pharmacokinetics of orally administered drugs. Pharm Res 26(9):2039–2054CrossRefGoogle Scholar
  35. 35.
    Misaka S, Miyazaki N, Yatabe MS et al (2013) Pharmacokinetic and pharmacodynamic interaction of nadolol with itraconazole, rifampicin and grapefruit juice in healthy volunteers. J Clin Pharmacol 53(7):738–745CrossRefGoogle Scholar
  36. 36.
    Momper JD, Tsunoda SM, Ma JD (2016) Evaluation of proposed in vivo probe substrates and inhibitors for phenotyping transporter activity in humans. J Clin Pharmacol 56(Suppl 7):S82–S98CrossRefGoogle Scholar
  37. 37.
    Jungbluth GL, Pasko MT, Beam TR et al (1989) Ceftriaxone disposition in open-heart surgery patients. Antimicrob Agents Chemother 33(6):850–856CrossRefGoogle Scholar
  38. 38.
    Yin J, Wang J (2016) Renal drug transporters and their significance in drug-drug interactions. Acta Pharm Sin B 6(5):363–373CrossRefGoogle Scholar
  39. 39.
    Ivanyuk A, Livio F, Biollaz J et al (2017) Renal drug transporters and drug interactions. Clin Pharmacokinet 56(8):825–892CrossRefGoogle Scholar
  40. 40.
    Ebner T, Ishiguro N, Taub ME (2015) The use of transporter probe drug cocktails for the assessment of transporter-based drug-drug interactions in a clinical setting-proposal of a four component transporter cocktail. J Pharm Sci 104(9):3220–3228CrossRefGoogle Scholar
  41. 41.
    Hagos Y, Wolff NA (2010) Assessment of the role of renal organic anion transporters in drug-induced nephrotoxicity. Toxins 2(8):2055–2082CrossRefGoogle Scholar
  42. 42.
    Hsu V, de LT Vieira M, Zhao P et al (2014) Towards quantitation of the effects of renal impairment and probenecid inhibition on kidney uptake and efflux transporters, using physiologically based pharmacokinetic modelling and simulations. Clin Pharmacokinet 53(3):283–293CrossRefGoogle Scholar
  43. 43.
    Rengelshausen J, Goggelmann C, Burhenne J et al (2003) Contribution of increased oral bioavailability and reduced nonglomerular renal clearance of digoxin to the digoxin-clarithromycin interaction. Br J Clin Pharmacol 56(1):32–38CrossRefGoogle Scholar
  44. 44.
    Megran DW, Lefebvre K, Willetts V et al (1990) Single-dose oral cefixime versus amoxicillin plus probenecid for the treatment of uncomplicated gonorrhea in men. Antimicrob Agents Chemother 34(2):355–357CrossRefGoogle Scholar
  45. 45.
    Gaspari F, Perico N, Remuzzi G (1997) Measurement of glomerular filtration rate. Kidney Int Suppl 63:S151–S154PubMedGoogle Scholar
  46. 46.
    Brochner-Mortensen J (1985) Current status on assessment and measurement of glomerular filtration rate. Clin Physiol 5(1):1–17CrossRefGoogle Scholar
  47. 47.
    Hellerstein S, Erwin P, Warady BA (2003) The cimetidine protocol: a convenient, accurate, and inexpensive way to measure glomerular filtration rate. Pediatr Nephrol 18(1):71–72CrossRefGoogle Scholar
  48. 48.
    Baciewicz AM, Chrisman CR, Finch CK et al (2008) Update on rifampin and rifabutin drug interactions. Am J Med Sci 335(2):126–136CrossRefGoogle Scholar
  49. 49.
    Wandel C, Bocker R, Bohrer H et al (1994) Midazolam is metabolized by at least three different cytochrome P450 enzymes. Br J Anaesth 73(5):658–661Google Scholar
  50. 50.
    Thummel KE, Shen DD, Podoll TD et al (1994) Use of midazolam as a human cytochrome P450 3A probe: ii. Characterization of inter- and intraindividual hepatic CYP3A variability after liver transplantation. J Pharmacol Exp Ther 271(1):557–566Google Scholar
  51. 51.
    Lown KS, Thummel KE, Benedict PE et al (1995) The erythromycin breath test predicts the clearance of midazolam. Clini Pharmacol Ther 57(1):16–24CrossRefGoogle Scholar
  52. 52.
    Watkins PB, Turgeon DK, Saenger P et al (1992) Comparison of urinary 6-beta-cortisol and the erythromycin breath test as measures of hepatic P450iiiA (CYP3A) activity. Clini Pharmacol Ther 52(3):265–273CrossRefGoogle Scholar
  53. 53.
    Hunt CM, Watkins PB, Saenger P et al (1992) Heterogeneity of CYP3A isoforms metabolizing erythromycin and cortisol. Clini Pharmacol Ther 51(1):18–23Google Scholar
  54. 54.
    Chiou WL, Jeong HY, Wu TC et al (2001) Use of the erythromycin breath test for in vivo assessments of cytochrome P4503A activity and dosage individualization. Clini Pharmacol Ther 70(4):305–310Google Scholar
  55. 55.
    Sarkar MA, Jackson BJ (1994) Theophylline N-demethylations as probes for P4501A1 and P4501A2. Drug Metab Dispos 22(6):827–834Google Scholar
  56. 56.
    Ziebell J, Shaw-Stiffel T (1995) Update on the use of metabolic probes to quantify liver function: caffeine versus lidocaine. Dig Dis 13(4):239–250CrossRefGoogle Scholar
  57. 57.
    Anthony LB, Boeve TJ, Hande KR (1995) Cytochrome P-450iiD6 phenotyping in cancer patients: debrisoquin and dextromethorphan as probes. Cancer Chemother Pharmacol 36(2):125–128CrossRefGoogle Scholar
  58. 58.
    Desta Z, Zhao X, Shin JG et al (2002) Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet 41(12):913–958Google Scholar
  59. 59.
    Fuhr U, Rost KL, Engelhardt R et al (1996) Evaluation of caffeine as a test drug for CYP1A2, NAT2 and CYP2E1 phenotyping in man by in vivo versus in vitro correlations. Pharmacogenetics 6(2):159–176CrossRefGoogle Scholar
  60. 60.
    Brockmoller J, Rost KL, Gross D et al (1995) Phenotyping of CYP2C19 with enantiospecific hplc-quantification of R- and S-mephenytoin and comparison with the intron4/exon5 g-->a-splice site mutation. Pharmacogenetics 5(2):80–88CrossRefGoogle Scholar
  61. 61.
    Guengerich FP (1997) Role of cytochrome p450 enzymes in drug-drug interactions. Adv Pharmacol 43:7–35CrossRefGoogle Scholar
  62. 62.
    Tanaka E (1998) Clinically important pharmacokinetic drug-drug interactions: role of cytochrome P450 enzymes. J Clinical Pharmacy Ther 23(6):403–416CrossRefGoogle Scholar
  63. 63.
    Lomaestro BM, Piatek MA (1998) Update on drug interactions with azole antifungal agents. Ann Pharmacother 32(9):915–928CrossRefGoogle Scholar
  64. 64.
    Caraco Y (1998) Genetic determinants of drug responsiveness and drug interactions. Ther Drug Monit 20(5):517–524CrossRefGoogle Scholar
  65. 65.
    Shannon M (1997) Drug-drug interactions and the cytochrome P450 system: an update. Pediatr Emerg Care 13(5):350–353CrossRefGoogle Scholar
  66. 66.
    Bradford PA, Sanders CC (1993) Use of a predictor panel to evaluate susceptibility test methods proposed for piperacillin-tazobactam. Antimicrob Agents Chemother 37(12):2578–2583CrossRefGoogle Scholar
  67. 67.
    Mikus G, Schowel V, Drzewinska M et al (2006) Potent cytochrome P450 2C19 genotype-related interaction between voriconazole and the cytochrome P450 3A4 inhibitor ritonavir. Clini Pharmacol Ther 80(2):126–135CrossRefGoogle Scholar
  68. 68.
    Isoherranen N, Ludington SR, Givens RC et al (2008) The influence of CYP3A5 expression on the extent of hepatic CYP3A inhibition is substrate-dependent: an in vitro-in vivo evaluation. Drug Metab Dispos 36(1):146–154CrossRefGoogle Scholar
  69. 69.
    Li D, Abudula A, Abulahake M et al (2010) Influence of CYP3A5 and MDR1 genetic polymorphisms on urinary 6 beta-hydroxycortisol/cortisol ratio after grapefruit juice intake in healthy Chinese. J Clin Pharmacol 50(7):775–784CrossRefGoogle Scholar
  70. 70.
    Cho JY, Yu KS, Jang IJ et al (2002) Omeprazole hydroxylation is inhibited by a single dose of moclobemide in homozygotic em genotype for CYP2C19. Br J Clin Pharmacol 53(4):393–397Google Scholar
  71. 71.
    Miura M, Inoue K, Kagaya H et al (2007) Influence of rabeprazole and lansoprazole on the pharmacokinetics of tacrolimus in relation to CYP2C19, CYP3A5 and MDR1 polymorphisms in renal transplant recipients. Biopharm Drug Dispos 28(4):167–175Google Scholar
  72. 72.
    Furuta T, Ohashi K, Kobayashi K et al (1999) Effects of clarithromycin on the metabolism of omeprazole in relation to CYP2C19 genotype status in humans. Clini Pharmacol Ther 66(3):265–274Google Scholar
  73. 73.
    Bramness JG, Skurtveit S, Gulliksen M et al (2005) The CYP2C19 genotype and the use of oral contraceptives influence the pharmacokinetics of carisoprodol in healthy human subjects. Eur J Clin Pharmacol 61(7):499–506CrossRefGoogle Scholar
  74. 74.
    Dumond JB, Vourvahis M, Rezk NL et al (2010) A phenotype-genotype approach to predicting CYP450 and p-glycoprotein drug interactions with the mixed inhibitor/inducer tipranavir/ritonavir. Clinical Pharmacol Ther 87(6):735–742Google Scholar
  75. 75.
    Zachariasen RD (1994) Loss of oral contraceptive efficacy by concurrent antibiotic administration. Women Health 22(1):17–26CrossRefGoogle Scholar
  76. 76.
    Suzuki E, Nakai D, Ikenaga H et al (2016) In vivo inhibition of acylpeptide hydrolase by carbapenem antibiotics causes the decrease of plasma concentration of valproic acid in dogs. Xenobiotica 46(2):126–131CrossRefGoogle Scholar
  77. 77.
    Nguyen VX, Nix DE, Gillikin S et al (1989) Effect of oral antacid administration on the pharmacokinetics of intravenous doxycycline. Antimicrob Agents Chemother 33(4):434–436CrossRefGoogle Scholar
  78. 78.
    Neuvonen PJ, Penttila O (1974) Effect of oral ferrous sulphate on the half-life of doxycycline in man. Eur J Clin Pharmacol 7(5):361–363CrossRefGoogle Scholar
  79. 79.
    Muller HJ, Gundert-Remy U (1994) The regulatory view on drug-drug interactions. Int J Clin Pharmacol Ther 32(6):269–273PubMedGoogle Scholar
  80. 80.
    Waller PC, Jackson PR, Tucker GT et al (1994) Clinical pharmacology with confidence. Br J Clin Pharmacol 37(4):309–310CrossRefGoogle Scholar
  81. 81.
    Fuhr U, Weiss M, Kroemer HK et al (1996) Systematic screening for pharmacokinetic interactions during drug development. Int J Clin Pharmacol Ther 34(4):139–151PubMedGoogle Scholar
  82. 82.
    Kuhlmann J (1994) Drug interaction studies during drug development: which, when, how? Int J Clin Pharmacol Ther 32(6):305–311PubMedGoogle Scholar
  83. 83.
    Pidgen AW (1992) Statistical aspects of bioequivalence--a review. Xenobiotica 22(7):881–893CrossRefGoogle Scholar
  84. 84.
    Steinijans VW, Hartmann M, Huber R et al (1996) Lack of pharmacokinetic interaction as an equivalence problem. Int J Clin Pharmacol Ther 34(1 Suppl):S25–S30PubMedGoogle Scholar
  85. 85.
    Gallicano K, Sahai J, Swick L et al (1995) Effect of rifabutin on the pharmacokinetics of zidovudine in patients infected with human immunodeficiency virus. Clin Infect Dis 21(4):1008–1011CrossRefGoogle Scholar
  86. 86.
    De Wit S, Debier M, De Smet M et al (1998) Effect of fluconazole on indinavir pharmacokinetics in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 42(2):223–227PubMedPubMedCentralGoogle Scholar
  87. 87.
    Hauschke D, Kieser M, Diletti E et al (1999) Sample size determination for proving equivalence based on the ratio of two means for normally distributed data. Stat Med 18(1):93–105CrossRefGoogle Scholar
  88. 88.
    Huang SM, Lesko LJ, Williams RL (1999) Assessment of the quality and quantity of drug-drug interaction studies in recent NDA submissions: study design and data analysis issues. J Clin Pharmacol 39(10):1006–1014CrossRefGoogle Scholar
  89. 89.
    Chow S, Liu JP (2000) Design and analysis of bioavailabilty and bioequivalence studies, second edition, revised and expanded. Marcel Dekker, New YorkGoogle Scholar
  90. 90.
    Wijnand H (1996) Some nonparametric confidence intervals are non-informative, notably in bioequivalence studies. Clin Res Reg Affairs 13:65–75CrossRefGoogle Scholar
  91. 91.
    Midha KK, Ormsby ED, Hubbard JW et al (1993) Logarithmic transformation in bioequivalence: application with two formulations of perphenazine[erratum appears in j pharm sci 1993 dec;82(12):1300]. J Pharm Sci 82(2):138–144CrossRefGoogle Scholar
  92. 92.
    Roe DJ, Karol MD (1997) Averaging pharmacokinetic parameter estimates from experimental studies: statistical theory and application. J Pharm Sci 86(5):621–624CrossRefGoogle Scholar
  93. 93.
    Zintzaras E (2000) The existence of sequence effect in cross-over bioequivalence trials. Eur J Drug Metab Pharmacokinet 25(3–4):241–244CrossRefGoogle Scholar
  94. 94.
    Hauschke D, Steinijans WV, Diletti E et al (1994) Presentation of the intrasubject coefficient of variation for sample size planning in bioequivalence studies. Int J Clin Pharmacol Ther 32(7):376–378PubMedGoogle Scholar
  95. 95.
    Steinijans VW, Sauter R, Hauschke D et al (1995) Reference tables for the intrasubject coefficient of variation in bioequivalence studies. Int J Clin Pharmacol Ther 33(8):427–430PubMedGoogle Scholar
  96. 96.
    Diletti E, Hauschke D, Steinijans VW (1992) Sample size determination: extended tables for the multiplicative model and bioequivalence ranges of 0.9 to 1.11 and 0.7 to 1.43. Int J Clini Pharmacol, Ther Toxicol 30(Suppl 1):S59–S62Google Scholar
  97. 97.
    Hauschke D, Steinijans VW, Diletti E et al (1992) Sample size determination for bioequivalence assessment using a multiplicative model. J Pharmacokinet Biopharm 20(5):557–561CrossRefGoogle Scholar
  98. 98.
    Liu JP, Chow SC (1992) Sample size determination for the two one-sided tests procedure in bioequivalence. J Pharmacokinet Biopharm 20(1):101–104CrossRefGoogle Scholar
  99. 99.
    Chow SC, Wang H (2001) On sample size calculation in bioequivalence trials.[erratum appears in j pharmacokinet pharmacodyn. 2002 feb;29(1):101]. J Pharmacokinet Pharmacodyn 28(2):155–169Google Scholar
  100. 100.
    Gallicano K, Sahai J, Zaror-Behrens G et al (1994) Effect of antacids in didanosine tablet on bioavailability of isoniazid. Antimicrob Agents Chemother 38(4):894–897CrossRefGoogle Scholar
  101. 101.
    Schall R, Hundt HK, Luus HG (1994) Pharmacokinetic characteristics for extent of absorption and clearance in drug/drug interaction studies. Int J Clin Pharmacol Ther 32(12):633–637PubMedGoogle Scholar
  102. 102.
    Tozer TN, Bois FY, Hauck WW et al (1996) Absorption rate vs. exposure: which is more useful for bioequivalence testing? Pharm Res 13(3):453–456CrossRefGoogle Scholar
  103. 103.
    van Giersbergen PL, Halabi A, Dingemanse J (2002) Single- and multiple-dose pharmacokinetics of bosentan and its interaction with ketoconazole. Br J Clin Pharmacol 53(6):589–595CrossRefGoogle Scholar
  104. 104.
    Sanchez Garcia P, Paty I, Leister CA et al (2000) Effect of zaleplon on digoxin pharmacokinetics and pharmacodynamics. Am J Health Syst Pharm 57(24):2267–2270PubMedGoogle Scholar
  105. 105.
    Depre M, Van Hecken A, Verbesselt R et al (1999) Effect of multiple doses of montelukast, a cyslt1 receptor antagonist, on digoxin pharmacokinetics in healthy volunteers. J Clin Pharmacol 39(9):941–944Google Scholar
  106. 106.
    Dilger K, Zheng Z, Klotz U (1999) Lack of drug interaction between omeprazole, lansoprazole, pantoprazole and theophylline. Br J Clin Pharmacol 48(3):438–444CrossRefGoogle Scholar
  107. 107.
    Auclair B, Nix DE, Adam RD et al (2001) Pharmacokinetics of ethionamide administered under fasting conditions or with orange juice, food, or antacids. Antimicrob Agents Chemother 45(3):810–814CrossRefGoogle Scholar
  108. 108.
    Damle BD, Mummaneni V, Kaul S et al (2002) Lack of effect of simultaneously administered didanosine encapsulated enteric bead formulation (videx EC) on oral absorption of indinavir, ketoconazole, or ciprofloxacin. Antimicrob Agents Chemother 46(2):385–391CrossRefGoogle Scholar
  109. 109.
    Banfield C, Herron J, Keung A et al (2002) Desloratadine has no clinically relevant electrocardiographic or pharmacodynamic interactions with ketoconazole. Clin Pharmacokinet 41(Suppl 1):37–44CrossRefGoogle Scholar
  110. 110.
    Hsu A, Granneman GR, Cao G et al (1998) Pharmacokinetic interaction between ritonavir and indinavir in healthy volunteers. Antimicrob Agents Chemother 42(11):2784–2791PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.The University of Arizona College of PharmacyTucsonUSA
  2. 2.Novum Pharmaceutical Research ServicesMurrietaUSA

Personalised recommendations