Drug Discovery and Evaluation: Methods in Clinical Pharmacology

Editors: Hans Gerhard Vogel, Jochen Maas, Alexander Gebauer

Pharmacodynamic Drug–Drug Interactions

DOI: https://doi.org/10.1007/978-3-540-89891-7_29


Pharmacodynamic drug–drug interactions occur when one drug (A) alters the effects of another drug (B) without affecting its pharmacokinetics.

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  1. Alain LWP, Zhanga WY (1998) What lessons can be learnt from withdrawal of mibefradil from the market? Lancet 351Google Scholar
  2. Apfel CC, Korttila K, Abdalla M, Kerger H, Turan A, Vedder I, Zernak C, Danner K, Jokela R, Pocock SJ, Trenkler S, Kredel M, Biedler A, Sessler DI, Roewer N; IMPACT Investigators. A factorial trial of six interventions for the prevention of postoperative nausea and vomiting. N Engl J Med 10;350(24):2441–2451Google Scholar
  3. Ariens EJ, Van Rossum JM, Simonis AM (1956) A theoretical basis of molecular pharmacology. Arzneimittelforsch 6:282–293, 611–621, 737–746PubMedGoogle Scholar
  4. Arunlakshana O, Schild HO (1959) Some quantitative uses of drug antagonists. British Journal of Pharmacology 14:48–58Google Scholar
  5. Belz GG, Butzer R, Kober S, Mutschler E (2002) Pharmacodynamic studies on the AT1 antagonists irbesartan and candesartan basing on angiotensin II dose–response in humans. Journal of Cardiovascular Pharmacology 39:561–568PubMedCrossRefGoogle Scholar
  6. Bentué-Ferrer D, Tribut O, Polard E, Allain H (2003) Clinically significant drug interactions with cholinesterase inhibitors: a guide for neurologists. CNS Drugs 17(13):947–963PubMedCrossRefGoogle Scholar
  7. Berenbaum MC (1978) A method for testing synergy with any number of agents. The Journal of Infectious Diseases 137:122–130PubMedGoogle Scholar
  8. Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Saltz L (2008) Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol 20;26(12):2006–2012CrossRefGoogle Scholar
  9. Cheitlin MD, Hutter AM Jr, Brindis RG, Ganz P, Kaul S, Russell RO Jr, Zusman RM (1999) Use of sildenafil (Viagra) in patients with cardiovascular disease. Technology and Practice Executive Committee. Circulation 99(1):168–177PubMedGoogle Scholar
  10. Chou TC (2006) Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev 58:621–681PubMedCrossRefGoogle Scholar
  11. Cohen M, Maritz F, Gensini GF, Danchin N, Timerman A, Huber K, Gurfinkel EP, White H, Fox KA, Vittori L, Le-Louer V, Bigonzi F (2000) The TETAMI trial: the safety and efficacy of subcutaneous enoxaparin versus intravenous unfractionated heparin and of tirofiban versus placebo in the treatment of acute myocardial infarction for patients not thrombolyzed: methods and design. Journal of Thrombosis and Thrombolysis 10(3):241–246PubMedCrossRefGoogle Scholar
  12. Cohen M, Gensini GF, Maritz F, Gurfinkel EP, Huber K, Timerman A, Krzeminska-Pakula M, Danchin N, White HD, Santopinto J, Bigonzi F, Hecquet C, Vittori L; TETAMI Investigators (2003) The safety and efficacy of subcutaneous enoxaparin versus intravenous unfractionated heparin and tirofiban versus placebo in the treatment of acute ST-segment elevation myocardial infarction patients ineligible for reperfusion (TETAMI): a randomized trial. J Am Coll Cardiol 15:42, 8, 1348–1356Google Scholar
  13. D’Aquila RT, Hughes MD, Johnson VA, Fischl MA, Sommadossi JP, Liou SH, Timpone J, Myers M, Basgoz N, Niu M, Hirsch MS (1996) Nevirapine, zidovudine, and didanosine compared with zidovudine and didanosine in patients with HIV-1 infection. A randomized, double-blind, placebo-controlled trial. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group Protocol 241 Investigators. Ann Intern Med 15;124(12):1019–30Google Scholar
  14. Danhof M, de Jongh J, De Lange EC, Della Pasqua OE, Ploeger BA, Voskuyl RA (2007) Mechanism-based pharmacokinetic-pharmacodynamic modeling: biophase distribution, receptor theory, and dynamical systems analysis. Annual Review of Pharmacology and Toxicology 47:357–400PubMedCrossRefGoogle Scholar
  15. EMEA (1997) CPMP, Note for guidance on the investigation of drug interactions, CPMP/560/95Google Scholar
  16. EMEA (2002) CPMP, Note for guidance on clinical investigation of medicinal products in the treatment of diabetes mellitus, CPMP/EWP/1080/00Google Scholar
  17. EMEA (2004) CPMP, Note for guidance on clinical investigation of medicinal products in the treatment of hypertension, CPMP/EWP/238/95 Rev. 2Google Scholar
  18. Essig J, Belz GG, Wellstein A (1989) The assessment of ACE activity in man following angiotensin I challenges: a comparison of cilazapril, captopril and enalapril. British Journal of Clinical Pharmacology 27:217S–223SPubMedGoogle Scholar
  19. FDA (2006) Guidance for industry, drug interaction studies – study design, data analysis, and implications for dosing and labeling sept. 2006Google Scholar
  20. FDA (2006) Guidance for industry fixed dose combinations, co-packaged drug products, and single-entity versions of previously approved antiretrovirals for the treatment of HIVGoogle Scholar
  21. FDA (2008) Guidance for industry, draft, guidance for industry, diabetes mellitus: developing drugs and therapeutic biologics for treatment and preventionGoogle Scholar
  22. Filitz J, Ihmsen H, Günther W, Tröster A, Schwilden H, Schüttler J, Koppert W (2008) Supra-additive effects of tramadol and acetaminophen in a human pain model. Pain 136(3):262–270PubMedCrossRefGoogle Scholar
  23. Gessner PK (1995) Isobolographic analysis of interactions: an update on applications and utility. Toxicol 105:161–179CrossRefGoogle Scholar
  24. Goldberg AC, Sapre A, Liu J, Capece R, Mitchel YB; Ezetimibe Study Group (2004) Efficacy and safety of ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia: a randomized, double-blind, placebo-controlled trial. Mayo Clin Proc 79(5):620–629Google Scholar
  25. Grant AM, Avenell A, Campbell MK, McDonald AM, MacLennan GS, McPherson GC, Anderson FH, Cooper C, Francis RM, Donaldson C, Gillespie WJ, Robinson CM, Torgerson DJ, Wallace WA; RECORD Trial Group (2005) Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial. Lancet 7–13;365(9471):1621–1628Google Scholar
  26. Greco WR, Bravo O, Parsons JC (1995) The search for synergy: a critical review from a response surface perspective. Pharmacological Reviews 47:331–385PubMedGoogle Scholar
  27. Haverkamp W, Breithardt G, Camm AJ, Janse MJ, Rosen MR, Antzelevitch C, Escande D, Franz M, Malik M, Moss A, Shah R (2000) The potential for QT prolongation and pro-arrhythmia by non-anti-arrhythmic drugs: clinical and regulatory implications. Cardiovascular Research 47(2):219–233PubMedCrossRefGoogle Scholar
  28. ONTARGET Investigators, Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, Dagenais G, Sleight P, Anderson C (2008) Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 10;358(15):1547–1559Google Scholar
  29. Loewe S (1953) The problem of synergism and antagonism of combined drugs. Arzneimittelforsch 3:285–290PubMedGoogle Scholar
  30. Loewe S, Muischnek H (1926) Über Kombinationswirkungen. Naunyn-Schmiedeberg’s Arch Pharmacol 114(5–6):313–326Google Scholar
  31. Lubsen J, Pocock SJ (1994) Factorial trials in cardiology: pros and cons. European Heart Journal 15:585–588PubMedGoogle Scholar
  32. McAlister FA, Straus SE, Sackett DL, Altman DG (2003) Analysis and reporting of factorial trials: a systematic review. J Am Med Assoc 21;289(19):2545–2553Google Scholar
  33. Minto CF, Schnider TW, Short TG, Gregg KM, Gentilini A, Shafer SL (2000) Response surface model for anesthetic drug interactions. Anesthesiol 92:1603–1616CrossRefGoogle Scholar
  34. Montes A, Warner W, Puig MM (2000) Use of intravenous patient-controlled analgesia for the documentation of synergy between tramadol and metamizol. British Journal of Anaesthesia 85(2):217–223PubMedCrossRefGoogle Scholar
  35. Nakornchai S, Konthiang P (2006) Activity of azithromycin or erythromycin in combination with antimalarial drugs against multidrug-resistant Plasmodium falciparum in vitro. Acta Tropica 100(3):185–191PubMedCrossRefGoogle Scholar
  36. Parsley TL, Provonchee RB, Glicksman C, Zinner SH (1977) Synergistic activity of trimethoprim and amikacin against gram-negative bacilli. Antimicrobial Agents and Chemotherapy 12(3):349–352PubMedGoogle Scholar
  37. Pöch G, Juan H (ed) (1985) In: Allgemeine pharmakodynamik. Thieme, Vol. 6. Wirkungen in Kombination, pp. 63–85Google Scholar
  38. Pordy RC (1994) Cilazapril plus hydrochlorothiazide: improved efficacy without reduced safety in mild to moderate hypertension. A double-blind placebo-controlled multicenter study of factorial design. Cardiology 85(5):311–322PubMedCrossRefGoogle Scholar
  39. Robbins GK, De Gruttola V, Shafer RW, Smeaton LM, Snyder SW, Pettinelli C, Dubé MP, Fischl MA, Pollard RB, Delapenha R, Gedeon L, van der Horst C, Murphy RL, Becker MI, D’Aquila RT, Vella S, Merigan TC, Hirsch MS; AIDS Clinical Trials Group 384 Team (2003) Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med 11;349(24):2293–2303Google Scholar
  40. Ross EM, Kenakin TP (2001) Pharmacodynamics: mechanisms of drug action and the relationship between drug concentration and effect. In: Hardman JG, Limbird LE, Gilman AG (eds) Goodman and Gilman’s. The pharmacological basis of therapeutics, 10th edn. McGraw and Hill, New YorkGoogle Scholar
  41. Scheen AJ (2005) Drug interactions of clinical importance with antihyperglycaemic agents: an update. Drug Safety 28(7):601–631PubMedCrossRefGoogle Scholar
  42. Schild HO (1947) pA, a new scale for the measurement of drug antagonism. Br J Pharmacol 2:189–206Google Scholar
  43. Scholze J, Breitstadt A, Cairns V, Bauer B, Bender N, Priestley C, Moreadith C, Phillips J, Vander Elst E, Koch G (1993) Short report: ramipril and hydrochlorothiazide combination therapy in hypertension: a clinical trial of factorial design. The East Germany Collaborative Trial Group. Journal of Hypertension 11(2):217–221PubMedCrossRefGoogle Scholar
  44. Seymour RM, Routledege PA (1998) Important drug–drug interactions in the elderly. Drugs and Aging 12(6):485–494PubMedCrossRefGoogle Scholar
  45. Tallarida RJ (2001) Drug synergism: its detection and applications. The Journal of Pharmacology and Experimental Therapeutics 298(3):865–872PubMedGoogle Scholar
  46. Tallarida RJ (2006) An overview of drug combination analysis with isobolograms. The Journal of Pharmacology and Experimental Therapeutics 319(1):1–7PubMedCrossRefGoogle Scholar
  47. Trujillo TC, Nolan PE (2000) Antiarrhythmic agents: drug interactions of clinical significance. Drug Safety 23(6):509–532PubMedCrossRefGoogle Scholar
  48. Wellstein A, Palm D, Pitschner HF, Belz GG (1985) Receptor binding of propranolol is the missing link between plasma concentrations kinetics and effect–time course in man. European Journal of Clinical Pharmacology 29:131–147PubMedCrossRefGoogle Scholar
  49. Wellstein A, Essig J, Belz GG (1987) Inhibition of angiotensin-I response by cilazapril and its time course in normal volunteers. Clinical Pharmacology and Therapeutics 41:639–644PubMedCrossRefGoogle Scholar
  50. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G (2000) Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 20;342(3):145–153. Erratum in: 4;342(18):1376, N Engl J Med 2000Google Scholar

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© Springer-Verlag Berlin Heidelberg 2011

Authors and Affiliations

  1. 1.Hochschule FreseniusIdsteinGermany