Does the placebo effect modulate drug bioavailability? Randomized cross-over studies of three drugs

Muhammad M Hammami, Ahmed Yusuf, Faduma S Shire, Rajaa Hussein, Reem Al-Swayeh, Muhammad M Hammami, Ahmed Yusuf, Faduma S Shire, Rajaa Hussein, Reem Al-Swayeh

Abstract

Background: Medication effect is the sum of its drug, placebo, and drug*placebo interaction effects. It is conceivable that the interaction effect involves modulating drug bioavailability; it was previously observed that being aware of caffeine ingestion may prolong caffeine plasma half-life. This study was set to evaluate such concept using different drugs.

Methods: Balanced single-dose, two-period, two-group, cross-over design was used to compare the pharmacokinetics of oral cephalexin, ibuprofen, and paracetamol, each described by its name (overt) or as placebo (covert). Volunteers and study coordinators were deceived as to study aim. Drug concentrations were determined blindly by in-house, high performance liquid chromatography assays. Terminal-elimination half-life (t½) (primary outcome), maximum concentration (Cmax), Cmax first time (Tmax), terminal-elimination-rate constant (λ), area-under-the-concentration-time-curve, to last measured concentration (AUCT), extrapolated to infinity (AUCI), or to Tmax of overt drug (AUCOverttmax), and Cmax/AUCI were calculated blindly using standard non-compartmental method. Covert-vs-overt effect on drug pharmacokinetics was evaluated by analysis-of-variance (ANOVA, primary analysis), 90% confidence interval (CI) using the 80.00-125.00% bioequivalence range, and percentage of individual pharmacokinetic covert/overt ratios that are outside the +25% range.

Results: Fifty, 30, and 50 healthy volunteers (18%, 10%, and 6% females, mean (SD) age 30.8 (6.2), 31.4 (6.6), and 31.2 (5.4) years) participated in 3 studies on cephalexin, ibuprofen, and paracetamol, respectively. Withdrawal rate was 4%, 0%, and 4%, respectively. Eighteen blood samples were obtained over 6, 10, and 14 h in each study period of the three drugs, respectively. ANOVA showed no significant difference in any pharmacokinetic parameter for any of the drugs. The 90% CIs for AUCT, AUCI, Cmax, AUCOverttmax, and Cmax/AUCI were within the bioequivalence range, except for ibuprofen Cmax (76.66-98.99), ibuprofen Cmax/AUCI (77.19-98.39), and ibuprofen (45.32-91.62) and paracetamol (51.45-98.96) AUCOverttmax. Out of the 126 individual covert/overt ratios, 2.0-16.7% were outside the +25% range for AUCT, 2.0-4.2% for AUCI, 25.0-44.9% for Cmax, 67.3-76.7% for AUCOverttmax, and 45.8-71.4% for Tmax.

Conclusions: This study couldn't confirm that awareness of drug ingestion modulates its bioavailability. However, it demonstrates the trivial effect of blinding in bioequivalence studies and the extent of bio-variability that would be expected when comparing a drug product to itself.

Trial registration: ClinicalTrials.gov identifier: NCT01501747 (registered Dec 26, 2011).

Keywords: Bioavailability; Cephalexin; Paracetamol; Pharmacokinetic parameters; Placebo effect; Plasma terminal half-life; ibuprofen.

Figures

Fig. 1
Fig. 1
Flow of participants through the study
Fig. 2
Fig. 2
Time-concentration curves of cephalexin (a), ibuprofen (b), and paracetamol (c) described as such (blue diamonds) or as placebo (red squares). Data represent mean concentrations
Fig. 3
Fig. 3
Time-log-concentration curves of cephalexin (a), ibuprofen (b), and paracetamol (c) described as such (blue diamonds) or as placebo (red squares). Data represent mean natural log-transformed concentrations
Fig. 4
Fig. 4
Average bioequivalence evaluation of covert-overt cephalexin, ibuprofen, and paracetamol. Data represent point estimate (antilog of mean covert-overt difference of log-transformed values) and parametric 90% confidence interval. The shaded area indicates the area of bioequivalence (80.00% to 125.00%). a, bioequivalence evaluation of area-under-the-concentration-time curve to last quantifiable concentration (AUCT). b, bioequivalence evaluation of area-under-the-concentration-time curve extrapolated to infinity (AUCI). c, bioequivalence evaluation of maximum concentration (Cmax). d, bioequivalence evaluation of area-under-the-concentration-time curve extrapolated to overt Tmax (AUCOverttmax). e, bioequivalence evaluation of Cmax/AUCI
Fig. 5
Fig. 5
Individual bioequivalence evaluation of covert-overt cephalexin, ibuprofen, and paracetamol. Data represent percentage of individual ratios that are ˂0.75 (closed bars) or ˃1.25 (open bars). a, bioequivalence evaluation of area-under-the-concentration-time curve to last quantifiable concentration (AUCT). b, bioequivalence evaluation of area-under-the-concentration-time curve extrapolated to infinity (AUCI). c, bioequivalence evaluation of maximum concentration (Cmax). d, bioequivalence evaluation of area-under-the-concentration-time curve extrapolated to overt Tmax (AUCOverttmax). e, bioequivalence evaluation of time to maximum concentration (Tmax)

References

    1. Tilburt JC, Emanuel EJ, Kaptchuk TJ, Curlin FA, Miller FG. Prescribing “placebo treatments”: Results of national survey of US internists and rheumatologists. BMJ. 2008;337:a1983. doi: 10.1136/bmj.a1938.
    1. Moerman DE, Jonas WB. Deconstructing the placebo effect and finding the meaning response. Ann Intern Med. 2002;136(6):471–476. doi: 10.7326/0003-4819-136-6-200203190-00011.
    1. Kienle GS, Kiene H. The powerful placebo effect: fact or fiction? J Clin Epidemiol. 1997;50(12):1311–1318. doi: 10.1016/S0895-4356(97)00203-5.
    1. Hróbjartsson A, Gøtzsche PC. Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N Engl J Med. 2001;344(21):1594–1602. doi: 10.1056/NEJM200105243442106.
    1. McRae C, Cherin E, Yamazaki TG, Diem G, Vo AH, Russell D, et al. Effects of perceived treatment on quality of life and medical outcomes in a double-blind placebo surgery trial. Arch Gen Psychiatry. 2004;61(4):412–20.
    1. Preference Collaborative Review Group Patients’ preferences within randomised trials: systematic review and patient level meta-analysis. BMJ. 2008;337:a1864. doi: 10.1136/bmj.a1864.
    1. Hammami MM, Al Gaai E, Alvi S, Hammami MB. Interaction between drug and placebo effect: across over balanced placebo design. Trials. 2010;11:110. doi: 10.1186/1745-6215-11-110.
    1. Hammami MM, Hammami S, Al-Swayeh R, Al-Gaai E, Farah FA, De Padua SJ. Drug*placebo interaction effect may bias clinical trials interpretation: hybrid balanced placebo and randomized placebo-controlled design. BMC Med Res Methodol. 2016;16:166. doi: 10.1186/s12874-016-0269-1.
    1. Krogsbøll LT, Hróbjartsson A, Gøtzsche PC. Spontaneous improvement in randomised clinical trials: meta-analysis of three-armed trials comparing no treatment, placebo and active intervention. BMC Med Res Methodol. 2009;9:1. doi: 10.1186/1471-2288-9-1.
    1. Sayette MA, Breslin FC, Wilson GT, Rosenblum GD. An evaluation of the balanced placebo design in alcohol administration research. Addict behave. 1994;19(3):333–342. doi: 10.1016/0306-4603(94)90034-5.
    1. Schneider R, Grüner M, Heiland A, Keller M, Kujanora Z, Peper M, et al. Effects of expectation and caffeine on arousal, well-being, and reaction time. Int J Behav Med. 2006;13(4):330–9.
    1. Dunne SS, Dunne CP. What do people really think of generic medicines? A systematic review and critical appraisal of literature on stakeholder perceptions of generic drugs. BMC Med. 2015;13:173. doi: 10.1186/s12916-015-0415-3.
    1. Piguet V, D’Incau S, Besson M, Desmeules J, Cedraschi C. Prescribing generic medication in chronic musculoskeletal pain patients: an issue of representations, trust, and experience in a Swiss cohort. PLoS One. 2015;10(8) doi: 10.1371/journal.pone.0134661.
    1. Lund K, Vase L, Petersen GL, Jensen TS, Finnerup NB. Randomised controlled trials may underestimate drug effects: balanced placebo trial design. PLoS One. 2014;9(1) doi: 10.1371/journal.pone.0084104.
    1. Kirsch I, Moore TJ, Scoboria A, Nicholls SS. The emperor's new drugs: An analysis of antidepressant medication data submitted to the U.S. Food and Drug Administration. Prevention & Treatment. 2002; 5(1): ArtID 23. . Accessed 1 May 2017.
    1. Wolf S. The pharmacology of placebos. Pharmacol Rev. 1959;11:689–704.
    1. Gundersen H, Specht K, Grüner R, Ersland L, Hugdahl K. Separating the effects of alcohol and expectancy on brain activation: an fMRI working memory study. NeuroImage. 2008;42(4):1587–1596. doi: 10.1016/j.neuroimage.2008.05.037.
    1. Davit B, Braddy AC, Conner DP, Yu LX. International guidelines for bioequivalence of systemically available orally administered generic drug products: a survey of similarities and differences. APPS J. 2013;15(4):974–990.
    1. Chen M-L, Shah VP, Crommelin DJ, Shargel L, Bashaw D, Bhatti M, et al. Harmonization of regulatory approaches for evaluating therapeutic equivalence and interchangeability of multisource drug products: workshop summary report. AAPS J. 2011;13(4):556–64.
    1. Kaushal N, Singh SK, Gulati M, Vaidya Y, Kaushik M. Study of regulatory requirements for the conduct of bioequivalence studies in US, Europe, Canada, India, ASEAN and SADC countries: Impact on generic drug substitution. J App Pharm Sci. 2016;6(4):206–222. doi: 10.7324/JAPS.2016.60430.
    1. Guidance for industry. Statistical approaches to establishing bioequivalence. US DHHS, FDA, CDER; 2001. Accessed 1 May 2017.
    1. Hsuan FC. Some statistical considerations on the FDA draft guidance for individual bioequivalence. Stat Med. 2000;19(20):2879–2884. doi: 10.1002/1097-0258(20001030)19:20<2879::AID-SIM552>;2-9.
    1. Buehler G. History of bioequivalence for critical dose drugs. . Accessed 1 May 2017.
    1. Lecaillon J, Hirtz J, Schoeller J, Humbert G, Vischer W. Pharmacokinetic comparison of cefroxadin (CGP 9000) and cephalexin by simultaneous administration to humans. Antimicrob Agents Chemother. 1980;18(4):656–660. doi: 10.1128/AAC.18.5.656.
    1. Deppermann K, Lode H, Hoffken G, Tschink G, Kalz C, Koeppe P. Influence of ranitidine, piprenzepine, and aluminum magnesium hydroxide on the bioavailability of various antibiotics, including amoxicillin, cephalexin, doxycycline, and amoxicillin-clavulanic avid. Antimicrob Agents Chemother. 1989;33(11):1901–1907. doi: 10.1128/AAC.33.11.1901.
    1. Schettler T, Paris S, Pellett M, Kidner S, Wilkinson D. Comparative pharmacokinetics of two fast-dissolving oral ibuprofen formulations and a regular-release ibuprofen tablet in healthy volunteers. Clin Drug Investig. 2001;21(1):73–78. doi: 10.2165/00044011-200121010-00010.
    1. Portoles A, Puerro M, Terleira A, Rodriguez A, Caturla MC, Fernandez N, et al. A new high-absorption-rate paracetamol 500-mg formulation: a comparative bioavailability study in healthy volunteers. Curr Ther Res Clin Exp. 2003;64(7):401–11.
    1. Dickert N, Grady C. What’s the price for a research subject? Approaches to payment for research participation. N Engl J Med. 1999;341(3):198–203. doi: 10.1056/NEJM199907153410312.
    1. Miller FG, Wendler D, Swartzman LC. Deception in research on the placebo effect. PLoS Med. 2005;2(9) doi: 10.1371/journal.pmed.0020262.
    1. United States Department of Health and Human Services. Institutional Review Board Guidebook (Chapter V): Biomedical and Behavioral Research – An Overview. . Accessed 1 May 2017.
    1. American Psychological Association. Ethical Principles of Psychologists and Code of Conduct (including 2010 and 2016 Amendments). . Accessed 1 May 2017.
    1. Council for International Organizations of Medical Sciences, International Ethical Guidelines for Health-related Research Involving Humans. Council for International Organizations of Medical Sciences (CIOMS). . Accessed 1 May 2017.
    1. Hussein RF, Hammami MM. Determination of cephalexin level and stability in human plasma by fully validated rapid HPLC analysis. WJPPS. 2014;3(12):20–31.
    1. Alvi SN, Yusuf A, Al Gaai E, Hammami MM. Rapid determination of ibuprofen concentration in human plasma by high performance liquid chromatography. WJPPS. 2014;3(8):1767–1777.
    1. Alswayeh R, Alvi SN, Hammami MM. Rapid determination of acetaminophen levels in human plasma by high performance liquid chromatography. Am J PharmTech Res. 2016;6(3):710–719.
    1. . Dallal GE. . Accessed 1 May 2017.
    1. Nuzzo R. Scientific method: statistical errors. Nature. 2014;506(7487):150–152. doi: 10.1038/506150a.
    1. Sterne JAC, Smith GD. Sifting the evidence—what's wrong with significance tests? BMJ. 2001;322(7280):226–231. doi: 10.1136/bmj.322.7280.226.
    1. Lilford RJ, Braunholtz DA. Is the placebo powerless: Correspondence to the Editor. N Engl J Med. 2001;345(17):1277–1278.
    1. Siegel S. Explanatory mechanisms for placebo effects: Pavlovian conditioning. In: Guess H, Kleinman A, Kusek J, Engel L, editors. The Science of the Placebo: Toward an interdisciplinary agenda. London, England: BMJ Publishing Group; 2002. pp. 133–157.
    1. Jiang W, Makhlouf F, Schuirmann DJ, Zhang X, Zheng N, Conner D, et al. A bioequivalence approach for generic narrow therapeutic index drugs: evaluation of the reference-scaled approach and variability comparison criterion. AAPS J. 2015;17(4):891–901.
    1. Henney JE. Review of generic bioequivalence studies. JAMA. 1999;282(21):1995. doi: 10.1001/jama.282.21.1995-JFD90010-2-1.
    1. Davit BM, Nwakama PE, Buehler GJ, Conner DP, Haider SH, Patel DT, et al. Comparing generic and innovator drugs: a review of 12 years of bioequivalence data from the United States Food and Drug Administration. Ann Pharmacother. 2009;43(10):1583–97.
    1. Birkett DJ. Generics-equal or not? Aust Prescr. 2003;26(4):85–87. doi: 10.18773/austprescr.2003.063.
    1. Yu Y, Teerenstra S, Neef C, Burger D, Maliepaard M. Investigation into the interchangeability of generic formulations using immunosuppressants and a broad selection of medicines. Eur J Clin Pharmacol. 2015;71(8):979–990. doi: 10.1007/s00228-015-1878-z.
    1. Tóthfalusi L, Endrényi L, Chow SC. Statistical and regulatory considerations in assessments of interchangeability of biological drug products. Eur J Health Econ. 2014;15(Suppl 1):S5–11. doi: 10.1007/s10198-014-0589-1.
    1. Johnston A. Equivalence and interchangeability of narrow therapeutic index drugs in organ transplantation. Eur J Hosp Pharm Sci Pract. 2013;20(5):302–307. doi: 10.1136/ejhpharm-2012-000258.
    1. Yim DS. Simulation of the AUC changes after generic substitution in patients. J Korean Med Sci. 2009;24(1):7–12. doi: 10.3346/jkms.2009.24.1.7.
    1. Ting TY, Jiang W, Lionberger R, Wong J, Jones JW, Kane MA, et al. Generic lamotrigine versus brand-name Lamictal bioequivalence in patients with epilepsy: A field test of the FDA bioequivalence standard. Epilepsia. 2015;56(9):1415–24.

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