PDF herunterladen
Pharmacopsychiatry 2014; 47(06): 195-201
DOI: 10.1055/s-0034-1385929
Original Paper
© Georg Thieme Verlag KG Stuttgart · New York

Pegylated Interferon Pharmacokinetics and Self-Reported Depressive Symptoms During Antiviral Treatment for Chronic Hepatitis C

D. M. Evon
1   Division of Gastroenterology and Hepatology, UNC School of Medicine, Chapel Hill, NC, USA
,
D. E. Esserman
2   Department of Biostatistics, Yale University School of Public Health, New Haven, CT, USA
,
M. A. Howell
3   United Therapeutic Corporation, Research Triangle Park, NC, USA
,
R. A. Ruffin
1   Division of Gastroenterology and Hepatology, UNC School of Medicine, Chapel Hill, NC, USA
4   Currently at Durham Veterans Affairs Medical Center, Durham, NC, USA
› Institutsangaben
Weitere Informationen

Publikationsverlauf

received 17. Dezember 2013
revised 16. Juni 2014

accepted 15. Juli 2014

Publikationsdatum:
14. August 2014 (online)

Auch verfügbar auf
    Lizenzen und Reprints

Abstract

Background: Pegylated interferon-2a (PegIFN-2a)+ribavirin treatment for chronic hepatitis C is often associated with depressive symptoms. Previous studies have failed to explore whether PegIFN-2a pharmacokinetic variability plays an etiologic role in PegIFN-2a-induced mood disorders. The objective of this investigation was to evaluate the association between trough PegIFN-2a concentration at treatment week 4 (“PegIFN-2a Cmin4”) and an increase in depressive symptoms.

Methods: Using data from Virahep-C, the association between PegIFN-2a Cmin4 and the following depression outcomes were evaluated using the Center for Epidemiological Studies-Depression scale (CES-D): (1) change in CES-D score from baseline to week 12; (2) greatest difference in CES-D score between baseline and weeks 4, 12, or 24; and (3) occurrence of severe depressive symptoms (CES-D greater than 23) at weeks 4, 12, or 24. One post-hoc analysis examined whether PegIFN-2a exposure during the first week of treatment was associated with change in CES-D score from baseline to week 4.

Results: No significant associations between PegIFN-2a Cmin4 and the depression outcomes were observed (p>0.05). Exploratory analyses suggest a possible relationship between PegIFN-2a exposure during the first week of therapy and CES-D score change from baseline to week 4 (p=0.03).

Conclusions: PegIFN-2a concentration levels from baseline to week 4 do not predict the onset and severity of depressive symptoms during 24 weeks of antiviral therapy; however PegIFN-2a levels during the first week of treatment may predict depressive symptoms in the first 4 weeks, earlier than anticipated and warrants further exploration.

Key words

depression - pharmacokinetics - liver disease patients - hepatitis C - interferon
 

  • References

  • 1 Fried MW, Shiffman ML, Reddy KR et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347: 975-982
    CrossrefPubMedGoogle Scholar
  • 2 Poordad F, McCone J, Bacon BR et al. Boceprevir for untreated chronic HCV genotype 1 infection. New England Journal of Medicine 2011; 364: 1195-1206
    CrossrefPubMedGoogle Scholar
  • 3 Jacobson IM, McHutchison JG, Dusheiko G et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011; 364: 2405-2416
    CrossrefPubMedGoogle Scholar
  • 4 Fried MW. Side effects of therapy of hepatitis C and their management. Hepatology 2002; 36: S237-S244
    CrossrefPubMedGoogle Scholar
  • 5 McGowan CE, Monis A, Bacon BR et al. A global view of hepatitis C: physician knowledge, opinions, and perceived barriers to care. Hepatology 2013; 57: 1325-1332
    CrossrefPubMedGoogle Scholar
  • 6 Ford N, Singh K, Cooke GS et al. Expanding access to treatment for hepatitis C in resource-limited settings: lessons from HIV/AIDS. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America 2012; 54: 1465-1472
    CrossrefPubMedGoogle Scholar
  • 7 Raison CL, Borisov AS, Broadwell SD et al. Depression during pegylated interferon-alpha plus ribavirin therapy: prevalence and prediction. J Clin Psychiatry 2005; 66: 41-48
    CrossrefPubMedGoogle Scholar
  • 8 Evon DM, Verma A, Simpson K et al. Psychiatric symptoms during interferon treatment for hepatitis C: experiences from a tertiary care hepatology centre. Aliment Pharmacol Ther 2008; 27: 1071-1080
    CrossrefPubMedGoogle Scholar
  • 9 Schafer A, Wittchen HU, Seufert J et al. Methodological approaches in the assessment of interferon-alfa-induced depression in patients with chronic hepatitis C – a critical review. Int J Methods Psychiatr Res 2007; 16: 186-201
    CrossrefPubMedGoogle Scholar
  • 10 Dieperink E, Willenbring M, Ho SB. Neuropsychiatric symptoms associated with hepatitis C and interferon alpha: A review. Am J Psychiatry 2000; 157: 867-876
    CrossrefPubMedGoogle Scholar
  • 11 Wichers M, Maes M. The psychoneuroimmuno-pathophysiology of cytokine-induced depression in humans. Int J Neuropsychopharmacol 2002; 5: 375-388
    CrossrefPubMedGoogle Scholar
  • 12 Evon DM, Ramcharran D, Belle SH et al. Prospective analysis of depression during peginterferon and ribavirin therapy of chronic hepatitis C: results of the Virahep-C study. Am J Gastroenterol 2009; 104: 2949-2958
    CrossrefPubMedGoogle Scholar
  • 13 Wichers MC, Koek GH, Robaeys G et al. Early increase in vegetative symptoms predicts IFN-alpha-induced cognitive-depressive changes. Psychol Med 2005; 35: 433-441
    CrossrefPubMedGoogle Scholar
  • 14 Maddrey WC. Safety of combination interferon alfa-2b/ribavirin therapy in chronic hepatitis C-relapsed and treatment-naive patients. Semin Liver Dis 1999; 19 (Suppl. 01) 67-75
    PubMedGoogle Scholar
  • 15 Evon DM, Verma A, Dougherty KA et al. High deferral rates and poorer treatment outcomes for HCV patients with psychiatric and substance use comorbidities. Dig Dis Sci 2007; 52: 3251-3258
    CrossrefPubMedGoogle Scholar
  • 16 Foster GR. Review article: pegylated interferons: chemical and clinical differences. Alimentary pharmacology & therapeutics 2004; 20: 825-830
    CrossrefPubMedGoogle Scholar
  • 17 Motzer RJ, Rakhit A, Ginsberg M et al. Phase I trial of 40-kd branched pegylated interferon alfa-2a for patients with advanced renal cell carcinoma. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2001; 19: 1312-1319
    PubMedGoogle Scholar
  • 18 Talpaz M, Rakhit A, Rittweger K et al. Phase I evaluation of a 40-kDa branched-chain long-acting pegylated IFN-alpha-2a with and without cytarabine in patients with chronic myelogenous leukemia. Clinical cancer research: an official journal of the American Association for Cancer Research 2005; 11: 6247-6255
    CrossrefPubMedGoogle Scholar
  • 19 Silva M, Poo J, Wagner F et al. A randomised trial to compare the pharmacokinetic, pharmacodynamic, and antiviral effects of peginterferon alfa-2b and peginterferon alfa-2a in patients with chronic hepatitis C (COMPARE). J Hepatol 2006; 45: 204-213
    CrossrefPubMedGoogle Scholar
  • 20 Bressler B, Wang K, Grippo JF et al. Pharmacokinetics and response of obese patients with chronic hepatitis C treated with different doses of PEG-IFN alpha-2a (40KD) (PEGASYS). British journal of clinical pharmacology 2009; 67: 280-287
    CrossrefPubMedGoogle Scholar
  • 21 Dieperink E, Ho SB, Thuras P et al. A prospective study of neuropsychiatric symptoms associated with interferon-alpha-2b and ribavirin therapy for patients with chronic hepatitis C. Psychosomatics 2003; 44: 104-112
    CrossrefPubMedGoogle Scholar
  • 22 Hauser P, Khosla J, Aurora H et al. A prospective study of the incidence and open-label treatment of interferon-induced major depressive disorder in patients with hepatitis C. Mol Psychiatry 2002; 7: 942-947
    CrossrefPubMedGoogle Scholar
  • 23 Bonaccorso S, Marino V, Puzella A et al. Increased depressive ratings in patients with hepatitis C receiving interferon-alpha-based immunotherapy are related to interferon-alpha-induced changes in the serotonergic system. J Clin Psychopharmacol 2002; 22: 86-90
    CrossrefPubMedGoogle Scholar
  • 24 Wichers MC, Kenis G, Leue C et al. Baseline immune activation as a risk factor for the onset of depression during interferon-alpha treatment. Biol Psychiatry 2006; 60: 77-79
    CrossrefPubMedGoogle Scholar
  • 25 Prather AA, Rabinovitz M, Pollock BG et al. Cytokine-induced depression during IFN-alpha treatment: the role of IL-6 and sleep quality. Brain, behavior, and immunity 2009; 23: 1109-1116
    CrossrefPubMedGoogle Scholar
  • 26 Wichers MC, Kenis G, Koek GH et al. Interferon-alpha-induced depressive symptoms are related to changes in the cytokine network but not to cortisol. J Psychosom Res 2007; 62: 207-214
    CrossrefPubMedGoogle Scholar
  • 27 Radloff LS. The CES-D Scale: A self-report depression scale for research in the general population. Applied Psychological Measurement 1977; 1: 385-401
    CrossrefPubMedGoogle Scholar
  • 28 Conjeevaram HS, Fried MW, Jeffers LJ et al. Peginterferon and ribavirin treatment in African American and Caucasian American patients with hepatitis C genotype 1. Gastroenterology 2006; 131: 470-477
    CrossrefPubMedGoogle Scholar
  • 29 Raison CL, Demetrashvili M, Capuron L et al. Neuropsychiatric adverse effects of interferon-alpha: recognition and management. CNS Drugs 2005; 19: 105-123
    CrossrefPubMedGoogle Scholar
  • 30 Bodenheimer Jr HC, Lindsay KL, Davis GL et al. Tolerance and efficacy of oral ribavirin treatment of chronic hepatitis C: a multicenter trial. Hepatology 1997; 26: 473-477
    CrossrefPubMedGoogle Scholar
  • 31 Evon DM, Esserman DA, Bonner JE et al. Adherence to PEG/ribavirin treatment for chronic hepatitis C: prevalence, patterns, and predictors of missed doses and nonpersistence. J Viral Hepat 2013; 20: 536-549
    CrossrefPubMedGoogle Scholar
  • 32 Howell CD, Dowling TC, Paul M et al. Peginterferon pharmacokinetics in African American and Caucasian American patients with hepatitis C virus genotype 1 infection. Clin Gastroenterol Hepatol 2008; 6: 575-583
    CrossrefPubMedGoogle Scholar
  • 33 Clark CH, Mahoney JS, Clark DJ et al. Screening for depression in a hepatitis C population: the reliability and validity of the Center for Epidemiologic Studies Depression Scale (CES-D). J Adv Nurs 2002; 40: 361-369
    CrossrefPubMedGoogle Scholar
  • 34 Yeh S. Using Trapezoidal rule for the area under the curve calculation. Paper presentation 229-27 presented at the SAS SUGI 17 Conference 2002 Florida
    PubMedGoogle Scholar
  • 35 Pegasys package insert. Nutley NJ Hoffman-La Roche, Inc 2002 http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/pegihof101602lb.htm
    PubMed
  • 36 Jen JF, Glue P, Ezzet F et al. Population pharmacokinetic analysis of pegylated interferon alfa-2b and interferon alfa-2b in patients with chronic hepatitis C. Clinical pharmacology and therapeutics 2001; 69: 407-421
    PubMedGoogle Scholar
  • 37 Raison CL, Dantzer R, Kelley KW et al. CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: relationship to CNS immune responses and depression. Mol Psychiatry 2010; 15: 393-403
    CrossrefPubMedGoogle Scholar
  • 38 Raison CL, Borisov AS, Majer M et al. Activation of central nervous system inflammatory pathways by interferon-alpha: relationship to monoamines and depression. Biological psychiatry 2009; 65: 296-303
    CrossrefPubMedGoogle Scholar
  • 39 Pierucci-Lagha A, Covault J, Bonkovsky HL et al. A functional serotonin transporter gene polymorphism and depressive effects associated with interferon-alpha treatment. Psychosomatics 2010; 51: 137-148
    PubMedGoogle Scholar
  • 40 Lotrich FE, Ferrell RE, Rabinovitz M et al. Risk for depression during interferon-alpha treatment is affected by the serotonin transporter polymorphism. Biological psychiatry 2009; 65: 344-348
    CrossrefPubMedGoogle Scholar