We appreciated the interesting case report by Wu et al,1 about a possible interaction between adalimumab
and duloxetine and/or pregabalin. In the case, a 22 year old woman with type 1 diabetes mellitus and peripheral neuropathy was well controlled for her neuropathy on duloxetine sustained release (SR) 60mg daily and pregabalin 200mg three times daily. The patient presented to dermatology with a long history
of treatment-resistant psoriasis and psoriatic arthritis. The patient
was started on adalimumab 80mg initially at week 0, 40mg at week 1, and then 40mg every other week. Though her psoriasis began to improve, she experienced worsening of her peripheral neuropathy, including increasing sensitivity of her foot and excruciating
pain in her lower extremities, after her third and fourth shots of adalimumab, respectively. After the patient’s duloxetine dose was doubled to 60mg twice daily, the patient’s pain subsided and her peripheral neuropathy has been stable for 36 months. The authors did not propose a mechanism of interaction between adalimumab and duloxetine and/or pregabalin.
Recently, the package inserts of 3 out of the 4 biologics have been updated to include warnings about the potential influence of biologics on the metabolism of small molecule drugs indirectly through the cytochrome P450 (CYP) pathway. This potential relationship
between biologics and the CYP pathway could explain the phenomenon seen in the patient and the possible interaction between adalimumab and duloxetine. Duloxetine is metabolized via the cytochrome P450 CYP pathway, specifically through the CYP2D6 and CYP1A2 enzymes.2 Clinical and in vitro studies have observed that high levels of inflammatory cytokines such as TNF-alpha suppress CYP activity.3 For example, investigators initially observed an inhibitory effect of TNF-alpha on different CYP isoenzymes
in rodent and human cell lines.4,5 Furthermore, a clinical study involving patients with congestive heart failure observed a significant inverse relationship between increased serum levels of TNF-alpha and lowered activity of a major CYP metabolizing enzyme.6 In another recent in vitro study, investigators found that cytochrome P450 activity (specifically CYP2D6 and CYP1A2, which both are the major enzymes that metabolize duloxetine) was decreased after exposing cryopreserved human hepatocytes to TNF-alpha.7 Since TNF-alpha inhibitors specifically target TNF-alpha, the decreased concentration of circulating TNF-alpha can increase CYP activity and subsequently increase clearance of any
drugs that are metabolized through the CYP pathway, such as duloxetine.
Specific to the case report, the decreased serum levels of duloxetine (after administration of adalimumab) could have become sub therapeutic and exacerbated the patient’s previously stable peripheral neuropathy. Furthermore, by doubling the dose of duloxetine to compensate for the increased clearance, the serum
levels of the medication were returned to a therapeutic range and the patient’s condition improved.1
Biologics have limited risks for drug-drug interactions with other small drug molecules as compared to the other oral systemic medications such as cyclosporine and methotrexate.8 Biologics
are unique in that they are not metabolized via a major end organ such as the liver and kidney like many small drug molecules.
9 However, dermatologists should be aware of the updated labels of the biologics suggesting that TNF-alpha inhibitors may indirectly affect CYP activity and thus alter the metabolism of certain small molecule drugs that are metabolized through CYP substrates. Further studies are needed to assess this relationship,
as it has not been validated in clinical studies.
JJW received research grants from Abbott Laboratories, AbbVie, Amgen, and Pfizer, which were not directly related to this study. JYMK is a speaker for AbbVie, Leo, and Stiefel-GSK. JYMK conducts
research for Amgen, Janssen, Novartis, Photomedex, Galderma, Merck and Pfizer. JYMK has no stocks, employment, or board memberships with any pharmaceutical company. None of the grants were directly related to this study. W.L. is supported by a grant from the National Institutes of Health (K08AR057763), which was not directly related to this study. RG and EL report no conflicts of interest.
Wu JJ, Fleming KF. Interaction between adalimumab with concurrent pregabalin and duloxetine administration in a psoriasis patient with diabetic peripheral neuropathy. Cutis 2011;87(5):249-250.
Knadler MP, Lobo E, Chappell J, Bergstrom R. Duloxetine: clinical pharmacokinetics and drug interactions. Clin Pharmacokinet. 2011;50(5):281-294.
Lee JI, Zhang L, Men AY, Kenna LA, Huang SM. CYP-mediated therapeutic protein-drug interactions: clinical findings, proposed mechanisms and regulatory implications. Clin Pharmacokinet. 2010;49(5):295-310.
Pan J, Xiang Q, Ball S. Use of a novel real-time quantitative reverse transcription-polymerase chain reaction method to study the effects of cytokines on cytochrome P450 mRNA expression in mouse liver.Drug Metab Dispos. 2000;28(6):709-713.
Nadin L, Butler AM, Farrell GC, Murray M. Pretranslational down-regulation of cytochromes P450 2C11 and 3A2 in male rat liver by tumor necrosis factor alpha. Gastroenterology. 1995;109(1):198-205.
Frye RF, Schneider VM, Frye CS, Feldman AM. Plasma levels of TNF-alpha and IL-6 are inversely related to cytochrome P450-dependent drug metabolism in patients with congestive heart failure. J Cardiac Failure. 2002;8(5):315-319.
Dallas S, Sensenhauser C, Batheja A, et al. De-risking bio-therapeutics for possible drug interactions using cryopreserved human hepatocytes. Current Drug Metab. 2012;13(7):923-929.
Seitz K, Zhou H. Pharmacokinetic drug-drug interaction potentials for therapeutic monoclonal antibodies: reality check. J Clin Pharmacol. 2007;47(9):1104-1118.
Zhao L, Ren TH, Wang DD. Clinical pharmacology considerations in biologics development. Acta Pharmacologica Sinica. 2012;33(11):1339-1347.