ALEMTUZUMAB
DACLIZUMAB
DIMETHYL FUMARATE
NATALIZUMAB
TERIFLUNOMIDE
- Action to be taken: Monitor therapy, interaction unlikely
- Rationale: Little is known about metabolism of alemtuzumab. As alemtuzumab is a recombinant humanised protein, the expected metabolic pathway is proteolysis. Furthermore there are no studies of pharmacodynamic or pharmacokinetic drug interactions performed with alemtuzumab. However based on its expected metabolism, alemtuzumab is an unlikely candidate for cytochrome P450 mediated drug-drug interactions.
DACLIZUMAB
- Action to be taken: No action needed, interaction unlikely
- Rationale:Daclizumab is eliminated via proteolysis, target-mediated elimination, and nonspecific endocytosis, and is not expected to undergo renal elimination. Daclizumab has no effect on CYP450 enzymes such as CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A. Therefore no dosage adjustments are needed when medications that are substrates for these enzymes are concomitantly given with daclizumab.
DIMETHYL FUMARATE
- Action to be taken: None
- Rationale: Dimethyl fumarate is extensively metabolized by esterases before it reaches the systemic circulation. Further metabolism of it occurs through the tricarboxylic acid (TCA) cycle, with no involvement of the cytochrome P450 (CYP) system. No potential drug interactions with dimethyl fumarate or MMF were identified in in vitro CYP inhibition and induction studies, or in P-glycoprotein studies.
NATALIZUMAB
- Action to be taken: Monitor therapy, interaction unlikely
- Rationale: Little is known about metabolism of natalizumab. As natalizumab is a partially humanized monoclonal antibody, the expected clearance pathway is Fc-mediated phagocytosis. There are no studies evaluating cytochrome P450 mediated drug -drug interactions with natalizumab. However based on its proteinous nature its not expected to interact with CYP450 enzyme substrates.
TERIFLUNOMIDE
- Action to be taken: Monitor for possible side effects of cannabis, adjust dose
- Rationale: Teriflunomide is not metabolized by Cytochrome P450 enzymes. In vivo and in vitro data has shown that Teriflunomide may increase exposure of drugs that are metabolized by CYP2C8 and decrease exposure of drugs metabolized by CYP1A2. In vitro data has shown that certain cannabinoids and their metabolites are potential CYP1A2 and CYP2C8 substrates. Although this may be a minimal pathway of metabolism, there still could be a potential for interaction. There was an increase in mean repaglinide Cmax and AUC, following repeated doses of teriflunomide and a single dose of 0.25 mg repaglinide. The magnitude of interaction could be higher at the recommended repaglinide dose. Therefore, monitoring patients with concomitant use of drugs metabolized by CYP2C8, is recommended as they may have higher exposure. Furthermore repeated doses of teriflunomide decreased mean Cmax and AUC of caffeine (CYP1A2 substrate) by 18% and 55% respectively, suggesting that teriflunomide may be in vivo a weak inducer of CYP1A2. Therefore, patients should be monitored when teriflunomide is coadministered with drugs metabolized by CYP1A2, as the efficacy of such drugs could be reduced.
References
- Tacfidera(dimethyl fumarate) package insert. Biogen Idec Inc. Cambridge, MA 2014
- Aubagio (teriflunomide) package insert. Genzyme Corporation. Cambridge, MA 2012
- Lemtrada (alemtuzumab) package insert. European Medicines Agency, 2013
- Tran JQ, Othman AA, Wolstencroft P, Elkins J. Therapeutic protein–drug interaction assessment for daclizumab high‐yield process in patients with multiple sclerosis using a cocktail approach. British Journal of Clinical Pharmacology. 2016;82(1):160-167. doi:10.1111/bcp.12936.
- Tysabri (natalizumab) Scientific Discussion. European Medicines Agency, 2006
- Watanabe K, Yamaori S, Funahashi T, et al. Cytochrome P450 enzymes involved in the metabolism of tetrahydrocannabinols and cannabinol by human hepatic microsomes. Life Sci. 2007;80:1415-1419.
- Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab Rev. 2014;46:86-95.