A novel drug interaction between busulfan and blinatumomab.

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Sweiss K, Quigley JG, Oh A, Lee J, Ye R, Rondelli D, Patel P

A novel drug interaction between busulfan and blinatumomab.

J Oncol Pharm Pract. 2017 Jan 1:1078155217729745. doi: 10.1177/1078155217729745.

PubMed ID

28857712 [ View in PubMed

]

Abstract

Busulfan is an alkylating agent used in pre-transplant conditioning for patients undergoing hematopoietic stem cell transplantation. Several factors contribute to variations in busulfan drug disposition including bioavailability, age, liver function, genetic polymorphisms, and concurrent administration of other drugs. Busulfan is metabolized by hepatic oxidation via the cytochrome P450 3A4 system as well as through conjugation with glutathione. Interactions with drugs such as phenytoin, itraconazole, and metronidazole have been reported to alter busulfan clearance and result in sub- or supra-therapeutic concentrations. We report a case of a clinically significant drug interaction between intravenous busulfan and the bifunctional T-cell engager, blinatumomab, observed through busulfan therapeutic drug monitoring. We found that busulfan clearance was reduced resulting in a higher area under the concentration-time curve when it was administered 48 h after blinatumomab. Repeat busulfan pharmacokinetic testing two weeks later demonstrated increased clearance of the drug and a 31% higher dose recommendation. Similar to other protein therapeutics, cytokine elevations during blinatumomab treatment can lead to cytochrome 3A4 suppression. We hypothesize that the increased busulfan levels observed could be related to a cytokine-mediated CYP3A4 suppression. This represents a unique pharmacologic consideration in hematopoietic stem cell transplantation which would impact several drugs that undergo CYP3A4 metabolism, including calcineurin inhibitors, cyclophosphamide, sirolimus, and triazole antifungals. Additionally, this mechanism of CYP3A4 suppression may be relevant in treatments and disease states where cytokine levels are elevated such as haploidentical stem cell transplantation, graft-versus-host disease, and use of chimeric antigen receptor T-cell therapy.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Busulfan	Cytochrome P450 3A4	Protein	Humans	Unknown	Substrate	Details

Drug Interactions

Drugs	Interaction
Integrate drug-drug interactions in your software
Busulfan Phenytoin	The serum concentration of Busulfan can be decreased when it is combined with Phenytoin.
Busulfan Fosphenytoin	The serum concentration of Busulfan can be decreased when it is combined with Fosphenytoin.

Food Interactions

Drug	Interaction
Busulfan	Exercise caution with grapefruit products.
Busulfan	Exercise caution with St. John's Wort.