The Impact of N-nitrosamine Impurities on Clinical Drug Development

Over the past few years, an increasing number of commercially available drugs have been reported to contain N-nitrosamine impurities above acceptable intake limits. Consequent interruption or discontinuation of the manufacturing and distribution of several marketed drugs has culminated into shortage...

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Bibliographic Details
Published inJournal of pharmaceutical sciences Vol. 112; no. 5; pp. 1183 - 1191
Main Authors Paglialunga, Sabina, van Haarst, Aernout
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 01.05.2023
Subjects
1-methyl-4-nitrosopiperazine
Carbamazepine
CYP3A4
Drug Development
Drug Interactions
Efavirenz
Humans
Lumacaftor
Pharmaceutical Preparations
Phenytoin
Rifampicin
Rifampin
Rifampin - therapeutic use
Tuberculosis - drug therapy
Rifampicin
1-methyl-4-nitrosopiperazine
Lumacaftor
CYP3A4
Rifampin
Efavirenz
Carbamazepine
Phenytoin
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Summary:Over the past few years, an increasing number of commercially available drugs have been reported to contain N-nitrosamine impurities above acceptable intake limits. Consequent interruption or discontinuation of the manufacturing and distribution of several marketed drugs has culminated into shortages of marketed drugs, including the antidiabetic drug metformin and the potentially life-saving drug rifampin for the treatment of tuberculosis. Alarmingly, the clinical development of new investigational products has been complicated as well by the presence of N-nitrosamine impurities in batches of marketed drug. In particular, rifampin is a key clinical index drug employed in drug-drug interaction (DDI) studies, and as a result of nitrosamine impurities regulatory bodies no longer accept the administration of rifampin in DDI studies involving healthy subjects. Drug developers are now forced to look at alternative approaches for commonly employed perpetrators, which will be discussed in this review.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:0022-3549
1520-6017
1520-6017
DOI:10.1016/j.xphs.2023.01.017