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Fatal interstitial lung disease associated with high erlotinib and metabolite levels. A case report and a review of the literature.

Item does not contain fulltextINTRODUCTION: Erlotinib is an agent in the class of oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Although this class of agents is considered to be relatively safe, the most serious, but rare, adverse reaction is drug-associated interstitial lung disease (ILD). This potentially fatal adverse reaction has been often described with gefitinib, but has been less well described for erlotinib. We here describe a case report of fatal interstitial lung disease in a Caucasian man associated with erlotinib and high erlotinib and metabolite plasma levels and discuss it in the context of all documented cases of erlotinib associated ILD. METHODS: Our case was described and for the literature review a Pubmed and Google Scholar search was conducted for cases of erlotinib associated ILD. The retrieved publications were screened for relevant literature. RESULTS: Besides our case, a total of 19 cases of erlotinib-associated ILD were found. Eleven out 19 cases had a fatal outcome and in only one case erlotinib plasma concentrations were measured and found to be high. CONCLUSION: Erlotinib-associated ILD is a rare, serious and often fatal adverse reaction. Most likely, the cause for erlotinib-associated ILD is multifactorial and high drug levels may be present in patients without serious adverse reactions. However, considering the pharmacology of EGFR inhibitors, high drug and metabolite levels may play a role and future studies are warranted to identify risk factors and to investigate the role of elevated levels of erlotinib and its metabolites in the development of pulmonary toxicity.1 maart 201

Absence of both cytochrome P450 3A and P-glycoprotein dramatically increases docetaxel oral bioavailability and risk of intestinal toxicity.

Contains fulltext : 79599.pdf (publisher's version ) (Closed access)Docetaxel is one of the most widely used anticancer drugs. A major problem with docetaxel treatment, however, is the considerable interpatient variability in docetaxel exposure. Another disadvantage of the drug is that it has a very low oral bioavailability and can therefore only be administered i.v. The drug-metabolizing enzyme cytochrome P450 3A (CYP3A) and the drug transporter P-glycoprotein (P-gp; MDR1) are considered to be major determinants of docetaxel pharmacokinetics. It has been hypothesized that CYP3A and P-gp work synergistically in limiting the systemic exposure to many orally ingested drugs. However, it has been difficult to examine this interplay in vivo. We therefore generated mice lacking all CYP3A and P-gp genes. Although missing two primary detoxification systems, Cyp3a/Mdr1a/1b(-/-) mice are viable, fertile, and without spontaneous abnormalities. When orally challenged with docetaxel, a disproportionate (>70-fold) increase in systemic exposure was observed compared with the increases in single Cyp3a(-/-) (12-fold) or Mdr1a/1b(-/-) (3-fold) mice. Unexpectedly, although CYP3A and P-gp collaborated extremely efficiently in lowering docetaxel exposure, their individual efficacy was not dependent on activity of the other protein. On reflection, this absence of functional synergism makes biological sense, as synergism would conflict with a robust detoxification defense. Importantly, the disproportionate increase in docetaxel exposure in Cyp3a/Mdr1a/1b(-/-) mice resulted in dramatically altered and lethal toxicity, with severe intestinal lesions as a major cause of death. Simultaneous inhibition of CYP3A/P-gp might thus be a highly effective strategy to improve oral drug bioavailability but with serious risks when applied to drugs with narrow therapeutic windows