Evaluation of Potential Interaction Between Vinorelbine and Clarithromycin

Department of Pharmacy, University of Fukui Hospital, Fukui, Japan.
Annals of Pharmacotherapy (Impact Factor: 2.06). 04/2009; 43(3):453-8. DOI: 10.1345/aph.1L432
Source: PubMed


Myelotoxicity, a major toxicity of vinorelbine. may be related to the degree of one's exposure to vinorelbine. In theory, clarithromycin has the potential to alter vinorelbine's pharmacokinetics by inhibiting CYP3A and/or P-glycoprotein; this may result in massive exposure to vinorelbine and severe toxicity. To date, macrolide-vinorelbine drug interactions have not been reported.
To estimate the clinical risk of a interaction between vinorelbine and clarithromycin.
In a retrospective cohort study, we searched computerized medical records of patients who had been administered vinorelbine in the University of Fukui Hospital. The study cohort was defined as all patients with non-small-cell lung cancer who received vinorelbine between May 30, 2003, and January 31, 2008. The treatment courses were classified according to whether or not clarithromycin was concomitantly administered with vinorelbine. Nadir neutrophil counts were recorded as the major outcomes. Vinorelbine-clarithromycin interaction was defined as a significant increase in the risk of severe neutropenia when the 2 drugs were administered concomitantly.
A total of 12 (63.2%) and 11 (27.5%) episodes of grade 3/4 neutropenia occurred among the patients who were and were not administered clarithromycin, respectively. The incidence of grade 4 neutropenia was higher in the group administered clarithromycin than in those who did not receive it (31.6% vs 2.5%; p = 0.0033). Vinorelbine dose, concomitant clarithromycin administration, and female sex were significantly correlated with severe neutropenia, with unadjusted odds ratios of 0.07 (95% CI 0.01 to 0.59), 4.52 (95% CI 1.41 to 14.45), and 4.55 (95% CI 1.39 to 14.29), respectively.
Compared with patients who are administered vinorelbine alone, patients who are administered clarithromycin during chemotherapy with vinorelbine are at a higher risk for severe neutropenia. Physicians should educate their patients about this interaction. If possible, clarithromycin administration should be avoided in patients who will undergo chemotherapy with vinorelbine in the near future. However, further prospective pharmacokinetic studies are required to confirm this interaction.

Download full-text


Available from: Hitoshi Tsukamoto, May 07, 2014
  • [Show abstract] [Hide abstract]
    ABSTRACT: Because cytotoxic chemotherapeutic agents have narrow therapeutic windows and large interindividual variability in pharmacokinetics/pharmacodynamics, dosing of these agents requires precise individual adjustment. Although the body-surface area (BSA) has long been used for this purpose, its effectiveness for minimizing interpatient variability in pharmacokinetics has been questioned. In this review, the factors that possibly contribute to inter-individual variability in drug response are reviewed, with a special focus on cytotoxic chemotherapeutic drugs such as platinum-containing agents, taxanes, irinotecan, and antimetabolites. Given that use of BSA fails to minimize inter-patient variability in drug response, causes inconvenience in reconstituting individual doses, and can result in human error, initial flat dosing with subsequent therapeutic drug monitoring might be a reasonable option that also has economic benefits.
    No preview · Article · Jan 2012 · Current Topics in Pharmacology

  • No preview · Article · Jan 2012
  • [Show abstract] [Hide abstract]
    ABSTRACT: Donepezil is a commonly used drug in older people that due to its procholinergic effects can provoke bradycardia and neurocardiogenic syncope. Donepezil is metabolized by the cytochrome P450 isozyme 3A4 (CYP3A4). Clarithromycin is a potent inhibitor of CYP3A4, and patients taking both of these drugs may be at increased risk of cardiac adverse events. The aim of this study was to evaluate the association between recent use of clarithromycin and adverse cardiovascular events in elderly patients receiving donepezil. A population-based, nested case-control study using provincial healthcare databases was conducted. The base cohort was made up of persons 66 years of age or older who were prescribed donepezil and also were prescribed clarithromycin, erythromycin, azithromycin, cefuroxime, moxifloxacin or levofloxacin. Cases were those members of the base cohort hospitalized for bradycardia, syncope or complete atrioventricular block. For each case patient, five controls were matched according to age, sex and residence (community or long-term care). Between July 2002 and March 2010, 17,712 patients continuously receiving donepezil were prescribed one of the antibacterials. In 1400 person-years of follow-up, 59 cases were identified. As compared with azithromycin, there was no statistically significant association between use of clarithromycin in donepezil users and subsequent adverse cardiovascular events (odds ratio 0.67; 95% CI 0.28, 1.63). There was no significant risk associated with exposure to either cefuroxime or respiratory quinolones. The use of clarithromycin in elderly donepezil users did not significantly increase the risk of adverse cardiovascular outcomes. However, our study cannot rule out a possible small increase in risk. Although antibacterials can be beneficial, care should be taken in selecting antibacterials for use in older people receiving donepezil.
    No preview · Article · Mar 2012 · Drugs & Aging
Show more