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Interactions Between Antiepileptic and Antibiotic Drugs: A Systematic Review and Meta-Analysis with Dosing Implications

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Abstract

Introduction

Qualitative studies on drug–drug interactions (DDIs) between anticonvulsants and antibiotics report pharmacokinetic changes that may increase the clinical risks in terms of adverse drug reactions (ADRs) and efficacy. However, no studies have provided a systematic and quantitative analysis of anticonvulsant–antibiotic pharmacokinetic DDIs. To provide such indications, we systematically and critically reviewed the literature on anticonvulsant–antibiotic DDIs in terms of quantitative pharmacokinetic changes and related ADRs. We also investigated less-known interactions for the possible occurrence of clinically relevant events.

Methods

We conducted a systematic review of all reports of DDIs between anticonvulsants and antibiotics assessing pharmacokinetic parameters published until 9 June 2017.

Results

We were able to meta-analyse the effect of macrolides on carbamazepine area under the concentration-time curve from time zero to infinity [AUC∞] (+ 34.5 µg/mL*h, p = 0.005, n = 38), clearance (− 2.88 mL/min, p < 0.001, n = 46) and trough plasma concentration [Ct] (+ 8.0 µg/mL, p = 0.002, n = 23), and of carbapenems on valproic acid Ct (− 42.9 µg/mL, p < 0.001, n = 262). Pharmacokinetic parameters with other DDIs were insufficiently reported to allow a statistical analysis.

Conclusions

Therapeutic drug monitoring in patients receiving long-term antiepileptic therapies may help, in specific conditions, to improve safety while preserving efficacy. Such a procedure would also increase scientific information on how pharmacokinetic variations are associated with ADR occurrence, and possibly epileptological outcomes for those DDIs for which available information is suggestive of a relevant effect but is not yet sufficient to draw conclusions.

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Author notes

  1. Carla Carnovale and Marco Pozzi contributed equally to this work.

Authors and Affiliations

  1. Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences L. Sacco, “Luigi Sacco” University Hospital, Università di Milano, Via GB Grassi 74, 20157, Milan, Italy

    Carla Carnovale, Faizan Mazhar, Giulia Mosini, Marta Gentili, Gabriëlla G. A. M. Peeters, Emilio Clementi & Sonia Radice

  2. Scientific Institute IRCCS Eugenio Medea, 23842 Bosisio Parini, Lecco, Italy

    Marco Pozzi & Emilio Clementi

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  1. Carla Carnovale
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Correspondence to Carla Carnovale.

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Funding

This work was supported by funds from the Regional Centre of Pharmacovigilance of Lombardy (to EC); the Italian Medicines Agency, Agenzia Italiana del Farmaco (AIFA; to EC); and the Italian Ministry of Health (Ricerca Corrente 2018; to MP). All funding is gratefully acknowledged. The public funding institutions had no role in any part of the work.

Conflict of interest

Carla Carnovale, Marco Pozzi, Faizan Mazhar, Giulia Mosini, Marta Gentili, Gabriëlla G.A.M. Peeters, Emilio Clementi and Sonia Radice have no conflicts of interest to declare that are directly relevant to the content of this article.

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Carnovale, C., Pozzi, M., Mazhar, F. et al. Interactions Between Antiepileptic and Antibiotic Drugs: A Systematic Review and Meta-Analysis with Dosing Implications. Clin Pharmacokinet 58, 875–886 (2019). https://doi.org/10.1007/s40262-018-0720-z

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  • DOI: https://doi.org/10.1007/s40262-018-0720-z

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