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

• Published in: Clinical pharmacokinetics Vol. 58; no. 7; pp. 875 - 886
• Main Authors: Carnovale, Carla, Pozzi, Marco, Mazhar, Faizan, Mosini, Giulia, Gentili, Marta, Peeters, Gabriëlla G. A. M., Clementi, Emilio, Radice, Sonia
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01-07-2019; Springer Nature B.V
• Subjects: Acids; Anti-Bacterial Agents - adverse effects; Anti-Bacterial Agents - pharmacokinetics; Antibiotics; Anticonvulsants - adverse effects; Anticonvulsants - pharmacokinetics; Drug dosages; Drug Interactions; Epilepsy; Humans; Internal Medicine; Medicine; Medicine & Public Health; Meta-analysis; Observational Studies as Topic; Pharmacology/Toxicology; Pharmacotherapy; Randomized Controlled Trials as Topic; Studies; Systematic Review; Therapeutic drug monitoring; Toxicity
• ISSN: 0312-5963; 1179-1926
• DOI: 10.1007/s40262-018-0720-z

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.