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Clinical Studies on Drug-Drug Interactions Involving Metabolism and Transport: Methodology, Pitfalls, and Interpretation.

ABSTRACT: Many drug-drug interactions (DDIs) are based on alterations of the plasma concentrations of a victim drug due to another drug causing inhibition and/or induction of the metabolism or transporter-mediated disposition of the victim drug. In the worst case, such interactions cause more than tenfold increases or decreases in victim drug exposure, with potentially life-threatening consequences. There has been tremendous progress in the predictability and modeling of DDIs. Accordingly, the combination of modeling approaches and clinical studies is the current mainstay in evaluation of the pharmacokinetic DDI risks of drugs. In this paper, we focus on the methodology of clinical studies on DDIs involving drug metabolism or transport. We specifically present considerations related to general DDI study designs, recommended enzyme and transporter index substrates and inhibitors, pharmacogenetic perspectives, index drug cocktails, endogenous substrates, limited sampling strategies, physiologically-based pharmacokinetic modeling, complex DDIs, methodological pitfalls, and interpretation of DDI information.

SUBMITTER: Tornio A

PROVIDER: S-EPMC6563007 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Clinical Studies on Drug-Drug Interactions Involving Metabolism and Transport: Methodology, Pitfalls, and Interpretation.

Tornio Aleksi A Filppula Anne M AM Niemi Mikko M Backman Janne T JT

Clinical pharmacology and therapeutics 20190420 6

Many drug-drug interactions (DDIs) are based on alterations of the plasma concentrations of a victim drug due to another drug causing inhibition and/or induction of the metabolism or transporter-mediated disposition of the victim drug. In the worst case, such interactions cause more than tenfold increases or decreases in victim drug exposure, with potentially life-threatening consequences. There has been tremendous progress in the predictability and modeling of DDIs. Accordingly, the combination ...[more]

PMID: 30916389

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Project description:BackgroundBabesia spp. are protozoan parasites of great medical and veterinary importance, especially in the northern Hemisphere. Ticks are known vectors of Babesia spp., although some Babesia-tick interactions have not been fully elucidated.MethodsThe present review was performed to investigate the specificity of Babesia-tick species interactions that have been identified using molecular techniques in studies conducted in the last 20 years under field conditions. We aimed to indicate the main vectors of important Babesia species based on published research papers (n = 129) and molecular data derived from the GenBank database.ResultsRepeated observations of certain Babesia species in specific species and genera of ticks in numerous independent studies, carried out in different areas and years, have been considered epidemiological evidence of established Babesia-tick interactions. The best studied species of ticks are Ixodes ricinus, Dermacentor reticulatus and Ixodes scapularis (103 reports, i.e. 80% of total reports). Eco-epidemiological studies have confirmed a specific relationship between Babesia microti and Ixodes ricinus, Ixodes persulcatus, and Ixodes scapularis and also between Babesia canis and D. reticulatus. Additionally, four Babesia species (and one genotype), which have different deer species as reservoir hosts, displayed specificity to the I. ricinus complex. Eco-epidemiological studies do not support interactions between a high number of Babesia spp. and I. ricinus or D. reticulatus. Interestingly, pioneering studies on other species and genera of ticks have revealed the existence of likely new Babesia species, which need more scientific attention. Finally, we discuss the detection of Babesia spp. in feeding ticks and critically evaluate the data on the role of the latter as vectors.ConclusionsEpidemiological data have confirmed the specificity of certain Babesia-tick vector interactions. The massive amount of data that has been thus far collected for the most common tick species needs to be complemented by more intensive studies on Babesia infections in underrepresented tick species.

Dataset Information

Clinical Studies on Drug-Drug Interactions Involving Metabolism and Transport: Methodology, Pitfalls, and Interpretation.

Publications

Clinical Studies on Drug-Drug Interactions Involving Metabolism and Transport: Methodology, Pitfalls, and Interpretation.

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