Pharmacokinetic drug-drug interactions occur when a drug alters the disposition absorption, distribution, elimination of a coadministered agent. Pharmacokinetic interactions may result in the increase or the decrease of plasma drug concentrations. These modifications are variable in intensity but can lead to contraindications of the association. The mechanisms of pharmacokinetic interactions involve drug metabolizing enzymes, drug transporters and orphan nuclear receptors that regulate at the transcriptional level the expression of enzymes and transporters.

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Newly approved drugs expand our therapeutic armamentarium, but augment the potential for drug—drug interactions. These can be broadly categorized into pharmaceutical physicochemical, usually occurring ex vivo , pharmacokinetic PK or pharmacodynamic PD. Importantly a drug—drug interaction that primarily causes a change in PK will consequently cause a secondary alteration in its pharmacodynamics.

The literature has a plethora of human drug—drug interaction studies with widely differing designs, addressing the existence and possible clinical importance of specific potential drug—drug interactions. Most drug—drug interaction studies in humans compare drug substrate D concentrations with and without the interacting drug I , thus focusing on the pharmacokinetic type of interaction.

The selection of which one of these to use, or an alternative study design, depends on factors which relate specifically to the drug substrate and the interacting drug.

In this issue of the Journal we publish several papers describing drug—drug interaction studies, and a cadre of papers that highlight the value of careful clinical observation and investigation in a single clinical case, which draws attention to potential, but previously undefined or poorly defined, drug—drug interactions. Derks et al. The pharmacokinetic profiles of each drug were determined on day 7 of each treatment. Based on the least mean squares ratios for AUC and C max ezetimibe had no significant effect on dalcetrapib pharmacokinetics, while dalcetrapib slightly reduced the AUC and C max of ezetimibe.

The plasma lipid profile effects were similar for all treatments, except that dalcetripib plus ezetimibe produced a greater reduction in LDL-C. While this study did not reveal a clinically significant pharmacokinetic interaction between the agents, it was a relatively short-term study and was not performed in patients taking these agents, where the findings could be different.

A number of reports to agencies in Canada and Europe of increased warfarin anticoagulant effects in patients concomitantly taking oseltamivir prompted Davies et al. They were randomized to concomitant oseltamivir 75 mg twice daily for 4. Anticoagulant effects were studied by calculating the area under the effect concentration curve AUEC 0,96 h , the observed maximum increase in INR from baseline, the decrease from baseline in Factor VIIa, and the change in vitamin K 1 concentrations.

The duration of oseltamivir treatment in the study, while appropriate for influenza treatment, may not be long enough for patients with severe H1N1 infection.

The authors also point out that the influenza virus infection can produce cytokines e. Egerer et al. Aprepitant is a moderate inhibitor of CYP and may inhibit drug transporter proteins. Melphalan C max , AUC and plasma clearance were the same with aprepitant and placebo. Thus, mg of aprepitant given orally 1 h before the melphalan infusion did not alter the disposition of melphalan. Monte et al. He developed the serotonin syndrome as diagnosed on clinical Hunter criteria [ 6 ] and made a good recovery.

A literature review revealed three cases of overdoses in which solely dextromethorphan and chlorphenamine including that reported in this paper had been ingested and in which serotonin syndrome developed.

The authors sensibly suggest that in patients who take a combined overdose of dextromethorphan and chlorphenamine, the development of serotonin syndrome should be considered a potential complication. Heine et al. Initially the gastrointestinal symptoms were treated with antacids and then with the proton pump inhibitor pantoprazole intravenously for 2 days and then orally for 5 days.

Erlotinib plasma C min trough concentrations were reduced during high dose intravenous pantoprazole therapy compared with baseline, but rose into the putative therapeutic range when pantoprazole was used orally in a lower dose. The proposed mechanism for this observation is reduced absorption of erlotinib pKa 5.

Clearly, further studies are needed to confirm the potential interaction between pantoprazole and erlotinib and to define its dose-dependency. There is a controversy in an evolving literature concerning the putative effect of proton pump inhibitors e. A recent paper in our sister Journal by Zahno et al.

The conversion of clopidogrel to its active metabolite R is a two-step CYPdependent process. It is difficult to interpret these data from a clinical perspective, because the C max of clopidogrel after 75 to mg oral doses is only 0. It appears that only a prospective randomized placebo controlled trial will settle this debate. The panoply of study designs outlined above may be used to generate definitive data on in vivo drug—drug interactions, but, not surprisingly, there is no one single optimal study design.

The suggested study designs using healthy volunteers may not be optimal for investigational or approved drugs, particularly when small numbers of subjects are studied where the drug—drug interaction only occurs in a few susceptible individuals [ 14 ]. Moreover, drug—drug interaction studies in appropriate patient populations have higher relevance and accuracy, providing they are feasible and can be conducted safely.

Well documented case reports play a definite role in informing and guiding well-controlled further studies. In vitro studies, particularly for CYPmediated interactions, can be helpful in estimating the likely magnitude of any interaction and understanding its mechanism. The incidence of drug—drug interactions in clinical therapeutics will continue to increase and challenge prescribers; as well as drawing the interest of clinical pharmacologists. National Center for Biotechnology Information , U.

Br J Clin Pharmacol. Author information Copyright and License information Disclaimer. This article has been cited by other articles in PMC.

Study designs used to determine drug—drug interactions Most drug—drug interaction studies in humans compare drug substrate D concentrations with and without the interacting drug I , thus focusing on the pharmacokinetic type of interaction. Drug—drug interaction studies, designs, and outcomes Derks et al.

The contribution of clinical cases as a signal for potential drug—drug interactions Monte et al. The role of in vitro studies in understanding drug—drug interactions There is a controversy in an evolving literature concerning the putative effect of proton pump inhibitors e. Drug interaction studies: study design, data analysis, and implications for dosing and labeling. Clin Pharmacol Ther.

Lack of clinically relevant drug—drug interactions when dalcetrapib is co-administered with ezetimibe. Effect of oseltamivir treatment on anticoagulation: a crossover study in warfarinized patients. The NK1 receptor antagonist aprepitant does not alter the pharmacokinetics of high-dose melphalan chemotherapy in patients with multiple myeloma. Dextromethorphan, chlorphenamine and serotonin toxicity: case report and systematic literature review.

The Hunter serotonin toxicity criteria: simple and accurate diagnostic decision rules for serotonin toxicity.

Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol. In vitro characterization of cytochrome P 2D6 inhibition by classic histamine H1 receptor antagonists. Drug Metab Dispos. Erlotinib and pantoprazole: a relevant interaction or not? A case report. Effect of proton pump inhibitors on clinical outcome in patients treated with clopidogrel: a systematic review and meta-analysis.

J Thromb Haemost. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med. Effects of drug interactions on biotransformation and antiplatelet effect of clopidogrel in vitro. Br J Pharmacol. Pharmacokinetics of clopidogrel. Semin Thromb Hemost. Aronson JK. Classifying drug interactions.

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Drug–drug interactions: is there an optimal way to study them?



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