Drug‐drug interactions – bridging the gulf between the bench and the bedside? (2011)

In this month's issue, we are pleased to present a collection of articles that illustrates the diverse manner in which drug-drug interactions can be studied, and the equally broad range of the clinical implications that follow. Eagle-eyed readers of the BJCP will have noticed that only a few months ago, we ran an Editor's View on the optimal methods of assessing drug-drug interactions. 1 It is clear though that interactions are currently a very hot topic, particularly with regard to the debate surrounding clopidogrel and proton pump inhibitors. Very few people would dispute the fact that proton pump inhibitors can produce measurable changes in platelet function of patients receiving clopidogrel. 2 Instead, the debate rages around the conflicting clinical results from a wide variety of studies that have attempted to quantify the actual cardiovascular risk. This is highlighted by findings of substantial heterogeneity and inconsistent results in a meta-analysis of cardiovascular outcomes, thus precluding any definitive conclusions on clinical implications of concomitant clopidogrel and proton pump inhibitors therapy. 3 This month's articles certainly illustrate some diverse and innovative ways of studying drug interactions, but do the results have an important impact on guiding rational therapeutic drug use? The randomized crossover trial is an elegant design with high internal validity (provided there is sufficient masking of participants and investigators) that is widely used in drug-drug interaction studies, and we have three examples here. The hypothesis for Abbas' study, 4 stemmed from preclinical data suggesting that the tyrosine kinase inhibitor, neratinib, could potentially be influenced by other drugs that affected CYP3A4. Here, Abbas et al. demonstrated a considerable increase in overall exposure to neratinib when the 22 healthy volunteers were given ketoconazole for five days. While the study is clearly not sufficiently powered for safety assessment, and only involved a single dose of neratinib, it is worth noting that adverse effects occurred in 65% of patients in the ketoconazole phase as compared to 50% during the non-ketoconazole phase, which although not statistically significant, would be sufficient to justify some caution against concomitant use of agents that affect CYP3A4. In another trial, Lima et al. found that the albendazole and praziquantel interaction led to increased levels of both drugs in an enantioselective manner. 5 The authors concluded that this may well lead to increased adverse effects, but could also result in greater therapeutic efficacy when used in combination. The true value of combination therapy and benefit harm trade-off in clinical practice will depend on the therapeutic index and shape of the dose-response curve. While ‘negative’ or ‘non-significant’ findings are sometimes thought to be less interesting, Anderson et al.'s study demonstrating lack of interaction between raltegravir (an HIV-1 integrase strand inhibitor) and the oral contraceptive pill can prove reassuring for patients and physicians.6 Where serious consequences may stem from failure of therapy (such as for women on the oral contraceptive pill), establishing the lack of a clinically significant interaction is valuable, even more so when there is a high prevalence of oral contraceptive use in the population of interest. The recruitment of healthy volunteers and rigidly controlled conditions makes the randomized crossover trial a marvellous experiment, but what about drug interactions in the real-world patient? Haslemo et al. based their study on olanzapine values recorded by the routine therapeutic drug monitoring service, and found that the women on oral contraceptive pills did not have significantly different olanzapine levels as compared to non-users. 7 While Haslemo's study did not measure clinical outcomes, the opposite limitation is true for Antoniou's study which recorded hospitalization for phenytoin toxicity but not the serum concentrations of phenytoin. 8 Intriguingly, hospital admission for phenytoin toxicity appeared to be associated with recent exposure to co-trimoxazole, but not with amoxicillin. While both studies are subject to confounding, they certainly give a flavour of what is actually happening out in the real world, as does the case report of a patient on a beta-blocker and calcium channel blocker who developed hypotension and bradycardia after receiving HIV post-exposure prophylaxis drugs. 9 Untangling the mechanisms and source of interactions in cases of multiple drug exposures proves to be a true challenge. Could in-vitro simulation models help us predict and evaluate interactions in an environment with multiple variables that may prove difficult to study in real-life patients? Rekic et al. demonstrate that their pharmacokinetic simulation model was able to predict with reasonable accuracy (as compared to previously published human studies) the extent of the efavirenz- rifampicin interaction. 10 This simulation yielded evidence for clinical advice that in patients of >50 kg bodyweight the dose of efavirenz will need to be adjusted when rifampicin is concomitantly administered. We started by mentioning clopidogrel and proton pump inhibitors, and will finish in the same vein, to illustrate why drug-drug interactions are such a complex and fascinating challenge for clinicians and researchers. Preliminary data now suggest that paraoxonase-1 may have a major role in activation of clopidogrel, 11 which leaves one wondering whether the substantial heterogeneity in clinical outcomes (as seen in the meta-analysis) might stem from individual variation in yet undiscovered metabolic pathways for clopidogrel, or genetic predispositions amongst different populations that have not been clarified. Equally, individuals taking proton pump inhibitors for gastrointestinal symptoms (e.g. acid reflux) may be more likely to present to their doctors with chest pains and be subjected to more cardiac tests, thus potentially accounting for a greater number of adverse outcomes recorded. 12, 13 It is clear that there remain considerable difficulties in bridging the gap between the bedside and bench, and piecing together this complex jigsaw puzzle will require all the tools for laboratory evaluation and epidemiological analysis that we have seen in this month's BJCP.