Translational aspects of cytochrome P450-mediated drug-drug interactions : A case study with clopidogrel

Multimorbidity, polypharmacotherapy and drug interactions are increasingly common in the ageing population. Many drug-drug interactions (DDIs) are caused by perpetrator drugs inhibiting or inducing cytochrome P450 (CYP) enzymes, resulting in alterations of the plasma concentrations of a victim drug. DDIs can have a major negative health impact, and in the past, unrecognized DDIs have resulted in drug withdrawals from the market. Signals to investigate DDIs may emerge from a variety of sources. Nowadays, standard methods are widely available to identify and characterize the mechanisms of CYP-mediated DDIs in vitro. Clinical pharmacokinetic studies, in turn, provide experimental data on pharmacokinetic outcomes of DDIs. Physiologically based pharmacokinetic (PBPK) modelling utilizing both in vitro and in vivo data is a powerful tool to predict different DDI scenarios. Finally, epidemiological studies can provide estimates on the health outcomes of DDIs. Thus, to fully characterize the mechanisms, clinical effects and implications of CYP-mediated DDIs, translational research approaches are required. This minireview provides an overview of translational approaches to study CYP-mediated DDIs, going beyond regulatory DDI guidelines, and an illustrative case study of how the DDI potential of clopidogrel was unveiled by combining these different methods.Peer reviewe

Medicines, environment and clinical pharmacology

Medical associations and other societies have announced their theses on protection of the climate and environmental aspects in medicine. The challenges with climate change and sustainability are complex, and no quick solutions are to be found. However, basic knowledge on these issues should be available to everyone, and environmental aspects of drugs are important to all healthcare professionals. We present here a study with medical students who were introduced for the first time to environmental aspects of medicines. The results confirmed the suitability and feasibility of the approach to introduce this subject to students, and we propose that the same method can be used also when explaining the issue to medical professionals. We would like to encourage particularly clinical pharmacologists, pharmacologists and pharmacists to take a more apparent position in this field and to participate in the discussions where the strategies for the choice of medicines are considered.Peer reviewe

Health service use and costs associated with fluoroquinolone-related tendon injuries

Y The aim of this study was to assess costs and health service use associated with tendon injuries after the use of fluoroquinolone antimicrobialsin Finland during 2002-2012. This retrospective observational study included data from the Finnish Pharmaceutical Insurance Pool's pharmaceutical injury claims. In total, 145 compensated claimants aged >= 18 years presenting tendon injuries after the use of fluoroquinolones (FQs) were included in the study. Outcomes of interest were the number of outpatient visits to primary, secondary, tertiary, and private healthcare services, hospital days, rehabilitation and their costs. Regression models were used to analyze the impact of patient characteristics on hospital days, as well as the relationship between patient characteristics and tendon ruptures. Direct costs of a tendon injury averaged 14,800euro and indirect costs were estimated to be 9,077euro for employed claimants. Fifty-one percent of the claimants were hospitalized, with an average duration of 21 days. Hospitalization was the costliest form of health service use with an average of 9,915euro per hospital episode. Hospital days and direct costs increased with the severity of the injury. Tendon ruptures, in particular bilateral ruptures, required substantially more hospital days and their direct costs were significantly higher than those of uncomplicated tendinitis. Concurrent use of oral corticosteroids and increasing age were associated with a higher likelihood of tendon ruptures. Although rare, FQ-related tendon injuries can result in considerable costs and health service use. Medical staff should remain vigilant when prescribing FQs, especially in groups at increased risk for tendon injuries.Peer reviewe

Incidence, preventability, and causality of adverse drug reactions at a university hospital emergency department

Purpose To investigate the characteristics of ADRs in patients admitting at the emergency room of a tertiary hospital. Methods We collected the patient records of 1600 emergency room visits of a university hospital in 2018. The patient files were studied retrospectively and all possible ADRs were identified and registered. Patient characteristics, drugs associated with ADRs, causality, severity, preventability, and the role of pharmacogenetics were assessed. Results There were 125 cases with ADRs, resulting in a 7.8% overall incidence among emergency visits. The incidence was greatest in visits among elderly patients, reaching 14% (men) to 19% (women) in the 80-89 years age group. The most common causative drugs were warfarin, acetylsalicylic acid (ASA), apixaban, and docetaxel, and the most common ADRs were bleedings and neutropenia and/or severe infections. Only two of the cases might have been prevented by pharmacogenetic testing, as advised in Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. Conclusion The same ATC classes, antithrombotics and cytostatics, were involved in ADRs causing university clinic hospitalizations as those identified previously in drug-related hospital fatalities. It seems difficult to prevent these events totally, as the treatments are vitally important and their risk-benefit-relationships have been considered thoroughly, and as pharmacogenetic testing could have been useful in only few cases.Peer reviewe

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

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.Peer reviewe

Performance of Plasma Coproporphyrin I and III as OATP1B1 Biomarkers in Humans

A previous study in 356 healthy Finnish volunteers showed that glycochenodeoxycholate 3-O-glucuronide (GCDCA-3G) and glycodeoxycholate 3-O-glucuronide (GDCA-3G) are promising biomarkers of organic anion transporting polypeptide 1B1 (OATP1B1). In the same cohort, we now evaluated the performances of two other OATP1B1 biomarkers, coproporphyrin I (CPI) and III (CPIII), and compared them with GCDCA-3G and GDCA-3G. Based on decreased (*5 and *15) and increased (*14 and *20) function SLCO1B1 haplotypes, we stratified the participants to poor, decreased, normal, increased, and highly increased OATP1B1 function groups. Fasting plasma CPI concentration was 68% higher in the poor (95% confidence interval, 44%, 97%; P = 1.74 x 10(-10)), 7% higher in the decreased (0%, 15%; P = 0.0385), 10% lower in the increased (3%, 18%; P = 0.0087), and 23% lower in the highly increased (1%, 40%; P = 0.0387) function group than in the normal function group. CPIII concentration was 27% higher (7%, 51%; P = 0.0071) in the poor function group than in the normal function group. CPI and CPIII detected poor OATP1B1 function with areas under the precision-recall curve (AUPRC) of 0.388 (95% confidence interval, 0.197, 0.689) and 0.0798 (0.0485, 0.203), and receiver operating characteristic curve (AUROC) of 0.888 (0.851, 0.919) and 0.731 (0.682, 0.776). The AUPRC and AUROC of GCDCA-3G were, however, 0.389 (0.258, 0.563) and 0.100 (-0.0046, 0.204; P = 0.0610) larger than those of CPI, and 0.697 (0.555, 0.831) and 0.257 (0.141, 0.373; P < 0.0001) larger than those of CPIII. In conclusion, these data indicate that plasma CPI outperforms CPIII in detecting altered OATP1B1 function, but GCDCA-3G is an even more sensitive OATP1B1 biomarker than CPI.Peer reviewe

Fluoroquinolone-related adverse events resulting in health service use and costs : A systematic review

Background and objectives Adverse events (AEs) associated with the use of fluoroquinolone antimicrobials include Clostridium difficile associated diarrhea (CDAD), liver injury and seizures. Yet, the economic impact of these AEs is seldom acknowledged. The aim of this review was to identify health service use and subsequent costs associated with ciprofloxacin, levofloxacin, moxifloxacin, norfloxacin and ofloxacin -related AEs. Methods A literature search covering Medline, SCOPUS, Cinahl, Web of Science and Cochrane Library was performed in April 2017. Two independent reviewers systematically extracted the data and assessed the quality of the included studies. All costs were converted to 2016 euro in order to improve comparability. Results Of the 5,687 references found in the literature search, 19 observational studies, of which five were case-controlled, fulfilled the inclusion criteria. Hospitalization was an AE-related health service use outcome in 17 studies. Length of hospital stay associated with AEs varied between <5 and 45 days. The estimated cost of an AE episode ranged between 140 and 18,252 (sic). CDAD was associated with the longest stays in hospital. Ten studies reported AE-related length of stays and five evaluated costs associated with AEs. Due to the lack of published literature, health service use and costs associated with many high-risk FQ-related AEs could not be evaluated. Conclusions Because of the wide clinical use of fluoroquinolones, in particular serious fluoroquinolone-related AEs can have substantial economic implications, in addition to imposing potentially devastating health complications for patients. Further measures are required to prevent and reduce health service use and costs associated with fluoroquinolone-related AEs. Equally, better-quality reporting and additional published data on health service use and costs associated with AEs are needed.Peer reviewe

Translational aspects of cytochrome P450-mediated drug-drug interactions: A case study with clopidogrel

Multimorbidity, polypharmacotherapy and drug interactions are increasingly common in the ageing population. Many drug-drug interactions (DDIs) are caused by perpetrator drugs inhibiting or inducing cytochrome P450 (CYP) enzymes, resulting in alterations of the plasma concentrations of a victim drug. DDIs can have a major negative health impact, and in the past, unrecognized DDIs have resulted in drug withdrawals from the market. Signals to investigate DDIs may emerge from a variety of sources. Nowadays, standard methods are widely available to identify and characterize the mechanisms of CYP-mediated DDIs in vitro. Clinical pharmacokinetic studies, in turn, provide experimental data on pharmacokinetic outcomes of DDIs. Physiologically based pharmacokinetic (PBPK) modelling utilizing both in vitro and in vivo data is a powerful tool to predict different DDI scenarios. Finally, epidemiological studies can provide estimates on the health outcomes of DDIs. Thus, to fully characterize the mechanisms, clinical effects and implications of CYP-mediated DDIs, translational research approaches are required. This minireview provides an overview of translational approaches to study CYP-mediated DDIs, going beyond regulatory DDI guidelines, and an illustrative case study of how the DDI potential of clopidogrel was unveiled by combining these different methods.</p

Clopidogrel and Gemfibrozil Strongly Inhibit the CYP2C8-Dependent Formation of 3-Hydroxydesloratadine and Increase Desloratadine Exposure In Humans

A recent in vitro study suggested that CYP2C8 is essential in the metabolism of desloratadine, an H1 receptor antagonist. If the proposed biotransformation mechanism takes place in vivo in humans, desloratadine could serve as a selective CYP2C8 probe substrate in drug-drug interaction studies. Glucuronide metabo-lites of clopidogrel and gemfibrozil act as time-dependent inhibitors of CYP2C8, but they have not been compared clinically. We conducted a randomized crossover study in 11 healthy subjects to characterize the involvement of CYP2C8 in desloratadine metabolism and to compare the CYP2C8 inhibitory strength of clopidogrel (300 and 75 mg on two following days) with that of gemfibrozil (600 mg BID for 5 days). Compared with placebo (control), clopidogrel increased the area under the plasma concentration-time curve (AUC(0-infinity)) and peak plasma concentration (C-max) of desloratadine to 280% (P = 3 x 10(-7)) and 165% (P = 0.0006), respectively. The corresponding increases by gemfibrozil were to 462% (P = 4 x 10(-7)) and 174% (P = 0.0006). Compared with placebo, clopidogrel and gemfibrozil decreased 3-hydroxyloratadine AUC(0-71h) to 52% (P = 5 x 10(-5)) and 6%(P = 2 X 10(-8)), respectively. Moreover, the 3-hydroxydesloratadine: desloratadine AUC(0-71h) ratios were 21% (P = 7 x 10(-10)) and 1.7% (P = 8 x 10(-11)) of control during the clopidogrel and gemfibrozil phases. Our results confirm that CYP2C8 plays a critical role in the formation of 3-hydroxydesloratadine in humans, making desloratadine a potential CYP2C8 probe substrate. Furthermore, the findings corroborate the previous estimates that clinically relevant doses of clopidogrel cause strong CYP2C8 inhibition, whereas those of gemfibrozil almost completely inactivate the enzyme in humans.Peer reviewe