Caroline Flora Samer

Genetic polymorphisms and drug interactions modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety

Background and purpose:  The major drug‐metabolizing enzymes for the oxidation of oxycodone are CYP2D6 and CYP3A. A high interindividual variability in the activity of these enzymes because of genetic polymorphisms and/or drug–drug interactions is well established. The possible role of an active metabolite in the pharmacodynamics of oxycodone has been questioned and the importance of CYP3A‐mediated effects on the pharmacokinetics and pharmacodynamics of oxycodone has been poorly explored.

The effects of CYP2D6 and CYP3A activities on the pharmacokinetics of immediate release oxycodone

Background and purpose:  There is high interindividual variability in the activity of drug‐metabolizing enzymes catalysing the oxidation of oxycodone [cytochrome P450 (CYP) 2D6 and 3A], due to genetic polymorphisms and/or drug–drug interactions. The effects of CYP2D6 and/or CYP3A activity modulation on the pharmacokinetics of oxycodone remains poorly explored.

Pharmacogenetics of analgesics: toward the individualization of prescription

The use of analgesics is based on the empiric administration of a given drug with clinical monitoring for efficacy and toxicity. However, individual responses to drugs are influenced by a combination of pharmacokinetic and pharmacodynamic factors that can sometimes be regulated by genetic factors. Whereas polymorphic drug-metabolizing enzymes and drug transporters may affect the pharmacokinetics of drugs, polymorphic drug targets and disease-related pathways may influence the pharmacodynamic action of drugs. After a usual dose, variations in drug toxicity and inefficacy can be observed depending on the polymorphism, the analgesic considered and the presence or absence of active metabolites. For opioids, the most studied being morphine, mutations in the ABCB1 gene, coding for P-glycoprotein (P-gp), and in the micro-opioid receptor reduce morphine potency. Cytochrome P450 (CYP) 2D6 mutations influence the analgesic effect of codeine and tramadol, and polymorphism of CYP2C9 is potentially linked to an increase in nonsteroidal anti-inflammatory drug-induced adverse events. Furthermore, drug interactions can mimic genetic deficiency and contribute to the variability in response to analgesics. This review summarizes the available data on the pharmacokinetic and pharmacodynamic consequences of known polymorphisms of drug-metabolizing enzymes, drug transporters, drug targets and other nonopioid biological systems on central and peripheral analgesics.

Moving towards dose individualization of tyrosine kinase inhibitors

Molecular targeted therapies with tyrosine kinase inhibitors (TKIs) have been a recent breakthrough in cancer treatment. These small molecules are mainly used at a fixed dose ignoring the possible need for dose individualization. Fixed dosing may indeed result in suboptimal treatment or excessive toxicity considering the high inter-individual variability in the pharmacokinetics (PK) of these therapies. The PK, toxicity and efficacy of ten commonly used molecular targeted anti-cancer therapies were reviewed in order to optimize their prescription. A wide interpatient variability in the pharmacokinetics of these small molecules is demonstrated. Moreover associations between certain toxicities and the treatment efficacy have also been demonstrated for some agents, such as erlotinib and skin rash, that may be used as a surrogate marker. Other biomarkers intended to substitute for a clinical endpoint have been described for some TKIs and may be useful for dose individualization. Promising alternatives to fixed dosing were explored such as therapeutic drug monitoring, genotype and phenotype adjusted dosing, and toxicity-adjusted dosing. Prospective studies are needed to validate these methods so that dosing algorithms may be developed in the near future in order to personalize therapeutics to the individual needs of each cancer patient.

Hepatic fat loss in advanced nonalcoholic steatohepatitis: Are alterations in serum adiponectin the cause?

Advanced liver fibrosis in nonalcoholic steatohepatitis (NASH) is often accompanied by a reduction in hepatic fat to the point of complete fat loss (burnt‐out NASH), but the mechanisms behind this phenomenon have not been elucidated. Adiponectin is raised in cirrhosis of any cause and has potent antisteatotic activity. In this study we examined 65 patients with advanced biopsy‐proven NASH (fibrosis stage 3‐4) and 54 with mild disease (fibrosis stage 0‐1) to determine if disappearance of steatosis correlated with changes in serum adiponectin. All patents had fasting blood tests and anthropometric measures at the time of liver biopsy. Liver fat was accurately quantitated by morphometry. Serum adiponectin was measured by immunoassay. When compared to those with early disease, patients with advanced NASH were more insulin‐resistant, viscerally obese, and older, but there was no difference in liver fat content or adiponectin levels. Adiponectin had a significant negative correlation with liver fat percentage in the whole cohort (r = −0.28, P < 0.01), driven by patients with advanced NASH (r = −0.40, P < 0.01). In advanced NASH, for each 4 μg/L increase in adiponectin there was an odds ratio OR of 2.0 (95% confidence interval [CI]: 1.3‐3.0, P < 0.01) for a 5% reduction in hepatic fat. Adiponectin was highly and significantly associated with almost complete hepatic fat loss or burnt‐out NASH (12.1 versus 7.4 μg/L, P = 0.001) on multivariate analysis. A relationship between adiponectin, bile acids, and adipocyte fexaramine activation was demonstrated in vivo and in vitro, suggestive of hepatocyte‐adipocyte crosstalk. Conclusion: Serum adiponectin levels in advanced NASH are independently associated with hepatic fat loss. Adiponectin may in part be responsible for the paradox of burnt‐out NASH. (HEPATOLOGY 2012)

Automated system for on-line desorption of dried blood spots applied to LC/MS/MS pharmacokinetic study of flurbiprofen and its metabolite

This paper illustrates the development of an automated system for the on-line bioanalysis of dried blood spots (on-line DBS). In this way, a prototype was designed for integration into a conventional LC/MS/MS, allowing the successive extraction of 30 DBS toward the analytical system without any sample pretreatment. The developed method was assessed for the DBS analysis of flurbiprofen (FLB) and its metabolite 4-hydroxyflurbiprofen (OH-FLB) in human whole blood (i.e. 5 μL). The automated procedure was fully validated based on international criteria and showed good precision, trueness, and linearity over the expected concentration range (from 10 to 1000 ng/mL and 100 to 10,000 ng/mL for OH-FLB and FLB respectively). Furthermore, the prototype showed good results in terms of recovery and carry-over. Stability of both analytes on filter paper was also investigated and the results suggested that DBS could be stored at ambient temperature for over 1 month. The on-line DBS automated system was then successfully applied to a pharmacokinetic study performed on healthy male volunteers after oral administration of a single 50-mg dose of FLB. Additionally, a comparison between finger capillary DBS and classic venous plasma concentrations was investigated. A good correlation was observed, demonstrating the complementarity of both sampling forms. The automated system described in this article represents an efficient tool for the LC/MS/MS analysis of DBS samples in many bioanalytical applications.

Impact of Genetic Polymorphisms and Drug – Drug Interactions on Clopidogrel and Prasugrel Response Variability

Thienopyridine antiaggregating platelet agents (clopidogrel and prasugrel) act as irreversible P2Y12 receptor inhibitors. They are used with aspirin to prevent thrombotic complications after an acute coronary syndrome or percutaneous coronary intervention. A large interindividual variability in response to clopidogrel and to a lesser extent to prasugrel is observed and may be related to their metabolism. Clopidogrel and prasugrel are indeed prodrugs converted into their respective active metabolites by several cytochromes P450 (CYPs). Besides clopidogrel inactivation (85%) by esterases to the carboxylic acid, clopidogrel is metabolized by CYPs to 2-oxo-clopidogrel (15%) and further metabolized to an unstable but potent platelet-aggregating inhibitor. Prasugrel is more potent than clopidogrel with a better bioavailability and lower pharmacodynamic variability. Prasugrel is completely converted by esterases to an intermediate oxo-metabolite (R-95913) further bioactivated by CYPs. Numerous clinical studies have shown the influence of CYP2C19 polymorphism on clopidogrel antiplatelet activity. Moreover, unwanted drug-drug pharmacokinetic interactions influencing CYP2C19 activity and clopidogrel bioactivation such as with proton pump inhibitors remain a matter of intense controversy. Several studies have also demonstrated that CYP3A4/5 and CYP1A2 are important in clopidogrel bioactivation and should also be considered as potential targets for unwanted drug-drug interactions. Prasugrel bioactivation is mainly related to CYP3A4 and 2B6 activity and therefore the question of the effect of drug-drug interaction on its activity is open. The purpose of this review is to critically examine the current literature evaluating the influence of genetic and environmental factors such as unwanted drug-drug interaction affecting clopidogrel and prasugrel antiplatelet activity.

Geneva Cocktail for Cytochrome P450 and P‐Glycoprotein Activity Assessment Using Dried Blood Spots

The suitability of the capillary dried blood spot (DBS) sampling method was assessed for simultaneous phenotyping of cytochrome P450 (CYP) enzymes and P‐glycoprotein (P‐gp) using a cocktail approach. Ten volunteers received an oral cocktail capsule containing low doses of the probes bupropion (CYP2B6), flurbiprofen (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and fexofenadine (P‐gp) with coffee/Coke (CYP1A2) on four occasions. They received the cocktail alone (session 1), and with the CYP inhibitors fluvoxamine and voriconazole (session 2) and quinidine (session 3). In session 4, subjects received the cocktail after a 7‐day pretreatment with the inducer rifampicin. The concentrations of probes/metabolites were determined in DBS and plasma using a single liquid chromatography–tandem mass spectrometry method. The pharmacokinetic profiles of the drugs were comparable in DBS and plasma. Important modulation of CYP and P‐gp activities was observed in the presence of inhibitors and the inducer. Minimally invasive one‐ and three‐point (at 2, 3, and 6 h) DBS‐sampling methods were found to reliably reflect CYP and P‐gp activities at each session.

Apixaban Pharmacokinetics at Steady State in Hemodialysis Patients

It is unclear whether warfarin is protective or harmful in patients with ESRD and atrial fibrillation. This state of equipoise raises the question of whether alternative anticoagulants may have a therapeutic role. We aimed to determine apixaban pharmacokinetics at steady state in patients on hemodialysis. Seven patients received apixaban 2.5 mg twice daily for 8 days. Blood samples were collected before and after apixaban administration on days 1 and 8 (nondialysis days). Significant accumulation of the drug was observed between days 1 and 8 with the 2.5-mg dose. The area under the concentration-time curve from 0 to 24 hours increased from 628 to 2054 ng h/ml (P<0.001). Trough levels increased from 45 to 132 ng/ml (P<0.001). On day 9, after a 2.5-mg dose, apixaban levels were monitored hourly during dialysis. Only 4% of the drug was removed. After a 5-day washout period, five patients received 5 mg apixaban twice daily for 8 days. The area under the concentration-time curve further increased to 6045 ng h/ml (P=0.03), and trough levels increased to 218 ng/ml (P=0.03), above the 90th percentile for the 5-mg dose in patients with preserved renal function. Apixaban 2.5 mg twice daily in patients on hemodialysis resulted in drug exposure comparable with that of the standard dose (5 mg twice daily) in patients with preserved renal function and might be a reasonable alternative to warfarin for stroke prevention in patients on dialysis. Apixaban 5 mg twice daily led to supratherapeutic levels in patients on hemodialysis and should be avoided.

Genetic polymorphism and drug interactions: their importance in the treatment of pain

RésuméCertains opioïdes sont substrats de la P-gp, transporteur transmembranaire également soumis à un polymorphisme génétique. La P-gp ne pourrait toutefois jouer chez ľhomme qu’un röle modulateur mineur sur les effets centraux de la morphine, de la méthadone et du fentanyl.ObjectifEvaluer ľimpact de certains polymorphismes génétiques sur la variabilité de réponse aux analgésiques.SourcesRevue systématique par recherche informatisée structurée dans la base Medline (1966-2004), mots clés : pharmacogénétique, polymorphisme, cytochrome P450 (CYP), glycoprotéine P (P-gp), douleur, antalgiques, opiacés, morphine, codéine, tramadol, anti-inflammatoires non stéroïdiens (AINS). Sélection ďarticles de langue anglaise et française. Bibliographies ďarticles pertinents également sélectionnées.Constatations principalesLa plupart des analgésiques sont métabolisés via les isoenzymes du CYP soumis à un polymorphisme génétique. Les AINS sont métabolisés par le CYP2C9; les opioïdes qualifiés de “ faibles ” (codéine, tramadol), antidépresseurs et dextrométhorphane par le CYP2D6 et certains opioïdes “forts” (buprénorphine, méthadone ou fentanyl) par le CYP3A4/5. Après administration de doses usuelles, une toxicité médicamenteuse ou, au contraire, une inefficacité thérapeutique peut survenir en fonction du polymorphisme et de la substance. Les interactions médicamenteuses, en mimant les défauts génétiques du fait de ľexistence ďinhibiteurs et ďinducteurs des CYP, participent également à la variabilité de réponse aux analgésiques.ConclusionLa pharmacogénétique devrait dans un avenir proche permettre ďoptimaliser la thérapeutique en individualisant ľapproche analgésique médicamenteuse et en améliorant la sécurité ďemploi et ľefficacité de nombreux analgésiques. Ľutilité clinique de ces approches individualisées devra être démontrée par des études et des analyses pharmacoéconomiques appropriées.AbstractSome opioids are substrates of P-gp, a transmembrane transporter also subject to genetic polymorphism. However, P-gp could only play a minor modulating role in man on the central effects of morphine, methadone and fentanyl.ObjectivesTo evaluate the impact of certain genetic polymorphisms on variable responses to analgesics,SourcesSystematic review, by means of a structured computerized search in the Medline database (1966-2004). Key words: pharmacogenetics, polymorphism, cytochrome P450 (CYP), glycoprotein P (P-gp), pain, antalgics, opiates, morphine, codeine, tramadol, non-steroidal anti-inflammatory drugs (NSAID). Articles in English and French were selected. References in relevant articles were also retrieved.Main findingsMost analgesics are metabolized by CYP isoenzymes subject to genetic polymorphism. NSAIDs are metabolized by CYP2C9; opioids described as “weak” (codeine, tramadol), antidepressants and dextromethorphan are metabolized by CYP2D6 and some “potent” opioids (buprenorphine, methadone or fentanyl) by CYP3A4/5. After the usual doses have been administered, drug toxicity or, on the contrary, therapeutic ineffectiveness may occur, depending on polymorphism and the substance. Drug interactions mimicking genetic defects because of the existence of CYP inhibitors and inducers, also contribute to the variable response to analgesics.ConclusionIn the near future, pharmacogenetics should enable us to optimize therapeutics by individualizing our approach to analgesic drugs and making numerous analgesics safer and more effective. The clinical usefulness of these individualized approaches will have to be demonstrated by appropriate pharmaco-economic studies and analyses.