Concomitant Cytochrome P450 Research Articles

A systematic review of the drug-drug interaction between Statins and Quinolones

BackgroundStatins are widely used in cardiovascular disease (CVD) as a common lipid-lowering drug, while quinolones are widely used for the treatment of infectious diseases. It is common to see CVD in combination with infectious diseases, therefore it is often the case that statins and quinolones are used in combination. Data suggest combinations of statin and quinolone may be associated with potentially life-threatening myopathy, rhabdomyolysis and acute hepatitis. This systematic review aims to characterize data regarding patients affected by the statin-quinolone interaction.MethodsThe purpose of this systematic review was to collect and evaluate the evidence surrounding statin-quinolone drug interactions and to discuss related risk mitigation strategies. The following databases were searched: PubMed (Medline), Embase, Scopus, and Cochrane Library. The systematic electronic literature search was conducted with the following search terms. In this study, three types of search terms were used: statins-related terms, quinolones-related terms, and drug interactions-related terms.ResultsThere were 16 case reports that met the criteria for qualitative analysis. Patients were involved in the following adverse reactions: rhabdomyolysis (n = 12), acute hepatitis (n = 1), muscle weakness (n = 1), hip tendinopathy (n = 1), or myopathy (n = 1). In the included literature, patients vary in the dose and type of statins they take, including simvastatin (n = 10) at a dose range of 20–80 mg/d and atorvastatin (n = 4) at a dose of 80 mg/d. There were 2 patients with unspecified statin doses, separately using simvastatin and atorvastatin. The quinolones in combination were ciprofloxacin (n = 9) at a dose range of 800–1500 mg/d, levofloxacin (n = 6) at a dose range of 250–1000 mg/d, and norfloxacin (n = 1) in an unspecified dose range. 81% of the case patients were over 60 years of age, and about 1/3 had kidney-related diseases such as diabetic nephropathy, post-transplantation, and severe glomerulonephritis. Nearly two-third of the patients were on concomitant cytochrome P450 3A4 (CYP3A4) inhibitors, P-glycoprotein (P-gp) inhibitors, or organic anion transporting polypeptide 1B1 (OATP1B1) inhibitors.ConclusionPatients treated with statin-quinolone combination should be monitored more closely for changes in aspartate aminotransferase or creatine kinase (CK) levels, and muscle symptoms, especially in patients with ciprofloxacin or levofloxacin, with simvastatin and high-dose atorvastatin, over 60 years of age, with kidney-related diseases, and on concomitant CYP3A4 inhibitors.

Population pharmacokinetics of mirvetuximab soravtansine in patients with folate receptor-α positive ovarian cancer: The antibody-drug conjugate, payload and metabolite.

Mirvetuximab soravtansine is a first-in-class antibody-drug conjugate recently approved for the treatment of folate receptor-α positive ovarian cancer. The aim of this study was to develop a population pharmacokinetic model to describe the concentration-time profiles of mirvetuximab soravtansine, the payload (DM4) and a metabolite (S-methyl-DM4). Mirvetuximab soravtansine was administered intravenously from 0.15 to 7mg/kg to 543 patients with predominantly platinum-resistant ovarian cancer in 3 clinical studies, and the plasma drug concentrations were analysed using a nonlinear mixed-effects modelling approach. Stepwise covariate modelling was performed to identify covariates. We developed a semi-mechanistic population pharmacokinetic model that included linear and nonlinear routes for the elimination of mirvetuximab soravtansine and a target compartment for the formation and disposition of the payload and metabolite in tumour cells. The clearance and volume of the central compartment were 0.0153 L/h and 2.63 L for mirvetuximab soravtansine, 8.83 L/h and 3.67 L for DM4, and 2.04 L/h and 6.3L for S-methyl-DM4, respectively. Body weight, serum albumin and age were identified as statistically significant covariates. Exposures in patients with renal or hepatic impairment and who used concomitant cytochrome P450 (CYP) 3A4 inhibitors were estimated. There is no need for dose adjustment due to covariate effects for mirvetuximab soravtansine administered at the recommended dose of 6mg/kg based on adjusted ideal body weight. Dose adjustment is not required for patients with mild or moderate renal impairment, mild hepatic impairment, or when concomitant weak and moderate CYP3A4 inhibitors are used.

Novel Drug-Drug Interaction of Potential Rifabutin-Induced Edoxaban Failure: A Case Report

Purpose: To report an incident of a breakthrough deep vein thrombosis (DVT) and potential example of a drug-drug interaction in a patient treated with edoxaban and rifabutin who was being treated for respiratory tuberculosis. Case: A 76-year-old male presented with anemia requiring transfusion and subsequent shortness of breath that was later diagnosed to be respiratory tuberculosis. He experienced a prolonged hospital stay due to persistently positive Mycobacterium tuberculosis respiratory samples and a complicated social situation that required continuous hospitalization for approximately five months. During his treatment the patient was transitioned from apixaban to edoxaban due to a drug-drug interaction with rifabutin. He subsequently had a DVT while on edoxaban after two months of therapy that would require him to transition to warfarin. Conclusion: This case represents an example of a potentially significant drug-drug interaction between edoxaban and rifabutin. Other direct oral anticoagulants (DOACs) exhibit a potential drug-drug interaction that limit their effectiveness when used with rifamycins. This report describes the first known case of a patient experiencing a DVT after prolonged edoxaban use in combination with rifabutin. Treatment with DOACs for patients taking concomitant cytochrome P450 (CYP) inducers such as rifabutin may be more complicated than previously believed.

High Intrapatient Variability in Tacrolimus Exposure Calculated Over a Long Period Is Associated With De Novo Donor-Specific Antibody Development and/or Late Rejection in Thai Kidney Transplant Patients Receiving Concomitant CYP3A4/5 Inhibitors.

High intrapatient variability in tacrolimus trough levels (Tac IPV) is associated with poor allograft outcomes. Tac IPV was previously calculated using trough levels 6-12 months after kidney transplantation (KT). Data on the accuracy of Tac IPV calculation over a longer period, the association between high Tac IPV and donor-specific antibody (DSA) development after KT in Asian patients, and the role of IPV in patients receiving concomitant cytochrome P450 (CYP)3A4/5 inhibitors (CYPinh) are limited. A retrospective review of patients who underwent KT at our center in 2005-2015, and who received Tac with mycophenolate during the first 2 years after KT was performed. IPV was calculated using Tac levels adjusted by dosage. DSA was monitored annually after KT using a Luminex microbead assay. In total, 236 patients were enrolled. CYPinh were prescribed to 189 patients (80.1%): 145 (61.4%), 31 (13.1%), and 13 (5.5%) received diltiazem, fluconazole, and ketoconazole, respectively. Mean IPV calculated from adjusted Tac levels for 6-12 months (IPV6-12) and 6-24 months (IPV6-24) after KT were 20.64% ± 11.68% and 23.53% ± 10.39%, respectively. Twenty-six patients (11%) showed late rejection and/or DSA occurrence, and had significantly higher IPV6-24 (29.42% ± 13.78%) than others (22.77% ± 9.64%; P = 0.02). There was no difference in IPV6-12 (24.31% ± 14.98% versus 20.17% ± 10.90%; P = 0.18). IPV6-12 and IPV6-24 were comparable in patients who did and did not receive CYPinh. When using mean IPV6-24 as a cutoff, patients with higher IPV6-24 had a higher probability of developing DSA and/or late rejection (P = 0.048). Tac IPV6-24 was higher and more significantly associated with DSA development and/or late rejection than Tac IPV6-12, independent of Tac trough level. This is the first study to demonstrate the impact of high IPV on DSA development in Asian patients, and that Tac IPV is comparable between patients with and without CYPinh.

Comprehensive PBPK model to predict drug interaction potential of Zanubrutinib as a victim or perpetrator.

A physiologically based pharmacokinetic (PBPK) model was developed to evaluate and predict (1) the effect of concomitant cytochrome P450 3A (CYP3A) inhibitors or inducers on the exposures of zanubrutinib, (2) the effect of zanubrutinib on the exposures of CYP3A4, CYP2C8, and CYP2B6 substrates, and (3) the impact of gastric pH changes on the pharmacokinetics of zanubrutinib. The model was developed based on physicochemical and in vitro parameters, as well as clinical data, including pharmacokinetic data in patients with B‐cell malignancies and in healthy volunteers from two clinical drug‐drug interaction (DDI) studies of zanubrutinib as a victim of CYP modulators (itraconazole, rifampicin) or a perpetrator (midazolam). This PBPK model was successfully validated to describe the observed plasma concentrations and clinical DDIs of zanubrutinib. Model predictions were generally within 1.5‐fold of the observed clinical data. The PBPK model was used to predict untested clinical scenarios; these simulations indicated that strong, moderate, and mild CYP3A inhibitors may increase zanubrutinib exposures by approximately four‐fold, two‐ to three‐fold, and <1.5‐fold, respectively. Strong and moderate CYP3A inducers may decrease zanubrutinib exposures by two‐ to three‐fold or greater. The PBPK simulations showed that clinically relevant concentrations of zanubrutinib, as a DDI perpetrator, would have no or limited impact on the enzyme activity of CYP2B6 and CYP2C8. Simulations indicated that zanubrutinib exposures are not impacted by acid‐reducing agents. Development of a PBPK model for zanubrutinib as a DDI victim and perpetrator in parallel can increase confidence in PBPK models supporting zanubrutinib label dose recommendations.

Population Pharmacokinetic Analysis of the Cathepsin K Inhibitor Odanacatib: Insights Into Intrinsic and Extrinsic Factor Effects on Exposure in Postmenopausal and Elderly Women.

This analysis developed a population pharmacokinetic (PK) model for odanacatib, characterized demographic and concomitant medication covariates effect, and provided odanacatib exposure estimates for subjects in phase2/3 studies. Data from multiple phase1 (P005, P025, and P014), phase2b (P004 and P022), and phase3 (Long-Term Odanacatib Fracture Trial; P018) studies were pooled to create a data set of 1280 postmenopausal women aged 45 to 91 years (102 from phase1, 514 from phase2b, and 664 from phase3) who received weekly oral odanacatib doses ranging from 3 to 100mg. A 1-compartment model with first-order absorption, dose-dependent relative bioavailability (F1), and first-order elimination best described odanacatib PK. F1 decreased from the 100% reference bioavailability for a 3-mg oral dose to 24.5% for a 100-mg dose. Eight statistically significant covariates were included in the final PK model: body weight, age, race, and concomitant cytochrome P450 (CYP)3A inhibitors on apparent clearance; body weight on apparent central volume of distribution; and concomitant hydrochlorothiazide, high-fat breakfast, and a study effect on F1. All fixed- and random-effects parameters were estimated with good precision (%standard error of the mean ≤29.5%). This population PK analysis provides insights into intrinsic- and extrinsic-factor effects on odanacatib exposure in postmenopausal and elderly women with osteoporosis. The magnitude of the intrinsic-factor effects was generally modest (odanacatib exposure geometric mean ratios, 0.80-1.21) even in subjects aged >80 years, or in subsets with multiple combinations of factors.

Drug-drug interaction (DDI) of darolutamide with cytochrome P450 (CYP) and P-glycoprotein (P-gp) substrates: Results from clinical and in vitro studies.

297 Background: Maintaining quality of survival, by delaying disease progression and minimizing therapy burden, is critical for patients and has been evaluated in the pivotal phase III ARAMIS study in patients with non-metastatic castration-resistant prostate cancer. Due to comorbidity, elderly men often receive multiple comedications, including CYP and P-gp substrates, eg, simvastatin and digoxin. Enzalutamide and apalutamide, approved androgen receptor (AR) inhibitors, are strong CYP3A4 inducers and thus have potential for CYP-mediated DDIs. The effect of darolutamide, a structurally unique AR antagonist, on CYP activity ( in vitro and in vivo) and P-gp activity ( in vivo) was assessed. Methods: Inhibition of CYP isoforms by Daro was investigated in human liver microsomes using standard substrates. In addition, CYP and P-gp activity during darolutamide treatment was studied in a phase I trial of 15 healthy men who received 75 mg dabigatran etexilate (DABE, P-gp substrate) + 1 mg midazolam (MDZ, CYP3A4 substrate) once followed by 600 mg darolutamide (two 300 mg tablets) twice daily (BID) given with food for 9 days. On day 9, darolutamide was concomitantly administered with a single dose of 75 mg DABE + 1 mg MDZ. Results: Based on in vitro data, no clinically relevant inhibition of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4 by darolutamide is expected. In 13 evaluable subjects in the phase I study, concomitant darolutamide reduced MDZ Cmax by ~32% and AUC by ~29% vs MDZ alone. Concomitant darolutamide reduced non-conjugated dabigatran Cmax by 16% and AUC by 9% vs DABE alone. The observed treatment-emergent adverse events were consistent with the known safety profile of darolutamide. No new safety risks were revealed by co-administration of darolutamide and DABE or MDZ. Safety data for patients in ARAMIS who received darolutamide, including those with concomitant CYP or P-gp substrates, will be presented. Conclusions: Darolutamide showed only weak effects or none on P-gp, CYP3A4, or any other relevant CYP enzyme. Thus, darolutamide is not expected to cause any clinically relevant DDI with CYP or P-gp substrates, minimizing complications of polypharmacy. Clinical trial information: NCT03237416.

Population Pharmacokinetics of Ivosidenib (AG-120) in Patients with IDH1-Mutant Advanced Hematologic Malignancies

BACKGROUNDIvosidenib, a potent mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor, is being assessed in a phase 1 study of mIDH1 advanced hematologic malignancies (NCT02074839). We characterized the pharmacokinetics (PK) of ivosidenib in this population, and the effects of patient/disease characteristics and concomitant medications. METHODSIvosidenib was given in continuous 28-day cycles at 100 mg twice daily and 300 mg, 500 mg, 800 mg, and 1200 mg once daily (QD). Enrollment is complete; 258 patients received ≥1 ivosidenib dose (78 in escalation, 180 in expansion); samples were available from 253 patients (223 received ivosidenib 500 mg QD). Ivosidenib concentrations were determined using validated liquid chromatography with tandem mass spectrometry (LC-MS/MS)-based methods. Population PK modeling was conducted using NONMEM software. The impact of demographics, renal and hepatic function, disease type, Eastern Cooperative Oncology Group (ECOG) performance status, and concomitant cytochrome P450 3A4 (CYP3A4) inhibitors/inducers and gastric acid reducers on ivosidenib PK was explored. RESULTSIvosidenib PK were best described using a 2-compartment model with first-order absorption, dose-dependent bioavailability, and a time-dependent change in relative bioavailability and clearance between Day 1 and steady state. Mean steady-state apparent clearance (CL/F) was 5.39 L/h (between-patient variability ~35%) and mean central volume of distribution (Vc/F) was 234 L (~47%). Less than dose-proportional bioavailability was observed, with a dose doubling translating to a ~40% increase in exposure. The moderate/strong CYP3A4 inhibitors voriconazole, fluconazole, and posaconazole were associated with 36%, 41%, and 35% reductions in CL/F, and hence 57%, 69%, and 53% increases in area under the plasma ivosidenib concentration-time curve (AUC), respectively (Figure 1). Baseline body weight had a significant impact on Vc/F. Low albumin at baseline and during treatment correlated with decreased CL/F and Vc/F. However, the effects of body weight and albumin did not appear to be clinically relevant. No effects of creatinine clearance or measures of liver function (alanine aminotransferase, aspartate aminotransferase, bilirubin, within the range studied) on ivosidenib CL/F were detected. Concomitant use of pantoprazole or famotidine did not affect ivosidenib CL/F. CONCLUSIONThis population PK model of ivosidenib suggests that no dose adjustments are needed based on the range of patient and disease characteristics analyzed. [Display omitted] DisclosuresLe:Millennium: Patents & Royalties; Agios: Employment, Equity Ownership. Wada:Certara: Employment; Agios: Consultancy. Dai:Agios: Employment, Equity Ownership. Fan:Agios: Employment, Equity Ownership. Liu:Agios: Employment, Equity Ownership. Liu:Agios: Employment, Equity Ownership. Attar:Agios: Employment, Equity Ownership. Agresta:Agios: Employment, Equity Ownership. Yang:Agios: Employment, Equity Ownership.

Population Pharmacokinetic/Pharmacodynamic Analyses of Avatrombopag in Patients With Chronic Liver Disease and Optimal Dose Adjustment Guide With Concomitantly Administered CYP3A and CYP2C9 Inhibitors.

Avatrombopag, a c-Mpl agonist, has been developed to provide an alternative therapy to standard platelet transfusion care for the treatment of thrombocytopenia. The main objectives of this article were to describe the pharmacokinetics (PK) of avatrombopag, to characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship between plasma avatrombopag concentrations and platelet count, and to identify potential intrinsic and extrinsic factors affecting PK or PK/PD in patients with chronic liver disease (CLD). Platelet count following avatrombopag administration with and without concomitant medication was further simulated using the final population PK/PD model to explore potential dose adjustments. Avatrombopag PK was described by a 1-compartment model with combined first- and zero-order absorption and linear elimination. The relationship between the plasma avatrombopag concentrations and platelet count was well described by a 6-compartment life-span model with a linear drug effect. The final PK and PK/PD models included statistically significant but not clinically relevant effects of body weight and CLD on apparent volume distribution and East Asian ethnicity, albumin, and thrombopoietin level on the slope parameter in the PK/PD relationship. PK/PD simulations showed comparable elevation in platelet count with and without concomitant cytochrome P450 (CYP) 3A and CYP2C9 inhibitors for the dosing regimens of 40 and 60 mg for 5 days, with predictions of <10% of CLD patients exceeding platelet count >200 × 109 /L. Dose adjustment is therefore not necessary with concomitant use of CYP3A and CYP2C9 interacting drugs considering the limited treatment duration (ie, 5 days) and lack of significant safety concerns in CLD patients.

Clinical Pharmacokinetics and Pharmacodynamics of Cabozantinib.

Cabozantinib inhibits receptor tyrosine kinases involved in tumor angiogenesis and metastasis. The capsule formulation (Cometriq®) is approved for the treatment of progressive metastatic medullary thyroid cancer at a 140-mg free base equivalent dose. The tablet formulation (Cabometyx™, 60-mg free base equivalent dose) is approved for the treatment of renal cell carcinoma following anti-angiogenic therapy. Cabozantinib displays a long terminal plasma half-life (~120 h) and accumulates ~fivefold by day 15 following daily dosing based on area under the plasma concentration-time curve (AUC). Four identified inactive metabolites constitute >65 % of total cabozantinib-related AUC following a single 140-mg free base equivalent dose. Cabozantinib AUC was increased by 63-81 % or 7-30 % in subjects with mild/moderate hepatic or renal impairment, respectively; by 34-38 % with concomitant cytochrome P450 3A4 inhibitor ketoconazole; and by 57 % following a high-fat meal. Cabozantinib AUC was decreased by 76-77 % with concomitant cytochrome P450 3A4 inducer rifampin, and was unaffected following administration of proton pump inhibitor esomeprazole. Cabozantinib is a potent in vitro inhibitor of P-glycoprotein, and multidrug and toxin extrusion transporter 1 and 2-K, and is a substrate for multidrug resistance protein 2. No clinically significant covariates affecting cabozantinib pharmacokinetics were identified in a population pharmacokinetic analysis. Patients with medullary thyroid cancer with low model-predicted apparent clearance were more likely to dose hold/reduce cabozantinib early, and had a lower average dose through day 85. However, longitudinal tumor modeling suggests that cabozantinib dose reductions from 140 to 60 mg/day did not markedly reduce tumor growth inhibition in medullary thyroid cancer patients.

Effects of concomitant cytochrome P450 inhibitors on the metabolism of citalopram: Analysis of data from routine therapeutic drug monitoring (TDM)

Introduction: Due to a dose-dependent risk for QTc prolongations, torsade de pointes tachyarrhythmia and sudden death age-dependet maximal daily doses of citalopram are recommended. Concomitant drugs which prolong QTc or inhibit the metabolism of citalopram may increase the risk for adverse events. The aim of this study was to further analyse the influence of the concomitant medication on the total clearance (Clt)of citalopram. Method: Plasma concentrations of citalopram – a total of 959 – were collected during routine therapeutic drug monitoring (TDM). The means of Clt values of different subgroups of patients were compared by one-way analysis of covariance (ANCOVA) after controlling for potential confounders. Results: 1. Age over 65 years and female sex significantly reduced the Clt of citalopram by 25% and 16%, respectively. 2. About 40% of the patients younger than 65 years who were prescribed more than 40 mg of citalopram daily and 35% of the older patients with doses of more than 20 mg per day had plasma concentrations exceeding the therapeutic reference range of citalopram. 3. Only concomitant medications with inhibitors of at least two different CYP enzymes (CYP2C19, CYP2D6 or CYP3A4) reduced significantly the Clt of citalopram. Conclusion: For patients with risk factors as female sex, age over 65 years or concomitant medications including inhibitors of more than two CYP enzymes TDM is recommended to minimize the risk for adverse reactions of citalopram.

Abstract P6-12-02: Use of cytochrome P450 interacting medications in the setting of adjuvant therapy for breast cancer.

Abstract Background: In the current era of personalized medicine, oral targeted therapies are increasingly used in cancer treatment. In breast cancer, oral anti-estrogen agents have historically been part of standard treatment for hormone receptor positive disease. More recently, other targeted agents have been introduced in the metastatic setting, and are being evaluated as adjuvant therapies. Many oral medications, including anticancer therapies, are metabolized by cytochrome P450 (CYP450) enzymes raising possibility of drug-drug interactions that may affect toxicities or breast cancer outcomes. We sought to evaluate concomitant CYP450 medication use among women seeing a medical oncologist to discuss adjuvant systemic therapy for breast cancer. Methods: We performed an electronic medical record database extraction. Adult women diagnosed with breast cancer from 1/2008-7/2011 were identified from the University of Wisconsin Hospital and Clinics Cancer Registry. Medication lists were extracted from the first encounter with a medical oncologist after the initial breast cancer diagnosis. Non-systemic medications were excluded. Cytochrome P450 (CYP450) enzyme-interacting medications were categorized as inhibitors, inducers, and/or substrates of specific enzymes including CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP2E1, and CYP3A4. CYP450 inhibitors and inducers were further characterized as strong, moderate or weak acting. Results: A total of 455 women with non-metastatic breast cancer were identified. Mean age was 56.6 years (range of 23–90) and 413 (91%) were Caucasian. Polypharmacy, defined as use of 3–5 medications, was seen in 123 (27.0%) women. A total of 236 (51.9%) women were on 0–4; 109 (24.0%) on 5–10; and 13 (2.9%) on &amp;gt; 10 medications at the time of first encounter with a medical oncologist after a breast cancer diagnosis. 23 (5.05%) women were on strong CYP450 enzyme inhibitors while 72 (15.8%) were on strong inducers. CYP450 enzymes most commonly affected were CYP3A4, CYP2C9, and CYP2D6. Among medications taken on a fixed schedule, levothyroxine and simvastatin were the most commonly used, while simvastatin and ranitidine were the most common CYP450 interacting medications. Further classification of potential CYP450 interactions is ongoing. Conclusions: A significant proportion of patients were on one or more CYP450 interacting medications in the setting of adjuvant therapy for breast cancer. Given the number of new oral cancer agents that are also CYP450 interacting, the potential for drug interactions should be recognized and appropriate management strategies implemented. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-12-02.

Antidepressants and the risk of sudden cardiac death and ventricular arrhythmia

To examine the association between exposure to antidepressants and emergency department or inpatient admission for sudden cardiac death and ventricular arrhythmia (SD/VA), and to examine the impact of dose and cytochrome P-450 inhibition. A cohort study was conducted using 1999-2003 Medicaid claims data from beneficiaries of five large states, supplemented with Medicare claims for dually eligible individuals. Exposures were prescription claims for antidepressants of interest or a reference antidepressant. Outcomes were incident first-listed emergency department or principal inpatient diagnoses indicative of SD/VA originating in the outpatient setting, an outcome previously found to have a positive predictive value of 85%. In 1.3 million person-years of antidepressant exposure, we identified 4222 SD/VA outcomes for a rate of 3.3/1000 person-years (95%CI, 3.2-3.4). Compared with paroxetine (a referent with a putatively favorable cardiovascular risk profile), adjusted hazard ratios (HRs) were 0.80 (0.67-0.95) for bupropion, 1.24 (0.93-1.65) for doxepin, 0.79 (0.55-1.15) for lithium, and 1.26 (1.11-1.42) for mirtazapine. HRs for amitriptyline, citalopram, fluoxetine, nefazodone, nortriptyline, sertraline, trazodone, and venlafaxine were near unity. For antidepressants having nonnull risks (bupropion and mirtazapine), we observed no relationship with antidepressant dose and some relationships with concomitant cytochrome P-450 inhibition. Of antidepressants studied, only mirtazapine had a statistically significantly greater SD/VA risk versus paroxetine. However, baseline differences between these users suggest that this finding may be attributable to residual confounding. Eleven other antidepressants had SD/VA risks no greater than that of paroxetine, thereby providing reassurance regarding the comparative cardiovascular safety of antidepressants.

Methadone-induced torsades de pointes: A twist of fate

A case of methadone-induced torsades de pointes is presented to demonstrate clinical features that predispose patients to this serious cardiac arrhythmia. A patient who was receiving methadone maintenance treatment for heroin addiction presented to the hospital with dizziness and near-syncope. He was taking a relatively high dose of methadone but was not taking any concomitant cytochrome P450 inhibitor or QT-prolonging drugs. He had prolonged corrected QT interval, hypokalemia, and hypomagnesemia on admission and was later found to have severe left ventricular dysfunction. On admission to a telemetry unit, the patient experienced chest discomfort and palpitations with corresponding torsades de pointes that was terminated with correction of hypokalemia and hypomagnesemia. The corrected QT interval became shorter but remained profoundly prolonged until methadone was substituted with buprenorphine.

Optimal Management of Peptic Ulcer Disease in the Elderly

Recent data report that the incidence of peptic ulcer is decreasing in the general population; conversely, the rates of gastric and duodenal ulcer hospitalization and mortality remain very high in older patients. Two major factors that might explain this epidemiological feature in the elderly population are the high prevalence of Helicobacter pylori infection and the increasing prescriptions of gastroduodenal damaging drugs, including NSAIDs and/or aspirin (acetylsalicylic acid). The main goals for treating peptic ulcer disease in old age are to reduce recurrence of the disease and to prevent complications, especially bleeding and perforation. The available treatments for peptic ulcer are essentially based on gastric acid suppression with antisecretory drugs and the eradication of H. pylori infection. The aim of this article is to report the available data on clinical efficacy and tolerability of peptic ulcer treatments in elderly patients and provide recommendations for their optimal use in this special population. Proton pump inhibitor (PPI)-based triple therapies for 7 days are highly effective for the cure of H. pylori-positive peptic ulcers as well as for reducing ulcer recurrence. Antisecretory drugs are also the treatment of choice for NSAID- or aspirin-related peptic ulcers and are useful as preventive therapy in chronic users of NSAIDs and low-dose aspirin as antiplatelet therapy. Antisecretory PPI therapy has a favourable tolerability profile in geriatric patients; however, monitoring is suggested in older patients with frequent pulmonary infections, gastrointestinal malabsorption, unexplained chronic diarrhoea, osteoporosis or those taking concomitant cytochrome P450 2C19-metabolized medications. The overall approach to the geriatric patient should include a comprehensive geriatric assessment that ensures multidimensional evaluation of the patient in order to better define the clinical risk of adverse outcomes in the older patient with peptic ulcer and its complications.

Statin Safety: An Assessment Using an Administrative Claims Database

The large administrative databases of health plans contain information on drug-related medical adverse events (AE) and constitute an increasingly powerful tool for the assessment of drug safety. We conducted a retrospective observational study using an administrative managed care claims database covering 9 million members from diverse regions of the United States. Patients aged >or=18 years who received >or=2 prescriptions for lipid-lowering drugs between July 1, 2000 and December 1, 2004 were included in the study. Hospitalizations with diagnosis codes (International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9]) related to muscle, kidney, and liver were determined for patients exposed to 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), fibrates, extended-release niacin, cholesterol absorption inhibitors, or statin combination therapy. A total of 473,343 patients contributed 490,988 person-years of monotherapy and 11,624 person-years of combination dyslipidemia therapy. Rates of hospitalization due to AEs in patients on monotherapy with currently available statins were similar, whereas the incidence of hospitalization for muscle disorders increased 6.7-fold with cerivastatin therapy. Patients who received a lipid-lowering medication with a concomitant cytochrome P450 3A4 (CYP3A4) inhibitor had a 6-fold increased rate of muscle disorders, including rhabdomyolysis. Hypertension was associated with a 5-fold increase in both muscle and renal events, whereas patients with diabetes mellitus had a 2.5-fold increased risk of renal events. No hospitalized cases of the index AEs were observed in study subjects during the 6-month period before initiation of the lipid-lowering drug. Statin monotherapy as currently prescribed is generally well tolerated and safe.

Novel substituted pyridinyl imidazoles as potent anticytokine agents with low activity against hepatic cytochrome P450 enzymes.

A series of polysubstituted pyridin-4-yl imidazole inhibitors of p38 MAP (mitogen-activated protein) kinase was prepared as small molecular anticytokine agents and drug candidates for the treatment of chronic inflammatory diseases. The contribution of substituents at the pyridinyl and imidazole moiety to selective inhibition of p38 without concomitant cytochrome P450 interaction was evaluated. Placement of a 1-phenylethyl (7e, p38: IC(50) 0.38 microM) or acetyl substituent at the exocyclic nitrogen of several 2-aminopyridine imidazoles led to the identification of potent p38 inhibitors which exceeded the starting lead ML 3375 (p38: IC(50) 0.63 microM) in potency. A preliminary modeling study related the enhanced bioactivity of 7e to a novel interaction between its 1-phenylethylamino side chain and a hydrophobic pocket close to the linker region of p38. The most active p38 inhibitors in this series maintained their efficacy in functional PBMC (peripheral blood mononuclear cells) and whole blood assays. Moreover, cytochrome P450 interaction, which has been linked to the liver toxicity observed for model p38 inhibitors, was very efficiently reduced through introduction of a tetramethylpiperidine substituent at the 1 position of the imidazole nucleus. Combination of both structural features provided 14c (p38: 0.34 microM, inhibition of CYP1A2 0%, 2C9 2.6%, 2C19 7.6% at 10 microM), which was selected for further development.

Microsomal ethanol oxidizing system (MEOS): Interaction with ethanol, drugs and carcinogens

Several studies in our unit showed that in men, baboons, rats and deermice, blood ethanol clearance is significantly accelerated at ethanol concentrations higher than the levels needed to effectively saturate the low K m forms of ADH present in animals, thereby incriminating a high K m non-ADH system such as microsomal ethanol oxidizing system (MEOS). Furthermore, kinetics of blood ethanol clearance were consistent with the K m of MEOS. After chronic ethanol consumption, there was an increase in rates of ethanol elimination and in the activity of MEOS. There was an associated rise in microsomal cytochrome P-450, including a form (different from that induced by phenobarbital and methylcholanthrene) which had a high affinity for ethanol in a reconstituted system. The role of a non-ADH pathway of ethanol metabolism and its increase after chronic ethanol consumption was most conclusively shown in ADH-negative deermice. Microsomal induction was also associated with enhanced metabolism of other drugs, resulting in metabolic drug tolerance. In addition, there was increased activation of known hepatotoxic agents (such as CCl 4 and acetaminophen) which may explain the enhanced susceptibility of alcoholics to the toxicity of solvents and commonly used drugs. There was enhanced activation of procarcinogens, sometimes at concentrations much lower than those required for other microsomal inducers. Moreover, catabolism of retinoic acid was accelerated possibly contributing to hepatic vitamin A depletion. In conclusion, after chronic ethanol consumption, enhanced MEOS activity and concomitant cytochrome P-450 changes may contribute to accelerated ethanol and drug metabolism and associated activation of hepatotoxic agents and carcinogens.