Serum Drug Levels Research Articles

Psychopharmacotherapy during pregnancy: Therapeutic drug monitoring (tdm) in maternal blood, amniotic fluid and umbilical cord blood

Objectives: Treatment of psychiatric diseases during pregnancy using psychotropic drugs is complicated by the concern for the safety of the mother and the child. Aim of the study was to measure drug levels in maternal serum and to determine the penetration ratio of different psychotropic drugs into amniotic fluid and umbilical cord blood and to account for the distribution of the drugs. Methods: In a non-interventional observational study design we collected maternal blood, amniotic fluid and cord blood samples of meanwhile more than 40 mother-child pairs and analyzed the drug levels. Daily doses were correlated with maternal serum- and umbilical cord blood-concentrations, and serum levels were correlated with levels in amniotic fluid. Results: The average penetration ratio into amniotic fluid was 61.38% for sertraline, 70.83% for citalopram, 12.16% for valproic acid, 356.06% for levetiracetam, and 55.00% for lamotrigine. In umbilical cord blood, the mean ratio was 56.76% for sertraline, 54.17% for citalopram, 118.01% for valproic acid, 101.63% for levetiracetam and 86.00% for lamotrigine. Conclusion: Quantifying the extent of placental passage or knowledge about the accumulation of a drug in amniotic fluid can facilitate medication selection based on the extent of fetal drug exposure and ultimately provide insight into whether or not neonatal complications are directly related to medication exposure with measurable drug levels in amniotic fluid or fetal circulation.

Temperature-responsive Solid-phase Extraction Column for Biological Sample Pretreatment.

We have developed a novel solid-phase extraction (SPE) system utilizing a temperature-responsive polymer hydrogel-modified stationary phase. Aminopropyl silica beads (average diameter, 40 - 64 μm) were coated with poly(N-isopropylacrylamide) (PNIPAAm)-based thermo-responsive hydrogels. Butyl methacrylate (BMA) and N,N-dimethylaminopropyl acrylamide (DMAPAAm) were used as the hydrophobic and cationic monomers, respectively, and copolymerized with NIPAAm. To evaluate the use of this SPE cartridge for the analysis of drugs and proteins in biological fluids, we studied the separation of phenytoin and theophylline from human serum albumin (HSA) as a model system. The retention of the analytes in an exclusively aqueous eluent could be modulated by changing the temperature and salt content. These results indicated that this temperature-responsive SPE system can be applied to the pretreatment of biological samples for the measurement of serum drug levels.

Advanced systolic heart failure and Mycobacterium avium complex (MAC) infection: Proposed immunologic mechanism, diagnostic dilemma and treatment considerations

Mycobacterium avium complex (MAC) infection is well recognized in patients with cellular immunodeficiency. Recognition of its morbidity in non-immunocompromised patients has emerged in the last few decades. Underlying chronic pulmonary disease, bronchiectasis, cigarette smoking, cystic fibrosis and chest wall deformities are well-recognized predisposing conditions. Weight loss, dyspnea, cough, fatigue and sputum production are the most common presenting symptoms. We present a case of culture proven MAC infection in an elderly female whose dyspnea and fatigue for a considerable period was inappropriately attributed to chronic heart failure exacerbations necessitating frequent hospital admissions. Despite optimal medical management, clinical improvement was not achieved until a broncho-alveolar lavage (BAL) culture grew MAC and antibiotic therapy targeted against MAC was introduced. Our case report proposes chronic systolic heart failure as a new (not well-recognized) predisposing condition for MAC infection in elderly patients. Because clinical diagnosis can be delayed for weeks, we recommend obtaining sputum/BAL cultures if no clinical improvement is achieved in heart failure patients despite optimal management. High Resolution Computerized Tomography (HRCT) of the chest may also provide meaningful information. We also emphasize the importance of adjusting antibiotics, especially clarithromycin (CLR), based on renal function and tailoring antibiotic management according to serum drug levels to avoid potential liver toxicity associated with CLR use.

Abstract 1612: Identification of mithramycin analogs with improved targeting of the EWS/FLI1 transcription factor

Abstract Background: Ewing sarcoma is a bone a soft tissue sarcoma with a poor overall survival. This tumor absolutely depends on the continued expression of the EWS-FLI1 transcription factor for cell survival. We are therefore focused on developing small molecules that inhibit EWS-FLI1. We have previously completed a high throughput screen that identified mithramycin as an inhibitor of EWS-FLI1 and translated this compound to the clinic in a phase I-II trial. The success of this compound in the clinic has been challenged by drug associated liver toxicity that has necessitated dose reductions. Therefore the goal of this study is to identify less toxic and-or more potent mithramycin analogs. Methods: The less toxic analog, EC8042, was identified by evaluating animal toxicity data and serum pharmacokinetics in mice and rats. In order to identify a more potent compound, a panel of more than 20 mithramycin analogs was screened using an EWS-FLI1 reporter NR0B1 luciferase construct to identify EC8105. EWS-FLI1 suppression was confirmed using quantitative PCR and western blot analysis in vitro. The ability of the drug to block EWS-FLI1 binding to chromatin was evaluated by performing chromatin immunoprecipitation in the presence and absence of drug. The relative hepatotoxicity of the analogs was modeled in vitro by comparing doses that achieve suppression of EWS-FLI1 to toxic doses of the drug in HepG2 cells and confirmed in vivo in xenograft experiments. Finally, we tested the ability of both analogs to suppress tumor growth in xenograft models of Ewing sarcoma and confirmed suppression of EWS-FLI1 using immunofluorescence of formalin fixed tissue from these experiments. Results: EC8042 shows equivalent suppression of EWS-FLI1 activity but is substantially less toxic than the parent compound, allowing higher serum levels of drug in vivo in animal models. In contrast, EC8105 is approximately 8 times more potent than the parent compound and demonstrates improved suppression of the EWS-FLI1 gene signature. Both compounds work to block EWS-FLI1 binding to chromatin. More importantly, in contrast to mithramycin, both analogs suppress EWS-FLI1 activity at concentrations that are non-toxic to HepG2 cells. These effects translate into improved suppression of Ewing sarcoma xenograft growth with a corresponding increase in mouse survival and regression of several tumors in both cohorts. Conclusions: We have identified the mithramycin analogs EC8042 and EC8105 as EWS-FLI1 inhibitors. These compounds are less toxic and more potent than the parent compound and suppress EWS-FLI1 at concentrations that do not appear to cause liver toxicity. Together these results suggest that the clinical development of these analogs is warranted. Citation Format: Christy Osgood, Nichole Maloney, Christopher G. Kidd, Meti Gebregiorgis, Luz E. Nunez, Javier Gonzalez-Sabin, Lee J. Helman, Francisco Moris, Patrick J. Grohar. Identification of mithramycin analogs with improved targeting of the EWS/FLI1 transcription factor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1612. doi:10.1158/1538-7445.AM2015-1612

Optimizing Biologic Agents in Ulcerative Colitis and Crohn's Disease.

The goals of therapy in inflammatory bowel disease (IBD) are the induction and maintenance of clinical and biological remission. Mucosal healing is desirable to prevent complications and reduce the need for surgery, hospitalizations, and steroid exposure. Therapeutic monoclonal antibodies (biologic agents) have revolutionized the treatment of IBD. The initial magnitude of the clinical/biologic response to these agents has been associated with a number of underlying phenotypic features in the recipient. In addition, the durability of the initial response often declines over time. This can occur due to low drug serum drug levels, anti-drug antibodies, and a shift to alternative inflammatory pathways. This review discusses strategies that may optimize the initial response to biologics and sustain this to improve patient outcomes.

Felbamate in intractable pediatric and young adult epilepsy

Felbamate (FBM) use in treatment of pediatric and adult epilepsy has sharply declined since early reports of FBM- associated hematologic and hepatic injury. We retrospectively reviewed the efficacy and safety profile of FBM in children and young adults with intractable epilepsy treated with this antiepileptic drug as adjunctive therapy in our pediatric epilepsy clinic from 2001-2010. We identified 101 patients 2-22 yr (mean 12.8 ± 1.8 yr) with various seizure types and epilepsy syn- dromes. FBM dosing was titrated according to tolerability and seizure control. Mean duration of FBM treatment was 43.7 ± 30.4 mo. Patients had periodic serum drug levels, serum hematologic and metabolic panels and body-mass index measurements during treatment and follow-up. No patient had serious adverse effects, including aplastic anemia or hepatic failure. Using sub- jective seizure counts, FBM also seemed to be effective in seizure control; 22 (22%) patients were reported as seizure-free; 59 (59%) patients were said by parents to have had fewer seizures, and 20 (20%) patients were estimated as having unchanged sei- zure frequency. Weight loss, though typically mild, was the major adverse effect. In children older than 3 yr, 46 (53%) of 86 lost weight during FBM administration and 40 (47%) children gained weight. No patients required discontinuation of FBM due to adverse effects. FBM was well-tolerated and without serious adverse effects in our patients. FBM seemed to be effective in reducing seizure frequency. It should be considered a viable current option for treatment of intractable seizures in children, though weight should be monitored in these patients.

Oral prenylation inhibition with lonafarnib in chronic hepatitis D infection: a proof-of-concept randomised, double-blind, placebo-controlled phase 2A trial

Therapies for chronic hepatitis delta virus (HDV) infection are unsatisfactory. Prenylation is essential for HDV and inhibition abrogates HDV production in experimental models. In a proof-of-concept study, we aimed to assess the effect on HDV RNA levels, safety, and tolerability of the prenylation inhibitor lonafarnib in patients with chronic delta hepatitis. In this phase 2A double-blind, randomised, placebo-controlled study, patients aged 18 years or older with chronic HDV infection were randomly assigned (3:1 in group 1 and 2:1 in group 2) to receive lonafarnib 100 mg (group 1) or lonafarnib 200 mg (group 2) twice daily for 28 days with 6 months' follow-up. Participants were randomised by random-number tables blocked in groups of four without stratification. Both groups enrolled six treatment participants and two placebo participants. Group 1 placebo patients received open-label lonafarnib as group 2 participants. The primary therapeutic endpoint was a decrease in HDV RNA viral titre in serum and the primary safety endpoint was the ability to tolerate the drug at the prescribed dose for the full 4-week duration, defined as drug discontinuation due to intolerance or grade 3/4 adverse events. This trial is registered with ClinicalTrials.gov, number NCT01495585. Between Jan 19, 2012, and April 28, 2014, 14 patients were enrolled, of whom eight were assigned to group 1 and six were assigned to group 2. At day 28, compared with placebo, mean log HDV RNA declines from baseline were -0·73 log IU/mL in group 1 (95% CI 0·17-1·31; p=0·03) and -1·54 log IU/mL in group 2 (1·21-1·93; p<0·0001). Lonafarnib serum concentrations correlated with HDV RNA change (r(2)=0·78, p<0·0001). Model fits show that hepatitis B surface antigen (HBsAg) remained stable after a short pharmacological delay (0·75 days [SE 0·24]), lonafarnib effectiveness in blocking HDV production was greater in group 2 than in group 1 (0·952 [SE 0·06] vs 0·739 [0·05], p<0·001), and the HDV half-life was 1·62 days (0·07). There was no evidence of virological resistance. Adverse events were mainly mild to moderate with group 1 patients experiencing diarrhoea in three patients (50%) and nausea in two patients (33%) and in group 2 with all patients (100%) experiencing nausea, diarrhoea, abdominal bloating, and weight loss greater than 2 kg (mean of 4 kg). No treatment discontinuations occurred in any treatment groups. Treatment of chronic HDV with lonafarnib significantly reduces virus levels. The decline in virus levels significantly correlated with serum drug levels, providing further evidence for the efficacy of prenylation inhibition in chronic HDV. National Institute of Diabetes and Digestive and Kidney Diseases and National Cancer Institute, National Institutes of Health, and Eiger Biopharmaceuticals Inc.

Defining medication adherence in individual patients.

BackgroundThe classification of patients as adherent or non-adherent to medications is typically based on an arbitrary threshold for the proportion of prescribed doses taken. Here, we define a patient as pharmacokinetically adherent if the serum drug levels resulting from his/her pattern of medication-taking behavior remained within the therapeutic range.MethodsWe used pharmacokinetic modeling to calculate serum drug levels in patients whose patterns of dosing were recorded by a medication event monitoring system. Medication event monitoring system data were from a previously published study of seven psoriasis patients prescribed 40 mg subcutaneous adalimumab at 14-day intervals for 1 year. Daily serum concentrations of adalimumab were calculated and compared with a known therapeutic threshold.ResultsNone of the seven patients took adalimumab precisely every 14 days. Three patients who took adalimumab at intervals of 6–26 days could be classified as pharmacokinetically adherent, because their daily adalimumab serum concentration never fell below the therapeutic threshold. The four other patients, who took adalimumab at intervals of 7–93 days, could be classified as pharmacokinetically non-adherent, because their adalimumab serum concentration fell below the therapeutic threshold on 3.5%–71.3% of days.ConclusionPatients with varying patterns of adalimumab dosing could be classified as pharmacokinetically adherent or non-adherent according to whether or not their serum drug concentrations remained within the therapeutic range.

Generic olanzapine substitution in patients with Schizophrenia: assessment of serum concentrations and therapeutic response after switching

Background:Several reports of loss of efficacy or adverse effects have been described after generic substitution of antipsychotics. To date, studies comparing serum drug levels in patients switched to generic antipsychotics in a standard clinical setting are lacking. The aim of this study was to inv

P34 – 2727: Optimization of approaches in treatment of patients with epilepsy

Objective Optimization of adequate plasma concentrations of antiepileptic drugs (AED)s to achieve a prolonged and sustained remission of epilepsy. Methods The study is based on the results of a survey of 40 patients with epilepsy, varying in age debut, duration and etiology of the disease, clinical phenomenology of seizures, but all of them taking carbamazepine as AED. Conducted therapeutic drug monitoring (TDM), MRI, EEG. Results The majority of patients were between the ages of 1 to 5 years of life 52.5%. Selection criteria were the children taking AEDs for at least 3 months. Therapeutic range of carbamazepine concentration is 4–12 mkg/ml, toxicity develops at the level of circulating carbamazepine above 15 mkg/ml TDM allowed to establish causes of no adequate treatment strategy, such as, prescribing AEDs in unreasonable low doses, the appointment of two and more AEDs from different groups without regard to their pharmacokinetic interactions, that caused subtherapeutic drug levels in the blood serum in 33 (82.5%) cases. Level of drugs was at the recommended therapeutic range in 6 (15%) cases, which directly reflects the high individual variability between the received dose and drug levels in the blood. Feedback was analyzed assignable dose of drugs in mg per patient's weight with its concentration in blood plasma. In patients with low drug concentration in blood plasma confirmed adequate calculation of the drug per body weight. Its once again confirm individual tolerability of each patient and the presence of unknown causes which impact on the drug perception, such as helminthes, enzymes deficiency, lack of the liver functional activity and not identified blood minerals. Conclusion Treatment correction on the basis of TDM in patients with various forms of epilepsy lead to the decreasing of the attacks frequency. Clinical positive trend was confirmed by EEG data.

Duration of focal complex, secondarily generalized tonic-clonic, and primarily generalized tonic-clonic seizures--A video-EEG analysis.

Identifying seizures with prolonged duration during video-electroencephalographic (EEG) monitoring is of importance to inform clinicians when to start emergency treatment of seizures to prevent status epilepticus. The aims of this study were to assess the clinical and EEG seizure duration (SD) in consecutive patients with epilepsy who underwent prolonged video-EEG monitoring and to identify a seizure type-dependent time point to start emergency treatment based on the likelihood that seizures will not stop spontaneously. Furthermore, we sought to determine predictors of SD and explored the relationship between antiepileptic drug (AED) serum levels and SD. We retrospectively analyzed 1796 seizures in 200 patients undergoing video-EEG monitoring between January 2006 and March 2008. Focal simple seizures lasted significantly shorter (clinical SD: 28s, EEG SD: 42 s) compared with focal complex seizures (clinical SD: 64 s, EEG SD: 62 s), and both seizure types lasted significantly shorter compared with secondarily generalized tonic-clonic seizures (GTCSs; clinical SD: 90 s, EEG SD: 96 s). There was no difference between the duration of the convulsive phase of primary GTCSs (defined as nonfocal) and that of secondarily GTCSs (each 65 s). Cumulative clinical SD (99%) was 7 min in focal complex seizures and 11 min in focal simple seizures. Mixed linear regression model demonstrated that history of status epilepticus (P = 0.034), temporal lobe seizure onset (P = 0.040), and MRI lesions (P = 0.013) were significantly associated with logarithmic EEG SD in focal epilepsies recorded with scalp electrodes. We found significant negative correlations between the AED serum level and the EEG SD in patients treated with monotherapy: carbamazepine (P < 0.001), levetiracetam (P = 0.001), oxcarbazepine (P = 0.001), and valproic acid (P = 0.038) but not with lamotrigine monotherapy and EEG SD. Based on the results of this study, we propose 2 min of convulsive seizure activity (irrespective of focal or generalized onset) as a prolonged seizure, which could serve as a time point to consider treatment to prevent status epilepticus. In focal complex seizures, we suggest an upper limit of 7 min, and in focal simple seizures 11 min, as definition of prolonged seizures. History of status epilepticus, temporal seizure onset, and lesional MRI findings are factors associated with significantly longer SD. Negative correlations of carbamazepine, levetiracetam, oxcarbazepine, and valproic acid serum levels and SD suggest a prolonging effect on seizures during withdrawal of these AEDs during video-EEG monitoring sessions. This article is part of a Special Issue entitled "Status Epilepticus".

Measurement of anti-TNF agents and anti-drug antibodies serum levels in patients with inflammatory bowel disease.

Despite its undoubted benefit in patients with inflammatory bowel disease, anti-TNF therapy has some limitations including the lack of primary response and the loss of response to treatment in some patients. An empirical approach to these problems is frequently used based on clinical outcome. The measurement of anti-TNF drug serum levels and anti-drug antibodies (ADAb) levels has been proposed for improving the management of anti-TNF drugs. Although their role in routine clinical practice has not been clearly defined, current data support their relationship with clinical outcomes and suggest their clinical utility primarily in patients with loss of response to anti-TNF agents. The presence of pre-existing ADAb before starting the anti-TNF therapy has recently been described. Transient ADAb, non-neutralizing ADAb and some cut-offs points have been proposed, extending the knowledge about this topic. A standardized and widely available test with cut-off points for each anti-TNF agent and the definition of the most appropriate actions to be taken given the serum concentration of the drugs and ADAb are needed before recommending their routine use.

Pharmacokinetics and pharmacodynamics of clofazimine in a mouse model of tuberculosis.

The antileprosy drug clofazimine has shown potential for shortening tuberculosis treatment; however, the current dosing of the drug is not evidence based, and the optimal dosing is unknown. Our objective was to conduct a preclinical evaluation of the pharmacokinetics and pharmacodynamics of clofazimine in the mouse model of tuberculosis, with the goal of providing useful information on dosing for future studies. Pharmacokinetic parameters were evaluated in infected and uninfected BALB/c mice. Pharmacodynamic parameters were evaluated in Mycobacterium tuberculosis-infected mice that were treated for 12 weeks with one of six different clofazimine dosing regimens, i.e., doses of 6.25, 12.5, and 25 mg/kg of body weight/day and 3 regimens with loading doses. Clofazimine progressively accumulated in the lungs, livers, and spleens of the mice, reaching levels of greater than 50 μg/g in all tissues by 4 weeks of administration, while serum drug levels remained low at 1 to 2 μg/ml. Elimination of clofazimine was extremely slow, and the half-life was dependent on the duration of drug administration. Clofazimine exhibited dose-dependent tissue and serum concentrations. At any dose, clofazimine did not have bactericidal activity during the first 2 weeks of administration but subsequently demonstrated potent, dose-independent bactericidal activity. The antituberculosis activity of clofazimine was dependent on neither the dose administered nor the drug concentrations in the tissues, suggesting that much lower doses could be effectively used for tuberculosis treatment.

Pharmacogenomics: personalizing pediatric heart transplantation.

In recent years, outcomes for pediatric cardiac transplantation (PCTx) have steadily improved, with current 5-year overall survival rates estimated at 83%.1 This progress may be attributed to improvements in pretransplantation management, selection of donor hearts, surgical technique, prevention and treatment of rejection, and minimization of treatment-related adverse events. Despite these advances, children who receive cardiac transplants experience significant morbidity and mortality, and there is considerable variability in outcomes, much of which cannot be explained by known clinical risk factors. One source of interindividual variability is genetic variation in the host. There is growing evidence that genomic variation leads to differences in immune response, response to therapies, and susceptibility to adverse outcomes such as malignancy and infection.2–4 This review will focus on the effect of variation in genes that encode enzymes, transporters, and drug target molecules that influence drug response. After review of the foundational principles of pharmacogenomics, evidence for the pharmacogenomic effects on cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil (MMF), and the mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus will be reviewed and clinical implications of these findings discussed. Given the limited nature of evidence from studies of PCTx patients, support will also be drawn from non-PCTx research and pediatric renal transplantation. Genetic studies of nonpharmacogenes such as those in immunomodulatory pathways and variation in the donor genotype may contribute to risk prediction but are beyond the scope of this review. ### Genetic Variation DNA variation can alter biological function through several mechanisms (Figure 1). Variation within the coding sequence or in intron/exon borders can change the protein product through changes in start codons, stop codons, splice sites, or within the coding sequence, leading to nonsense-mediated decay or altered protein function. Other variants associated with pharmacogenomic outcomes are not predicted to change the encoded protein. These synonymous and …

Drug- not carrier-dependent haematological and biochemical changes in a repeated dose study of cyclosporine encapsulated polyester nano- and micro-particles: size does not matter.

Biodegradable nanoparticles are being considered more often as drug carriers to address pharmacokinetic/pharmacodynamic issues, yet nano-product safety has not been systematically proven. In this study, haematological, biochemical and histological parameters were examined on 28 day daily dosing of rats with nano- or micro-particle encapsulated cyclosporine (CsA) to confirm if any changes observed were drug or carrier dependent. CsA encapsulated poly(lactide-co-glycolide) [PLGA] nano- (nCsA) and micro-particles (mCsA) were prepared by emulsion techniques. CsA (15, 30, 45 mg/kg) were administered by oral gavage to Sprague Dawley (SD) rats over 28 days. Haematological and biochemical metrics were followed with tissue histology performed on sacrifice. Whether presented as nCsA or mCsA, 45 mg/kg dose caused significant loss of body weight and lowered food consumption compared to untreated control. Across the doses, both nCsA and mCsA produce significant decreases in lymphocyte numbers compared to controls, commensurate with the proprietary product, Neoral(®) 15. Dosing with nCsA showed higher serum drug levels than mCsA presumably owing to the smaller particle size facilitating absorption. The treatment had no noticeable effects on inflammatory/oxidative stress markers or antioxidant enzyme levels, except an increase in ceruloplasmin (CP) levels for high dose nCsA/mCsA group. Further, only subtle, sub-lethal changes were observed in histology of nCsA/mCsA treated rat organs. Blank (drug-free) particles did not induce changes in the parameters studied. Therefore, it is extremely important that the encapsulated drug in the nano-products is considered when safety of the overall product is assessed rather than relying on just the particle size. This study has addressed some concerns surrounding particulate drug delivery, demonstrating safe delivery of CsA whilst achieving augmented serum concentrations.

Ulcerative Colitis: What is the Optimal Treatment Goal and How Do We Achieve It?

The treatment paradigms and therapeutic options for ulcerative colitis (UC) have rapidly evolved during the past decade. Traditionally, the treatment target has focused on achieving successful induction and maintenance of steroid-free clinical remission. This has been shown to provide a better quality of life and a reduction in complications, hospitalizations, and surgery. Recent studies, however, suggest that achieving "mucosal healing" or endoscopic remission may be the optimal treatment endpoint. In this review, we will examine the treatment goals for UC and the efficacy of each therapy to reach these targets. We will also review the therapeutic options available for UC: mesalamines, steroids, immunomodulators, and biologics, including the first anti-integrin inhibitor, approved in May 2014, for the treatment of UC. Therapeutic drug monitoring, which measures serum drug level and anti-drug antibody concentrations, is emerging as an important clinical decision tool in patients on tumor necrosis factor (TNF)-antagonists. These evolving treatment strategies allow gastroenterologists to optimize control of the disease and offer patients a better quality of life.

Assessment of adherence to treatment in patients with resistant hypertension using toxicological serum analysis. A subgroup evaluation of the RESIST-POL study.

Nonadherence to antihypertensive therapy is one of the main causes of resistant hypertension. The aim of our study was to evaluate adherence to therapy in patients with resistant hypertension by determining serum antihypertensive drug levels with the use of liquid chromatography-tandem mass spectrometry (LC-MS/MS). The study included 36 patients with primary resistant hypertension selected from the RESIST-POL study (23 men and 13 women; mean age, 52.5 ±9.1 years; range, 22-67 years; mean number of antihypertensive drugs, 5.3 ±1.4), who met all 3 inclusion criteria: use of ≥4 antihypertensive drugs; average daytime ambulatory systolic blood pressure ≥140 mmHg; one of the clinical features suggesting nonadherence. All patients had their serum drug levels assessed using LC-MS/MS. Patients in whom the serum level of at least 1 drug was below the limit of quantification for the method used were regarded as nonadherent. Of all study patients, nonadherence was observed in 31 patients (86.1%), and none of the prescribed drugs was detected (complete nonadherence) in 5 patients (13.9%). In 26 patients (72.2%), at least 1 of the prescribed drugs could not be detected (partial nonadherence). In our study, we documented a surprisingly low adherence to antihypertensive treatment in patients with resistant hypertension. Our results suggest that, particularly in those patients, the analysis of serum antihypertensive drug levels using LC-MS/MS might allow to avoid a comprehensive and costly diagnostic work-up including biochemical and imaging studies.

Optimizing the use of biological therapy in patients with inflammatory bowel disease.

Biological therapy revolutionized the treatment of inflammatory bowel disease (IBD) during the last decade. These monoclonal antibodies, which target tumor necrosis factor (TNF), integrins or IL12/23, have been approved—or are in development for—both Crohn’s disease (CD) and ulcerative colitis (UC). Early use of these agents taught clinicians that induction and maintenance therapy, coupled with immunomodulator agents, reduced the immunogenicity of these agents, and led to sustained remission in many patients. More recent data has demonstrated that, through dose adjustments, optimizing serum drug levels may also provide more durable maintenance of remission, and improved mucosal healing. This review examines clinical practices that may enhance clinical outcomes from biological therapy in IBD.

How Useful is Anti-TNF Serum Level and Anti-drug Antibodies Detection in Evaluating Patients with Spondyloarthritis?

Objective: The aim of this study was to assess whether infliximab and adalimumab drug serum levels and the detection of anti-drug antibodies can be of use in better observing disease activity in patients with spondyloarthritis, besides classical tools such as BASDAI, ASDAS and inflammatory markers. We proposed to evaluate the influence of ADA in non-responders and in drug-related adverse events. Methods: Over one year, we enrolled 115 patients with SpA, treated with infliximab or adalimumab. Patients who delayed prescribed drug administration were excluded from the study cohort. The population comprised 69 patients - 33 on IFX and 35 on ADA. NSAIDs administration was recommended “on demand”. Demographic, clinical (BASDAI, ASDAS) and laboratory (ESR, CRP) data was collected together with drug serum level and anti-drug antibodies using ELISA. The statistical analysis was performed using the SPSS software, version 20.0 with the aid of Student t-test, Spearman and Pearson tests. Results: Detectable IFX serum levels were identified in 60% of patients while 40% had undetectable drug titers. The IFX-negative had significantly higher disease activity scores: BASDAI (P=0.023), ASDAS-ESR (P<0.001) and ASDAS-CRP (P<0.001). Significant differences were found in the same subgroups regarding inflammatory markers, with higher ESR (P<0.001) and CRP (P=0.032) in patients with undetectable IFX levels. When measuring ADL serum levels, 82% had detectable drug concentrations, with lower BASDAI (P<0.001), ASDAS-ESR and ASDASCRP (P<0.001) and higher ESR and CRP at collection time when compared to ADL-negative patients. NSAID consumption correlated to undetectable levels of IFX and ADL as well as with anti-drug antibodies for both IFX and ADL positivity. All patients who experienced drug related adverse events on both IFX and ADL had positive anti-drug antibodies. Conclusion: Serum drug level measurement and anti-drug antibody detection can be used as a completion of a clinician’s tools in assessing disease activity, leading to an optimal patient management.

Dose-Tapering Of TNF Inhibitors in Daily Rheumatology Practice Enables the Maintenance of Clinical Efficacy While Improving Cost-Effectiveness

Background The fact that biologics consume a growing portion of health care budget has resulted in an increased attention towards therapy optimization. One of the potential ways to optimize treatment is the down-titration of the administered drug dose. Objective To assess whether the clinical activity remains stable after dose tapering of TNF inhibitors in patients with low disease activity and to evaluate the potential benefit of this strategy on the treatment costs. Method A cohort of 77 patients with low disease activity treated with TNF inhibitors (TNFi) was monitored. The patients were studied over two time periods: in the 1st period with the drug standard dose, and in the 2nd period with a reduced dose. Clinical efficacy was monitored by DAS28 in rheumatoid arthritis (RA) and by BASDAI in spondyloarthritis (SpA). Serum drug and anti-drug antibody levels were measured by ELISA. The amount of drug dispensed per patient in both periods was compared. Results In the 2nd period, although patients received a lower amount of TNF inhibitor, no differences in clinical activity were observed (DAS28 in RA patients: 2.37 ± 0.50 in the 2nd P vs 2.28 ± 0.47 in the 1st P, p=0.20; BASDAI in SpA patients: 1.90 ± 0.93 in the 2nd P vs 1.88 ± 0.95 in the 1st P, p=0.910) and circulating serum trough drug levels were lower (Infliximab: 3.2 ± 2.5 μg/ml in the 1st P vs 1.8 ± 1.5 μg/ml in the 2nd P, p<0.0001; Adalimumab: 5.5 ± 2.8 μg/ml in the 1st P vs 3.1 ± 2.1 μg/ml in the 2nd P, p<0.0001; Etanercept: 1.8 ± 1.1 μg/ml in the 1st P vs 1.3 ± 0.8 μg/ml in the 2nd P p<0.05). The amount of administered drug per patient was reduced in an average of 20% per year. Conclusion Dose tapering can be successfully performed in patients with low disease activity, resulting in remarkable savings in the amount of drug used and in the associated costs.