Serum Drug Concentrations Research Articles

CE: The Effects of Smoking on Bone Health and Healing.

The number of orthopedic surgeries performed in the United States has increased substantially over the past several years. The most recent data available from the Agency for Healthcare Research and Quality indicate that five of the 10 operative procedures most commonly performed during inpatient stays involve the musculoskeletal system. Cigarette smoking is one of the most prevalent and preventable risk factors for musculoskeletal disorders and orthopedic surgery complications. This article discusses the effects of smoking on bone health, the importance of smoking cessation among patients scheduled for or recovering from orthopedic surgery, and the vital role nurses play in supporting patient efforts to lead a tobacco-free life.

Multidrug-Resistant Orthopaedic Surgical Site Infections Treated with Linezolid in Four Dogs

Abstract Objective This study aimed to report the adverse drug events and treatment outcome of systemic linezolid therapy to manage multi-drug resistant orthopaedic surgical site infection in dogs. Materials and Methods Retrospective case review of four dogs that received linezolid to treat surgical site infections after orthopaedic surgery. Reevaluations consisted of a clinical examination or a telephone interview. Results Serum drug concentrations varied. All dogs showed a temporary resolution of clinical signs of surgical site infection. Two dogs that received linezolid at the previously reported dose developed drug-associated side effects. The side effects were anorexia, nausea, vomiting and regenerative anaemia. All side effects resolved after the discontinuation of linezolid. Surgical site infection recurred in two dogs 52 and 177 days after discontinuing linezolid respectively. Clinical significance Adverse drug events occurred in dogs receiving oral linezolid at the dosage of 10 to 20 mg/kg. Oral linezolid therapy failed to resolve deep orthopaedic surgical site infections in two out of four dogs. As a tertiary antimicrobial, linezolid should only be used in carefully selected cases while monitoring for drug-associated side effects.

Impact of antipsychotic polypharmacy on nonadherence of oral antipsychotic drugs – A study based on blood sample analyses from 24,239 patients

Nonadherence to oral antipsychotic drugs is a major issue in clinical psychiatry giving rise to treatment failure. Further, polypharmacy is common in the treatment of psychotic disorders due to insufficient treatment effect during monotherapy. As a potential circuit problem, we hypothesized that antipsychotic polypharmacy is associated with increased risk of nonadherence. To investigate this, in terms of ‘complete’ nonadherence, the rates of undetectable serum drug concentrations during prescribing of doses used in psychotic disorders were compared during antipsychotic ‘monotherapy’ vs ‘polypharmacy’ treatment using therapeutic drug monitoring (TDM) data of 24,239 patients. A complete nonadherence patient was objectively defined as the detection of at least one event of undetectable serum concentration of a prescribed antipsychotic drug. The rate of complete nonadherence patients was compared between antipsychotic monotherapy and polypharmacy by multivariate logistic regression analyses. The overall rate of complete nonadherence in the population was 6.8% (n = 1,644; 95%CI: 6.5–7.1). Compared to monotherapy patients, the rate of nonadherence increased significantly with the number of co-prescribed antipsychotic drugs. After adjusting for sex (p = 0.091) and age (p < 0.001) as covariates, the rates of nonadherence vs monotherapy were 1.69-fold (95% CI: 1.48–1.92; p < 0.001) for two, 2.60-fold (95% CI: 1.88–3.59; p < 0.001) for three, and 3.54-fold (95% CI: 1.46–8.58; p = 0.005) for four or more co-prescribed antipsychotics, respectively. The present naturalistic study shows that antipsychotic polypharmacy significantly increases the rate of complete nonadherence, which is positively correlated with increasing number of concurrently used antipsychotic drugs. Thus, the intended clinical benefit of combining oral antipsychotic drugs may probably be reduced by increased nonadherence.

Prevalence and sort of pharmacokinetic drug-drug interactions in hospitalized psychiatric patients.

Psychiatric patients are high-risk patients for the development of pharmacokinetic drug-drug interactions (DDIs), leading to highly variable (victim) drug serum concentrations. Avoiding and targeting high-risk drug combinations could reduce preventable adverse drug reactions (ADRs). Pharmacokinetic cytochrome P450 (CYP)-mediated DDIs are often predictable and, therefore, preventable. The retrospective, longitudinal analysis used informations from a large pharmacovigilance study (Optimization of pharmacological treatment in hospitalized psychiatric patients study, study number 01VSF16009, 01/2017), conducted in 10 psychiatric hospitals in Germany. Medication data were examined for the co-prescription of clinically relevant CYP inhibitors or inducers and substrates of these enzymes (victim drugs). In total, data from 27,396 patient cases (45.6% female) with a mean (mean ± standard deviation (SD)) age of 47.3 ± 18.3years were available for analysis. CYP inhibitors or inducers were at least once prescribed in 14.4% (n = 3946) of the cases. The most frequently prescribed CYP inhibitors were melperone (n = 2504, 28.1%) and duloxetine (n = 1324, 14.9%). Overall, 51.0% of the cases taking melperone were combined with a victim drug (n = 1288). Carbamazepine was the most frequently prescribed CYP inducer (n = 733, 88.8%). Combinations with victim drugs were detected for 58% (n = 427) of cases on medication with carbamazepine. Finally, a DDI was detected in 43.6% of the cases in which a CYP inhibitor or inducer was prescribed. The frequency of CYP-mediated DDI is considerably high in the psychiatric setting. Physicians should be aware of the CYP inhibitory and inducing potential of psychotropic and internistic drugs (especially, melperone).

FRI0536 SERUM GOLIMUMAB CONCENTRATIONS AND ANTI-DRUG ANTIBODIES ARE ASSOCIATED WITH TREATMENT RESPONSE AND DRUG SURVIVAL IN PATIENTS WITH INFLAMMATORY JOINT DISEASES: DATA FROM THE NOR-DMARD STUDY

Background:Lack or loss of response to TNFα-inhibitors can be caused by subtherapeutic drug levels and anti-drug antibodies (ADAb). Knowledge about associations between clinical efficacy and drug levels as well as occurrence of ADAb is limited in patients with inflammatory joint diseases (IJD) treated with golimumab.Objectives:To identify the therapeutic target concentration and assess the frequency of ADAb in golimumab-treated patients with IJD.Methods:91 patients from the NOR-DMARD study with a clinical diagnosis of axial spondyloarthritis (n=41), rheumatoid arthritis (n=20) or psoriatic arthritis (n=30) starting treatment with golimumab, with an available biobank sample at 3 months follow-up, were included. Treatment response was defined by ASDAS Clinically important improvement in axial spondyloarthritis, EWULAR good/moderate response in rheumatoid arthritis and improvement of ≥50% in modified DAPSA (using 28 swollen/tender joint counts) in psoriatic arthritis. Serum drug concentrations were analysed in non-trough samples collected 3 months after treatment initiation, using an automated in-house target-based immunofluorometric assay. ADAb was measured with an inhibition assay that measures neutralising antibodies. The association between drug levels and treatment response was assessed by multivariable logistic regression (adjusted for age, sex and prior bDMARD (Y/N)). Drug-survival was assessed by Kaplan-Meier curves and Cox proportional hazard regression analysis.Results:Golimumab serum concentrations varied considerably between patients on standard dose (range 0.0-8.2 mg/L) with a median of 2.2 (IQR 1.0-3.5) mg/L. The proportions of responders after 3 months among patients with golimumab concentration &lt;1.0, 1.0-3.9 and ≥4.0 mg/L, were 19%, 49% and 74%, respectively (Fig.1). The likelihood of response after 3 months of treatment was significantly higher among patients with serum golimumab concentration ≥1.0 mg/L compared to those with golimumab &lt;1.0 mg/L (OR 5.8 (95% CI 1.7-19.7), P =0.005). The proportion of responders was highest among patients with golimumab concentrations ≥4.0 mg/L, but the difference in response between patients with concentrations ≥4.0 mg/L compared to 1.0-4.0 mg/L was not statistically significant (OR 2.1 (95% CI 0.6-7.1), P=0.24). We also found a higher rate of treatment discontinuation in patients with serum golimumab concentration &lt;1.0 mg/L compared to ≥1.0 mg/L (HR 3.6 (95% CI 1.9-6.9), P &lt;0.001) (Fig.2). ADAb were detected in 5 of 91 samples and were associated with lower drug concentrations. Only 1 out of 5 ADAb-positive patients was a responder at 3 months, and all 5 ADAb positive patients discontinued treatment within the first 14 months.Conclusion:Golimumab concentrations ≥1.0 mg/L were associated with improved treatment response and better drug survival, but our results also indicate that some patients might benefit from higher concentrations. ADAb were associated with lower drug concentrations and both reduced treatment response and drug survival. These findings suggest a rationale for personalised dosing guided by measurements of drug concentration and ADAb in golimumab-treated patients with IJD, which should be addressed in future randomised strategy trials.Disclosure of Interests:Johanna Elin Gehin Speakers bureau: Roche, David J Warren: None declared, Silje Watterdal Syversen Speakers bureau: Roche, Thermo Fisher, Elisabeth Lie: None declared, Joe Sexton: None declared, Liz Loli: None declared, Ada Wierød: None declared, Trine Bjøro: None declared, Tore K. Kvien Grant/research support from: Received grants from Abbvie, Hospira/Pfizer, MSD and Roche (not relevant for this abstract)., Consultant of: Have received personal fees from Abbvie, Biogen, BMS, Celltrion, Eli Lily, Hospira/Pfizer, MSD, Novartis, Orion Pharma, Roche, Sandoz, UCB, Sanofi and Mylan (not relevant for this abstract)., Paid instructor for: Have received personal fees from Abbvie, Biogen, BMS, Celltrion, Eli Lily, Hospira/Pfizer, MSD, Novartis, Orion Pharma, Roche, Sandoz, UCB, Sanofi and Mylan (not relevant for this abstract)., Speakers bureau: Have received personal fees from Abbvie, Biogen, BMS, Celltrion, Eli Lily, Hospira/Pfizer, MSD, Novartis, Orion Pharma, Roche, Sandoz, UCB, Sanofi and Mylan (not relevant for this abstract)., Nils Bolstad Consultant of: Pfizer, Janssen, Speakers bureau: Orion Pharma, Napp Pharmaceuticals, Takeda, Roche, Novartis, Guro Løvik Goll Consultant of: Novartis, Pfizer, Speakers bureau: Abbvie, Biogen, Boehringer Ingelheim, Orion Pharma, Eli Lilly, Novartis, Pfizer, MSD, Roche, UCBTable 1.Change in FVC(ml) and DLCO% in the 6–12 months before and after different treatmentTreatment groupPre-TxPost-TxpR9.8% (11)FVCDLCO2015±74672.4±17.22024±80360.7±27.90.780.43CYC25.0% (28)FVCDLCO1853±58561.2±23.81796±57861.4±23.90.740.79R+CYC17.9% (20)FVCDLCO1901±66758.2±14.51922±67246.7±18.80.900.90Non-R, CYC47.3% (53)FVCDLCO2177±65746.7±18.82286±70445.8±19.60.470.69SubgroupUIP31.3% (35)FVCDLCO2053±72158.9±22.71949±72749.3±25.10.570.15Non-UIP68.8% (77)FVCDLCO(%)1908±60859.0±18.71961±65460.5±1850.530.46Table 2.Secondary outcome and multivariable Cox model for overall survival

Construction of Quantitative Analysis Workflow for Determination of Serum Concentrations of Monoclonal Antibody Drugs Aiming to Promote Therapeutic Drug Monitoring in Clinical Practice

Construction of Quantitative Analysis Workflow for Determination of Serum Concentrations of Monoclonal Antibody Drugs Aiming to Promote Therapeutic Drug Monitoring in Clinical Practice

Transfer of monoclonal antibodies into breastmilk in neurologic and non-neurologic diseases.

ObjectiveTo review currently available data on the transfer of monoclonal antibodies (mAbs) in the breastmilk of women receiving treatment for neurologic and non-neurologic diseases.MethodsWe systematically searched the medical literature for studies referring to 19 selected mAb therapies frequently used in neurologic conditions and “breastmilk,” “breast milk,” “breastfeeding,” or “lactation.” From an initial list of 288 unique references, 29 distinct full-text studies met the eligibility criteria. One additional study was added after the literature search based on expert knowledge of an additional article. These 30 studies were reviewed. These assessed the presence of our selected mAbs in human breastmilk in samples collected from a total of 155 individual women.ResultsDrug concentrations were typically low in breastmilk and tended to peak within 48 hours, although maximum levels could occur up to 14 days from infusion. Most studies did not evaluate the breastmilk to maternal serum drug concentration ratio, but in those evaluating this, the highest ratio was 1:20 for infliximab. Relative infant dose, a metric comparing the infant with maternal drug dose (<10% is generally considered safe), was evaluated for certolizumab (<1%), rituximab (<1%), and natalizumab (maximum of 5.3%; cumulative effects of monthly dosing are anticipated). Importantly, a total of 368 infants were followed for ≥6 months after exposure to breastmilk of mothers treated with mAbs; none experienced reported developmental delay or serious infections.ConclusionsThe current data are reassuring for low mAb drug transfer to breastmilk, but further studies are needed, including of longer-term effects on infant immunity and childhood development.

Phase I trial characterizing the pharmacokinetic profile and NK and CD8+ t cell expansion with n-803, a chimeric IL-15 superagonist, in healthy volunteers.

e15008 Background: The oncotherapeutic promise of IL-15, a potent immune stimulant, is limited by short serum half-life. The fusion protein N-803 is an IL-15 superagonist complex that has &gt; 20-fold longer half-life in vivo vs IL-15. This study characterized the pharmacokinetic (PK) profile, biological activity, and safety of N-803 after subcutaneous administration to healthy human volunteers. Methods: Volunteers were randomized 1:1 to receive 1 mg/mL or 2 mg/mL N-803. Each subject received 2 doses of N-803: 10 µg/kg followed 24 days later by 20 µg/kg. After each dose, PK and safety measures were assayed for 9 successive days. Primary endpoint was the PK profile of N-803; secondary was safety; and exploratory endpoints were cytokine levels, immune cell characterization, and immunogenicity. Results: N-803 resulted in no grade ≥3 or serious adverse events (AEs). Mild injection site reactions, chills, and pyrexia were the most common AEs. Serum N-803 concentrations peaked 10.3-15.4 hours after administration and declined with a half-life of 20.0-20.7 hours. Peak N-803 serum concentrations were dose-dependent, with a 1.5-fold increase in Cmax after administration of 20 µg/kg vs 10 µg/kg. In the peripheral blood, N-803 induced a transient decline, followed by a significant increase (3-fold) in NK cell number that persisted for ≥24 days. N-803 also caused a significant proliferation of NK (22-fold increase in Ki-67+ cells), CD8+ (27-fold) and CD4+ T (11-fold) cells; however, increased cell number occurred only in NK cells. N-803 administration also increased serum levels of interferon gamma, IL-10, and IL-6. One of 14 evaluable subjects had measureable anti-N-803 antibodies at the end-of-study visit. Conclusions: N-803 results in prolonged elevation of drug serum concentrations, contrasting with rapid clearance of recombinant human IL-15 (ie, half-life of ~20 vs &lt; 1 hour). N-803 administration was well-tolerated in healthy volunteers, without evidence of adverse systemic inflammatory responses, and resulted in proliferation of NK cells and CD8+ T cells, as well as sustained increases in NK cell number. Findings in this study are consistent with published results from N-803 administration in treating liquid tumors and lung cancer. Our results demonstrate N-803 administration potentiates the proliferation and activity of lymphocytes with antitumor and antivirus properties, and suggest this investigational product holds promise in treatment of cancer as well as infectious disease such as HIV. Clinical trial information: NCT03381586 .

Assessment of adherence to diuretics and β-blockers by serum drug monitoring in comparison to urine analysis

Purpose: Toxicological screenings for identifying antihypertensive drugs proved to be a useful tool for assessing adherence. However, misinterpretation may occur in case of highly metabolised drugs with low renal excretion, as well as for drugs with a prolonged detectability. The aim of the present study was to compare a recently developed therapeutic drug monitoring (TDM) method based on serum concentrations to an urine drug detection method for assessing adherence in outpatients.Materials and methods: Corresponding urine and blood samples were obtained at the same time from 26 outpatients without supervised medication. Urine and serum analyses were performed using established high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodologies. Adherence was assumed if drugs were detectable in urine or if serum concentrations were above individually calculated lower dose-related concentrations (DRC) or literature-based therapeutic reference ranges (TRR) used as cut-off, respectively.Results: The identification of analytes in urine as well as the quantitative serum assay were performed for atenolol (n = 6 patients), bisoprolol (n = 8), nebivolol (n = 6), canrenone (n = 6, metabolite of spironolactone), hydrochlorothiazide (n = 12) and furosemide (n = 2). On the basis of drug detectability in urine, adherence was assumed in 88% of prescriptions. In 81% (DRC) and 50% (TRR) of the serum analyses the cut-off value was exceeded, which confirms patients’ adherence in a lower number. Differences in adherence rates were found in five patients, mainly for β-blockers.Conclusion: This study suggests that assessment of adherence can be performed more precisely on the basis of serum drug concentrations with individually calculated lower DRC than by using the TRR or qualitative urinalysis.

Optimizing Antitumor Necrosis Factor Treatment in Pediatric Inflammatory Bowel Disease With Therapeutic Drug Monitoring.

Biological agents have revolutionized inflammatory bowel disease treatment but primary nonresponse and secondary loss of response are common with resulting adverse outcomes. Clinical trials demonstrated an association between serum drug concentrations, as well as the presence of antidrug antibodies, and loss-of-response. Therapeutic drug monitoring (TDM), defined as the evaluation of drug concentrations and antidrug antibodies, is appearing as a strategy to optimize treatment and take full advantage from these drugs. TDM appears to be a promising tool in clinical practice, especially in pediatric patients, who have pronounced fluctuations in the pharmacokinetics of the drugs.The authors present a literature review about antitumor necrosis factor therapy optimization based on personalized treatment strategies according to TDM and possible strategies to recapture loss of response, including an algorithm for practical management.

Aminoglycoside Dosing and Volume of Distribution in Critically Ill Surgery Patients.

Background: At a tertiary referral and Level I trauma center, current institutional guidelines suggest initial aminoglycoside doses of gentamicin or tobramycin 4 mg/kg and amikacin 16 mg/kg for patients admitted to surgical intensive care units (SICUs) with suspected gram-negative infection. The objective of this study was to evaluate initial aminoglycoside dosing and peak serum drug concentrations in critically ill surgery patients to characterize the aminoglycoside volume of distribution (Vd) and determine an optimal standardized dosing strategy. Methods: This retrospective, observational, single-center study included adult SICU patients who received an aminoglycoside for additional gram-negative coverage. Descriptive statistics were used to evaluate the patient population, aminoglycoside dosing, and Vd. Multivariable linear regression was applied to determine variables associated with greater aminoglycoside Vd. The mortality rate was compared in patients who achieved adequate initial peak concentrations versus those who did not. Results: One hundred seventeen patients received an aminoglycoside in the SICUs, of whom 58 had an appropriately timed peak concentration measurement. The mean Acute Physiology, Age, and Chronic Health Evaluation (APACHE) II score was 27.8 ± 8.9. The Vd in patients receiving gentamicin, tobramycin, and amikacin was 0.49 ± 0.10, 0.41 ± 0.09, and 0.53 ± 0.13 L/kg, respectively. Together, the mean aminoglycoside Vd was 0.50 ± 0.12 L/kg. Gentamicin or tobramycin 5 mg/kg achieved goal peak concentrations in 24 patients (63.2%), and amikacin 20 mg/kg achieved the desired concentrations in nine patients (50.0%). Net fluid status, Body Mass Index, and vasopressor use were not predictive of Vd. There was no difference in the in-hospital mortality rate in patients who achieved adequate peak concentrations versus those who did not (26.8% versus 26.7%; p = 0.99). Conclusion: High aminoglycoside doses are needed in critically ill surgery patients to achieve adequate initial peak concentrations because of the high Vd. Goal peak concentrations were optimized at doses of gentamicin or tobramycin 5 mg/kg, and amikacin 20 mg/kg.

Optimized timing of using infliximab in perianal fistulizing Crohn's disease.

Infliximab (IFX), as a drug of first-line therapy, can alter the natural progression of Crohn’s disease (CD), promote mucosal healing and reduce complications, hospitalizations, and the incidence of surgery. Perianal fistulas are responsible for the refractoriness of CD and represent a more aggressive disease. IFX has been demonstrated as the most effective drug for the treatment of perianal fistulizing CD. Unfortunately, a significant proportion of patients only partially respond to IFX, and optimization of the therapeutic strategy may increase clinical remission. There is a significant association between serum drug concentrations and the rates of fistula healing. Higher IFX levels during induction are associated with a complete fistula response in these patients. Given the apparent relapse of perianal fistulizing CD, maintenance therapy with IFX over a longer period seems to be more beneficial. It appears that patients without deep remission are at an increased risk of relapse after stopping anti-tumor necrosis factor agents. Thus, only patients in prolonged clinical remission should be considered for withdrawal of IFX treatment when biomarker and endoscopic remission is demonstrated, especially when the hyperintense signals of fistulas on T2-weighed images have disappeared on magnetic resonance imaging. Fundamentally, the optimal timing of IFX use is highly individualized and should be determined by a multidisciplinary team.

Dose-Related Concentrations of Neuroactive/Psychoactive Drugs Expected in Blood of Children and Adolescents.

Therapeutic drug monitoring is highly recommended for children and adolescents treated with neurotropic/psychotropic drugs. For interpretation of therapeutic drug monitoring results, drug concentrations (C/D) expected in a "normal" population are helpful to identify pharmacokinetic abnormalities or nonadherence. Using dose-related concentration (DRC) factors obtained from pharmacokinetic data, C/D ranges expected under steady state can be easily calculated by multiplication of DRC by the daily dose. DRC factors, however, are defined only for adults so far. Therefore, it was the aim of this study to estimate DRC factors for children and adolescents and compare them with those of adults. To obtain pharmacokinetic data (apparent total clearance of drugs from plasma after oral administration, elimination half-life, area under the curve, and minimum serum drug concentration) from children and adolescents treated with psychotropic drugs, a systematic review of published literature was performed, and the pharmaceutical companies that market these drugs were contacted. Available information was used for the calculation of DRC factors. Fourteen of 26 drugs had similar DRC factors to those reported for adults; 8 and 4 had higher and lower factors, respectively. The antidepressants citalopram, clomipramine, fluvoxamine, and imipramine and the antipsychotics haloperidol and olanzapine showed higher DRC factors than those calculated for adults. The DRC factors of amphetamine and methylphenidate were higher in children (6-12 years) but not in adolescents (13-17 years). On the contrary, the antipsychotic quetiapine and the mood-stabilizing antiepileptics lamotrigine, oxcarbazepine, and topiramate showed lower DRC factors than those calculated for adults. It was concluded that concentrations of neuroactive/psychoactive drugs to be expected in blood for a given dose may differ between adults and children or adolescents, most probably owing to age-dependent differences in the elimination of these drugs.

Treatment of Bupropion Toxicity with Lipid Emulsion

We have read with interest the case report, “Successful Management of Adolescent Bupropion Overdose with Intravenous Lipid Emulsion Therapy,” recently published in the Journal of Pediatric Intensive Care.[1] Lipid emulsion is effective in the treatment of acute toxicity induced by local anesthetics or nonlocal anesthetic drugs, including amitriptyline, bupropion, and verapamil, in pediatric patients.[2] A previous in vitro study reported that the magnitude of the reduction of the serum concentration of bupropion, which is a highly lipid-soluble antidepressant (log [octanol/water partition coefficient]: 3.2), was 46 by 2% lipid emulsion (Intralipid).[3] In addition, the magnitude of the sequestration of drugs with varied lipid solubility by lipid emulsion is dependent mainly on the lipid partition coefficient and partially on the volume of distribution, which appears to account for 88% of variations in the reduction of drug serum concentration by lipid emulsion.[3] As suggested by Bornstein et al, the lipid sink theory, which is considered the mechanism underlying the effect of lipid emulsion as a nonspecific antidote, states that lipid emulsion absorbs highly lipid-soluble drugs, such as bupivacaine (log [octanol/water partition coefficient]: 3.41), from the heart.[1] [4] However, the following comments should be considered to understand this case report well. First, the first administration of lipid emulsion improved the mental status of the patient.[1] On day 3, the second administration of lipid emulsion was performed due to the recurrence of an altered mental status.[1] The elimination half-life of bupropion is 29 ± 9 hours.[5] In addition, the absorption of a toxic dose following oral administration (enteral route) is more prolonged than that following intravenous administration, leading to extended toxicity.[6] In contrast, Intralipid has a very short half-life (13.7 ± 5.2 minutes).[7] Considering previous reports, the lipid phase of lipid emulsion appears to absorb highly lipid-soluble bupropion from the heart and brain for a very short period following lipid emulsion administration.[3] [7] Furthermore, 1% of plasma triglyceride concentration, which provides lipemic plasma without fat overload, is sufficient to exert scavenging and cardiotonic effects on the toxicity induced by an enteral overdose.[6] Thus, the altered mental status on day 3 following a marked improvement after the first administration of lipid emulsion may be ascribed to a greatly reduced concentration of Intralipid.[1] A previous report recommends the following lipid emulsion regimen to treat toxicity induced by enteral overdose: bolus administration of Intralipid 1.5 mL/kg for 1 minute and subsequently 0.25 mL/kg/min for an additional 3 minutes, followed by intravenous infusion of 0.025 mL/kg/min (up to 6.5 hours) to theoretically maintain a 1% plasma triglyceride concentration.[6] This regimen, as an adjuvant, can be used with supportive care in cases of toxicity induced by oral overdose.[6] However, further research in an in vivo model on the optimal dosing regimen of lipid emulsion for the treatment of toxicity following oral overdose of bupropion is needed because the pharmacokinetics of an oral overdose are different from those of intravenous overdose (e.g., local anesthetic systemic toxicity). Second, initially, lipid sink was widely accepted as the underlying mechanism of lipid emulsion treatment.[4] However, a previous study using a physiologically based pharmacokinetic model reported that lipid emulsion decreased only 11 and 18% bupivacaine concentrations in the heart and brain, respectively.[8] The free bupivacaine concentration was not significantly different between the control and lipid emulsion groups in an in vivo study after administration of a nontoxic dose of bupivacaine in humans.[9] Thus, lipid shuttle has recently been widely accepted as the mechanism of lipid emulsion treatment; it states that lipid emulsion absorbs lipid-soluble drugs, such as bupivacaine, from the heart and then the lipid emulsion, containing the sequestered lipid-soluble drug (e.g., bupivacaine), is transported to the liver and muscle for detoxification and storage, leading to enhanced redistribution.[4] We believe that this case report contributes valuable data on the efficacy of lipid emulsion treatment in bupropion toxicity and emphasizes the need for continuous infusion of lipid emulsion following the initial bolus administration in lipid emulsion treatment.

In vitro killing of canine strains of Staphylococcus pseudintermedius and Escherichia coli by cefazolin, cefovecin, doxycycline and pradofloxacin over a range of bacterial densities.

BackgroundBacterial densities likely fluctuate during infection and may exceed the bacterial density used in susceptibility testing. As such, investigation of bacterial killing by antibiotics over a range of varying bacterial densities may provide important differences between compounds and could impact drug selection for therapy.Hypothesis/ObjectivesTo measure killing of clinical isolates of Staphylococcus pseudintermedius and Escherichia coli by cefazolin, cefovecin, doxycycline and pradofloxacin at clinically relevant (minimum inhibitory, mutant prevention, maximum serum and maximum tissue) drug concentrations against varying densities of bacteria.Animals/MaterialsBacterial strains collected from dogs with urinary tract infections were studied.Methods and materialsHigh bacterial densities ranging from 106 to 109 colony forming units (cfu)/mL were exposed to minimum inhibitory, mutant prevention, blood and tissue drug concentrations, and the percentages (log10) of viable cells killed following 30 min, 1, 2, 4, 6, 12 and 24 h of drug exposure were quantified.ResultsDoxycycline exhibited bacteriostatic properties with less killing than the other three agents. For example, at a 107 cfu/mL density of S. pseudintermedius, more cells were killed by pradofloxacin (P < 0.0001) and cefovecin (P = 0.0014) but not cefazolin when compared to doxycycline at the maximum serum drug concentration following 12 h of drug exposure.Conclusions and clinical importanceDifferences were seen between some drugs in the speed and extent of bacterial killing; this could be clinically important and may impact drug selection and length of therapy.

In Vitro ELISA and Cell-Based Assays Confirm the Low Immunogenicity of VNAR Therapeutic Constructs in a Mouse Model of Human RA: An Encouraging Milestone to Further Clinical Drug Development.

Anti-drug antibodies (ADAs), specific for biotherapeutic drugs, are associated with reduced serum drug levels and compromised therapeutic response. The impact of ADA on the bioavailability and clinical efficacy of blockbuster anti-hTNF-α monoclonal antibodies is well recognised, especially for adalimumab and infliximab treatments, with the large and complex molecular architecture of classical immunoglobulin antibody drugs, in part, responsible for the immunogenicity seen in patients. The initial aim of this study was to develop solid-phase enzyme-linked immunosorbent assays (ELISA) and an in vitro cell-based method to accurately detect ADA and estimate its impact on the preclinical in vivo efficacy outcomes of two novel, nonimmunoglobulin VNAR fusion anti-hTNF-α biologics (Quad-X™ and D1-NDure™-C4) and Humira®, a brand of adalimumab. Serum drug levels and the presence of ADA were determined in a transgenic mouse model of polyarthritis (Tg197) when Quad-X™ and Humira® were dosed at 1 mg/kg and D1-NDure™-C4 was dosed at 30 mg/kg. The serum levels of the Quad-X™ and D1-NDure™-C4 modalities were consistently high and comparable across all mice within the same treatment groups. In 1 mg/kg and 3 mg/kg Quad-X™- and 30 mg/kg D1-NDure™-C4-treated mice, an average trough drug serum concentration of 8 μg/mL, 50 μg/mL, and 350 μg/mL, respectively, were estimated. In stark contrast, Humira® trough serum concentrations in the 1 mg/kg treatment group ranged from <0.008 μg/mL to 4 μg/mL with trace levels detected in 7 of the 8 animals treated. Trough serum Humira® and Quad-X™ concentrations in 3 mg/kg treatment samples were comparable; however, the functionality of the detected Humira® serum was significantly compromised due to neutralising ADA. The impact of ADA went beyond the simple and rapid clearance of Humira®, as 7/8 serum samples also showed no detectable capacity to neutralise hTNF-α-mediated cytotoxicity in a murine fibrosarcoma (L929) cell assay. The neutralisation capacity of all the VNAR constructs remained unchanged at the end of the experimental period (10 weeks). The data presented in this manuscript goes some way to explain the exciting outcomes of the previously published preclinical in vivo efficacy data, which showed complete control of disease at Quad-X™ concentrations of 0.5 mg/kg, equivalent to 10x the in vivo potency of Humira®. This independent corroboration also validates the robustness and reliability of the assay techniques reported in this current manuscript, and while it comes with the caveat of a mouse study, it does appear to suggest that these particular VNAR constructs, at least, are of low inherent immunogenicity.

Daily Oral Administration of the Novel Androgen 11β-MNTDC Markedly Suppresses Serum Gonadotropins in Healthy Men.

11β-methyl-19-nortestosterone (11β-MNT) is a modified testosterone (T) with androgenic and progestational activity. A single oral dose of the prodrug, 11β-MNT dodecylcarbonate (11β-MNTDC), was well tolerated in healthy men. We conducted a randomized, double-blind study at 2 academic medical centers. 42 healthy men (18-50 years) were randomized to receive oral placebo or 11β-MNTDC, 200 or 400 mg daily, for 28 consecutive days. Primary outcome (safety and tolerability) measures were assessed twice per week. Subjects underwent serial blood sampling over 24 hours on days 1 and 28 to assess secondary outcomes: pharmacokinetics (serum drug concentrations); pharmacodynamics of 11β-MNTDC (serum sex steroids and gonadotropins); and mood and sexual function (via validated questionnaires). There were no serious adverse events. No participants discontinued because of an adverse event or laboratory test abnormality. 11β-MNTDC resulted in a dose-related increase in serum 11β-MNTDC and 11β-MNT concentrations sustained over 24 hours. Administration of 11β-MNTDC resulted in a marked suppression of serum gonadotropins, T, calculated free T, estradiol, and SHBG over the treatment period (P < 0.01). Adverse effects that may be related to 11β-MNTDC included weight gain, acne, headaches, fatigue, and mild mood changes, with 5 men reporting decreased libido and 3 decreased erectile/ejaculatory function. Serum low-density lipoprotein cholesterol, weight (~2 kg), hematocrit, and hemoglobin increased and serum high-density lipoprotein cholesterol decreased in both 11β-MNTDC groups. Daily oral 11β-MNTDC for 28 days in healthy men markedly suppressed serum gonadotropin and T concentrations without serious adverse effects. These results warrant further evaluation of 11β-MNTDC as a potential male oral contraceptive.

P465 Therapeutic drug monitoring in Crohn’s disease patients, a comparison between homogeneous mobility shift assay and point of care method

Abstract Background Therapeutic Drug Monitoring (TDM) is a useful tool to help physicians managing patients with Inflammatory Bowel Disease treated with anti-tumour necrosis factor (TNF) drugs. Different techniques are available to evaluate serum drug concentration (TL), However, these techniques are time-consuming. A point-of-care (POC) method has been proposed to evaluate drug TL and overcome the limitations inherent to other methodologies. Our aim was to evaluate the capability of POC to discriminate between IBD relapse and remission and to evaluate the concordance of drug TL measured with POC and HMSA Methods We analysed with Quantum BlueÒ (Buhlmann Laboratories AG, Schonenbuch, Switzerland) (POC) 200 Adalimumab (ADA) and 200 Infliximab serum samples of 46 Crohn’s disease (CD) patients previously assessed with HMSA. Blood samples were drawn at standardised time points during anti-TNF treatment (2, 6, and every 8 weeks), before anti-TNF administration. Disease activity was assessed by the Harvey–Bradshaw Index (HBI, remission defined by HBI&amp;lt;5). Results We evaluated 46 CD patients responders to anti-TNF induction with ADA (n = 25, 54.3%) and IFX (n = 21, 45.6%) with a median follow-up of 83 weeks (range 16–144 weeks). At week 16, median ADA TL of patients in remission were significantly higher as compared with patients in disease relapse using both HMSA [12.7 μg/ml (range, 8.9–23.6 μg/ml) vs. 6.6 μg/ml (range, 0.7–9.6 μg/ml), p = 0.0001] and POC [17.8 μg/ml (range 7.6–35.0 μg/ml) vs. 9.8 μg/ml (range 5.8–11.4 μg/ml), p = 0.0003]. The concordance between the two different techniques has been assessed as 0.76 by Choen Kappa. Considering IFX TL, patients in remission had higher serum drug concentration using both HMSA [7.0 μg/ml (range, 0.0–21.8 μg/ml)] and POC [6.2 μg/ml (range 0.4–14.3 μg/ml)] as compared with patients who experienced disease relapse [HMSA, 0.1 μg/ml (range, 0.0–4.1 μg/ml), p = 0.019; POC, 0.45 μg/ml (range 0.4–3.3 μg/ml), p = 0.0072]. The concordance between the two different test for IFX TL was 0.81. We obtained similar results at the end of follow-up: median ADA TL was higher in remission than in disease relapse patients using both HMSA and POC [p = 0.001 and p = 0.0012] with a concordance of 0.75. Median IFX TL was higher in remission than in disease relapse patients using both HMSA and POC (p = 0.13 and p = 0.25) with a concordance of 0.70. Conclusion Both POC and HMSA are TL tests able to differentiate relapse and remission in IBD patients. The association between anti-TNF TL and disease status (remission/relapse) was better in ADA-treated patients rather than patients treated with IFX. Finally, we demonstrated a good concordance between HMSA and POC. Anti-drug antibody concentrations while available on HMSA were not available on POC

N22 Nurse led therapeutic drug monitoring (TDM) of Infliximab in IBD

Abstract Background Therapeutic drug monitoring (TDM) is the clinical practice of measuring serum drug concentrations to guide clinical decision making. Achieving therapeutic drug concentrations has been associated with clinical, endoscopic and histological outcomes in IBD. The use of TDM offers a more personalised treatment approach and is associated with sustained clinical remission. Proactive TDM was introduced to the Mercy University Hospital in 2014 for all patients on biologics. Methods One hundred patients receiving biologic infusion (Infliximab) were evaluated post induction (week 12) for therapeutic drug trough concentration and for clinical response. Serum samples were taken from all IBD patients at week 12. Biologic response assessment forms were complete for all patients to assess symptom improvement. Results Thirty-five per cent of patients had sub therapeutic trough levels at week 12. They subsequently received 3 increased doses of 10mgs/kg and levels were rechecked. Of these 90% achieved therapeutic levels after the dose escalation. 65% of patients had therapeutic levels at week 12. There was a correlation between therapeutic trough levels and patient reported improvement of clinical symptoms in 85% of respondents. Conclusion TDM in our unit facilitates appropriate dose 100 patients receiving biologic infusion (Infliximab) were evaluated post induction (week 12) for therapeutic drug trough concentration and for clinical response. Serum samples were taken from all IBD patients at week 12. Biologic response assessment forms were complete for all patients to assess symptom improvement.

Therapeutic drug monitoring of infliximab compared to standard clinical treatment with infliximab: study protocol for a randomised, controlled, open, parallel-group, phase IV study (the NOR-DRUM study)

BackgroundInfliximab (INX) and other tumour necrosis factor inhibitors (TNFi) have revolutionised the treatment of several immune mediated inflammatory diseases. Still, many patients do not respond sufficiently to therapy or lose efficacy over time. The large interindividual variation in serum drug concentrations on standard doses and the development of anti-drug antibodies are thought to be major reasons for treatment failures. Therapeutic drug monitoring (TDM), an individualised treatment strategy based on systematic assessments of serum drug concentrations, has been proposed as a clinical tool to optimise efficacy of INX treatment. TDM seems reasonable both from a clinical and an economical point of view, but the effectiveness of this treatment strategy has not yet been demonstrated in randomised clinical trials. The NORwegian DRUg Monitoring study (NOR-DRUM) aims to assess the effectiveness of TDM, both with regard to the achievement of remission in patients starting INX treatment (part A) as well as to maintain disease control in patients on INX treatment (part B).MethodsThe NOR-DRUM study is a randomised, open, controlled, parallel-group, comparative, multi-centre, national, superiority, phase IV study with two separate parts, NOR-DRUM A and NOR-DRUM B. Patients with rheumatoid arthritis, psoriatic arthritis, spondyloarthritis, ulcerative colitis, Crohn’s disease and psoriasis are included. In both study parts participants are randomised 1:1 to either TDM of infliximab (intervention group) or to standard treatment with infliximab without knowledge of drug levels or ADAb status (control group). NOR-DRUM A will include 400 patients starting INX therapy. The primary outcome is remission at 30 weeks. In NOR-DRUM B, 450 patients on maintenance treatment with INX will be included. The primary endpoint is occurrence of disease worsening during the 52-week study period.DiscussionAs the first trial to assess the effectiveness, safety and cost-effectiveness of TDM in patients receiving TNFi for a range of immune mediated inflammatory diseases, we hope that the NOR-DRUM study will contribute to the advancement of evidence based personalised treatment with biological medicines.Trial registrationClinicaltrials.gov, NCT03074656. Registered on 090317.