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Safety and disease monitoring biomarkers in Duchenne muscular dystrophy: results from a Phase II trial.
Wagner, KR, Guglieri, M, Ramaiah, SK, Charnas, L, Marraffino, S, Binks, M, Vaidya, VS, Palmer, J, Goldstein, R, Muntoni, F
Biomarkers in medicine. 2021;(15):1389-1396
Abstract
Aim: Evaluate the utility of glutamate dehydrogenase (GLDH) and cardiac troponin I as safety biomarkers, and creatine kinase and muscle injury panel as muscle health biomarkers in Duchenne muscular dystrophy. Patients & methods: Data were collected during a Phase II trial of domagrozumab. Results: GLDH was a more specific biomarker for liver injury than alanine aminotransferase. Cardiac troponin I elevations were variable and not sustained, limiting its applicability as a biomarker. Muscle injury panel biomarkers were no more informative than creatine kinase as a muscle health biomarker. Conclusion: Results support the use of GLDH as a specific biomarker for liver injury in patients with Duchenne muscular dystrophy. Clinical trial registration: ClinicalTrials.gov, NCT02310763.
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Examining therapeutic equivalence between branded and generic warfarin in Brazil: The WARFA crossover randomized controlled trial.
Gomes Freitas, C, Walsh, M, Coutinho, EL, Vincenzo de Paola, AA, Atallah, ÁN
PloS one. 2021;(4):e0248567
Abstract
OBJECTIVES To determine whether the generic and branded warfarins used as anticoagulants in Brazil are therapeutic equivalents based on their international normalized ratio (INR) results. METHODS This crossover randomized controlled trial had four periods. We used the branded Marevan and two generic versions of warfarin sodium tablets, manufactured by União Química and Teuto laboratories, all purchased from retail drugstores. Eligible participants were outpatients from an anticoagulation clinic at a university hospital in São Paulo, Brazil. They had atrial fibrillation or flutter and had been using warfarin for at least 2 months with an INR therapeutic range of 2.0-3.0. Randomization was by numbered, opaque, sealed envelopes. Healthcare personnel and outcome assessors were blinded to treatments, but patients were not. The primary outcome was the variability in the INR (ΔINR) and secondary outcomes included mean INR. We accepted formulations as equivalent if the 95% confidence interval (CI) of the comparison of ΔINR between branded and generic formulations was within the limit of ±0.49. RESULTS One hundred patients were recruited and randomized to six sequences of treatment (four sequences with n = 17 and two sequences with n = 16). União Química generic warfarin had equivalent variability in the INR to Marevan (ΔINR +0.09 [95% CI -0.29 to +0.46], n = 84). Comparison between Teuto generic warfarin and Marevan was inconclusive (ΔINR +0.29 [95% CI -0.09 to +0.68], n = 84). CONCLUSIONS Marevan and União Química warfarin had equivalent therapeutic effectiveness and both could be confidently used for anticoagulation. The comparison between Marevan and TW was inconclusive and does not warrant a statement of equivalence. Our methods are especially important for comparing generic and branded drugs that raise concerns and may be subject of future investigations by regulatory agents. TRIAL REGISTRATION ClinicalTrials.gov NCT02017197.
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Proactive Monitoring of Adalimumab Trough Concentration Associated With Increased Clinical Remission in Children With Crohn's Disease Compared With Reactive Monitoring.
Assa, A, Matar, M, Turner, D, Broide, E, Weiss, B, Ledder, O, Guz-Mark, A, Rinawi, F, Cohen, S, Topf-Olivestone, C, et al
Gastroenterology. 2019;(4):985-996.e2
Abstract
BACKGROUND & AIMS Proactive monitoring of drug trough concentrations and antibodies against drugs might help determine whether patients are likely to respond to treatment and increase efficacy. We investigated whether proactive drug monitoring is associated with higher rates of clinical remission in pediatric patients with Crohn's disease (CD). METHODS We performed a nonblinded, randomized controlled trial of 78 children with CD (6-18 years old; 29% female; mean age, 14.3 ± 2.6 years) who had not received prior treatment with a biologic agent but had responded to adalimumab induction therapy, under scheduled monitoring of clinical and biologic measures (based on clinical factors and levels of C-reactive protein and fecal calprotectin), at pediatric gastroenterology units in Israel from July 2015 through December 2018. The patients were randomly assigned to groups that received proactive monitoring (trough concentrations measured at weeks 4 and 8 and then every 8 weeks until week 72, n = 38) or reactive monitoring (physicians were informed of trough concentrations after loss of response, n = 40). In both groups, doses and intervals of adalimumab were adjusted to achieve trough concentrations of 5 μg/mL. The primary endpoint was sustained corticosteroid-free clinical remission at all visits (week 8 through week 72). RESULTS The primary endpoint was achieved by 31 children (82%) in the proactive group and 19 children (48%) in the reactive group (P = .002). Sixteen patients in the proactive monitoring group (42%) achieved a composite outcome of sustained corticosteroid-free remission, C-reactive protein ≤0.5 mg/dL, and level of fecal calprotectin ≤150 μg/g compared with 5 patients in the reactive monitoring group (12%) (P = .003). By week 72 of treatment, 33 patients in the proactive monitoring group had received adalimumab intensification (87%) compared with 24 patients in the reactive monitoring group (60%) (P = .001). CONCLUSIONS In a randomized controlled trial of pediatric patients with CD, we found that proactive monitoring of adalimumab trough concentrations and adjustment of doses and intervals resulted in significantly higher rates corticosteroid-free clinical remission than reactive monitoring (measuring trough concentration after loss of response). Clinicaltrials.gov no.: NCT02256462.
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Optimal Sampling Strategies for Therapeutic Drug Monitoring of First-Line Tuberculosis Drugs in Patients with Tuberculosis.
Saktiawati, AMI, Harkema, M, Setyawan, A, Subronto, YW, Sumardi, , Stienstra, Y, Aarnoutse, RE, Magis-Escurra, C, Kosterink, JGW, van der Werf, TS, et al
Clinical pharmacokinetics. 2019;(11):1445-1454
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Abstract
BACKGROUND The 24-h area under the concentration-time curve (AUC24)/minimal inhibitory concentration ratio is the best predictive pharmacokinetic/pharmacodynamic (PK/PD) parameter of the efficacy of first-line anti-tuberculosis (TB) drugs. An optimal sampling strategy (OSS) is useful for accurately estimating AUC24; however, OSS has not been developed in the fed state or in the early phase of treatment for first-line anti-TB drugs. METHODS An OSS for the prediction of AUC24 of isoniazid, rifampicin, ethambutol and pyrazinamide was developed for TB patients starting treatment. A prospective, randomized, crossover trial was performed during the first 3 days of treatment in which first-line anti-TB drugs were administered either intravenously or in fasting or fed conditions. The PK data were used to develop OSS with best subset selection multiple linear regression. The OSS was internally validated using a jackknife analysis and externally validated with other patients from different ethnicities and in a steady state of treatment. RESULTS OSS using time points of 2, 4 and 8 h post-dose performed best. Bias was < 5% and imprecision was < 15% for all drugs except ethambutol in the fed condition. External validation showed that OSS2-4-8 cannot be used for rifampicin in steady state conditions. CONCLUSION OSS at 2, 4 and 8 h post-dose enabled an accurate and precise prediction of AUC24 values of first-line anti-TB drugs in this population. TRIAL REGISTRATION ClinicalTrials.gov (NCT02121314).
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A Randomized, Placebo-Controlled, Double-Blind Crossover Study to Assess a Unique Phytosterol Ester Formulation in Lowering LDL Cholesterol Utilizing a Novel Virtual Tracking Tool.
Reaver, A, Hewlings, S, Westerman, K, Blander, G, Schmeller, T, Heer, M, Rein, D
Nutrients. 2019;(9)
Abstract
Elevated blood concentration of low-density lipoprotein cholesterol (LDLc) is a primary risk factor for developing cardiovascular disease. Lifestyle interventions including an increase in dietary phytosterols as well as medications have proven effective in lowering LDLc. The primary objective of this randomized, placebo controlled, double blind, crossover study was to determine the impact of a new phytosterol emulsion for dietary supplements (1.5 g/day phytosterol equivalents) on LDLc concentrations. Thirty-two healthy adults were randomly assigned to receive placebo or treatment followed by a washout period, followed by placebo or treatment, each phase lasting one month. Secondary endpoints related to cardiovascular health were also assessed. Study management, including screening, recruitment, monitoring, compliance, and data collection, were done remotely (a siteless clinical trial) utilizing a novel virtual tool. Phytosterol supplementation significantly lowered LDLc concentrations by 10.2% (16.17 mg/dL or 0.419 mmol/L, p = 0.008 by paired t-test, p = 0.014 by Wilcoxon signed rank testing). No secondary biomarkers were found to change significantly. Supplementation with phytosterols in a new dietary supplement formulation efficiently and safely decreases LDLc within one month in a free-living setting.
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Home Management of Warfarin Treatment Through a Real-Time Supervised Telemedicine Solution: A Randomized Controlled Trial.
Brasen, CL, Madsen, JS, Parkner, T, Brandslund, I
Telemedicine journal and e-health : the official journal of the American Telemedicine Association. 2019;(2):109-115
Abstract
BACKGROUND Many patients are undergoing oral anticoagulation treatment with vitamin K antagonists, which necessitates measuring international normalized ratio (INR) several times each month. INTRODUCTION Patients can learn to measure their INR at home and choose their own dose for the next period with potential gains in treatment quality and reduced healthcare expenses. This is, however, connected to the potential problem of losing tight external control of the patient treatment. MATERIALS AND METHODS We performed a randomized controlled trial using the telemedicine software CSO/AC together with the INR point-of-care-test CoaguChek XS for 10 months to investigate the use of criteria-driven healthcare interactions. A total of 87 patients were divided into two groups. The patient self-management (PSM) group was surveilled using the criteria INR <1.8, INR >4.5, change in warfarin/week >1.25 mg, missing INR or dosage. The patient self-testing (PST) group was handled as routine care. RESULTS A total of 84 patients were followed for 10 months. No differences were seen in average INR or fraction of INR in therapeutic range (2-3) in the two groups or the start compared with the end. The PST group was handled using 4.2 interactions per month whereas the PSM group used 1.1 interactions per month. No adverse effects of PSM were observed. DISCUSSION Using criteria-driven interactions enabled a considerable reduction in interactions per month. The two groups were comparable in terms of treatment effect and safety. CONCLUSIONS Using criteria to guide PSM interactions maintains good treatment effect while reducing healthcare expenses.
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Pharmacokinetic Drug Interactions Between Amlodipine, Valsartan, and Rosuvastatin in Healthy Volunteers.
Seong, SJ, Ohk, B, Kang, WY, Gwon, MR, Kim, BK, Cho, S, Yang, DH, Lee, HW, Yoon, YR
Advances in therapy. 2019;(7):1642-1656
Abstract
INTRODUCTION Amlodipine, valsartan, and rosuvastatin are among the medications widely coadministered for the treatment of hyperlipidemia accompanied by hypertension. The aim of this study was to investigate the possible pharmacokinetic drug-drug interactions between amlodipine, valsartan, and rosuvastatin in healthy Korean male volunteers. METHODS In this phase 1, open-label, multiple-dose, two-part, two-period, fixed-sequence study, the enrolled subjects were randomized into two parts (A and B). In part A (n = 32), each subject received one fixed-dose combination (FDC) tablet of amlodipine/valsartan 10 mg/160 mg alone for 10 consecutive days in period I, and the same FDC for 10 days with concomitant 7-day administration of 20 mg rosuvastatin in period II. In part B (n = 25), each subject received rosuvastatin alone for 7 days in period I, and the FDC for 10 days with concomitant 7-day administration of rosuvastatin in period II. In both parts, there was a 12-day washout between periods. Serial blood samples were collected for up to 72 h for amlodipine and rosuvastatin, and for up to 48 h for valsartan after the last dose of each period. The plasma concentrations of amlodipine, valsartan, and rosuvastatin were determined by using liquid chromatography-tandem mass spectrometry. RESULTS Fifty-seven subjects were enrolled; 30 and 25 subjects completed part A and part B, respectively. The geometric mean ratios and 90% confidence intervals for the maximum plasma concentration at steady state (Cmax,ss) and the area under the plasma concentration-time curve over the dosing interval at steady state (AUCτ,ss) were 0.9389 (0.9029-0.9763) and 0.9316 (0.8970-0.9675) for amlodipine, 0.7698 (0.6503-0.9114) and 0.7888 (0.6943-0.8962) for valsartan, and 0.9737 (0.8312-1.1407) and 0.9596 (0.8826-1.0433) for rosuvastatin, respectively. Of the 57 subjects enrolled in this study, 10 subjects experienced 13 adverse events (AEs); no severe or serious AEs were reported. CONCLUSION When amlodipine, valsartan, and rosuvastatin were coadministered to healthy volunteers, the pharmacokinetic exposure to valsartan was decreased, but no change in exposure to amlodipine and rosuvastatin occurred. All treatments were well tolerated. CLINICAL TRIAL REGISTRATION https://cris.nih.go.kr CRIS KCT0001660. FUNDING KyungDong Pharmaceutical Corp. Ltd., Seoul, Republic of Korea.
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Computer-guided normal-low versus normal-high potassium control after cardiac surgery: No impact on atrial fibrillation or atrial flutter.
Hoekstra, M, Hessels, L, Rienstra, M, Yeh, L, Lansink, AO, Vogelzang, M, van der Horst, IC, van der Maaten, JM, Mariani, MA, de Smet, AM, et al
American heart journal. 2016;:45-52
Abstract
INTRODUCTION This study was designed to determine the effect of 2 different potassium regulation strategies with different targets (within the reference range) on atrial fibrillation (AF) or atrial flutter (AFL) in a cohort of intensive care unit patients after cardiac surgery. METHODS The GRIP-COMPASS study was a prospective double-blinded interventional study in 910 patients after cardiac surgery (coronary artery bypass grafting and/or valvular surgery). Patients were assigned to either the normal-low potassium target (nLP group, 4.0 mmol/L) or the normal-high potassium target (nHP group, 4.5 mmol/L) in alternating blocks of 50 patients. Potassium levels were regulated using a validated computer-assisted potassium replacement protocol (GRIP-II). The primary end point was the incidence of AF/AFL on a 12-lead electrocardiogram during the first postoperative week. RESULTS Of the 910 patients, 447 were assigned to the nLP group; and 463, to the nHP group, with no baseline differences between the 2 groups. The mean daily administered dose of potassium was 30 ± 23 mmol (nLP) versus 52 ± 27 mmol (nHP) (P < .001), which resulted in mean intensive care unit potassium concentration of 4.22 ± 0.36 mmol/L and 4.33 ± 0.34 mmol/L, respectively (P < .001). The incidence of AF/AFL after cardiac surgery did not differ: 38% in the nLP group and 41% in the nHP group. Also in several subgroups (eg, patients not known with prior AF/AFL or with valve surgery), there were no differences. CONCLUSIONS There were no differences in incidence of AF/AFL with 2 potassium regulation strategies with different potassium targets and different amounts of potassium administered in patients after cardiac surgery.
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Quantification of Aerosol Hydrofluoroalkane HFA-134a Elimination in the Exhaled Human Breath Following Inhaled Corticosteroids Administration.
Shin, HW, Barletta, B, Yoonessi, L, Meinardi, S, Leu, SY, Radom-Aizik, S, Randhawa, I, Nussbaum, E, Blake, DR, Cooper, DM
Clinical and translational science. 2015;(5):445-50
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Abstract
Inhaled corticosteroids (ICS) and β2-agonists are the primary pharmacotherapies of asthma management. However, suboptimal medication compliance is common in asthmatics and is associated with increased morbidity. We hypothesized that exhaled breath measurements of the aerosol used in the inhaled medications might prove useful as surrogate marker for asthma medication compliance. To explore this, 10 healthy controls were recruited and randomly assigned to ICS (Flovent HFA) or short acting bronchodilators (Proventil HFA). Both inhalers contain HFA-134a as aerosol propellant. Exhaled breath sampling and pulmonary function tests were performed prior to the inhaler medication dispersion, immediately after inhalation, then at 2, 4, 6, 8, 24, and 48 hours postadministration. At baseline, mean (SD) levels of HFA-134a in the breath were 252 (156) pptv. Immediately after inhalation, HFA-134a breath levels increased to 300 × 10(6) pptv and were still well above ambient levels 24 hours postadministration. The calculated ratio of forced expiratory volume in 1 second over forced vital capacity did not change over time following inhaler administration. This study demonstrates, for the first time, that breath HFA-134a levels can be used to assess inhaler medication compliance. It may also be used to evaluate how effectively the medicine is delivered.
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Limited Sampling Strategy for Mycophenolic Acid in Chinese Kidney Transplant Recipients Receiving Enteric-Coated Mycophenolate Sodium and Tacrolimus During the Early Posttransplantation Phase.
Yao, X, Huang, H, Wei, C, Chen, Y, Peng, W, Xie, W, Chen, J
Therapeutic drug monitoring. 2015;(4):516-23
Abstract
BACKGROUND Mycophenolic acid (MPA), a potent immunosuppressant, is widely used in solid organ transplantations. This study aimed to investigate the pharmacokinetics of enteric-coated mycophenolate sodium (EC-MPS) in Chinese adult renal allograft recipients and to generate optimal model equations for estimation of the MPA area under the concentration-time curve from 0 to 12 hours (AUC0-12 h), using a limited sampling strategy (LSS). METHODS Serial blood samples were collected over 12 hours from 38 recipients of a primary living-related donor kidney graft treated with EC-MPS, tacrolimus, and corticosteroid. MPA concentrations were evaluated using an enzyme-multiplied immunoassay technique. The LSSs were developed and validated by multiple regression analysis using a 2-group method (test group, n = 19; validation group, n = 19). RESULTS The best algorithms obtained from the test group were the following: 15.09 + 1.05 × C1.5 + 1.8 × C4 + 4.18 × C6 (for 3 time points, r = 0.902) and 10.44 + 0.7 × C1 + 1.22 × C2 + 1.75 × C4 + 4.36 × C6 (for 4 time points, r = 0.941). When these algorithms were tested in the validation group, there were no significant differences in prediction errors. CONCLUSIONS LSSs using time points of 1.5, 4, and 6 hours or 1, 2, 4, and 6 hours after dose provide effective and reliable estimations of the MPA AUC0-12 h in Chinese renal allograft recipients treated concomitantly with EC-MPS and tacrolimus during the early posttransplantation phase.