Application of an Integrative Drug Safety Model for Detection of Adverse Drug Events Associated With Inhibition of Glutathione Peroxidase 1 in Chronic Obstructive Pulmonary Disease.

BACKGROUND: Chronic Obstructive Pulmonary Disease is characterised by declining lung function and a greater oxidative stress burden due to reduced activity of antioxidant enzymes such as Glutathione Peroxidase 1. OBJECTIVES: The extent to which drugs may contribute to this compromised activity is largely unknown. An integrative drug safety model explores inhibition of Glutathione Peroxidase 1 by drugs and their association with chronic obstructive pulmonary disease adverse drug events. METHODS: In silico molecular modelling approaches were utilised to predict the interactions that drugs have within the active site of Glutathione Peroxidase 1 in both human and bovine models. Similarities of chemical features between approved drugs and the known inhibitor tiopronin were also investigated. Subsequently the Food and Drug Administration Adverse Event System was searched to uncover adverse drug event signals associated with chronic obstructive pulmonary disease. RESULTS: Statistical and molecular modelling analyses confirmed that the use of several registered drugs, including acetylsalicylic acid and atenolol may be associated with inhibition of Glutathione Peroxidase 1 and chronic obstructive pulmonary disease. CONCLUSION: The integration of molecular modelling and pharmacoepidemological data has the potential to advance drug safety science. Ongoing review of medication use and further pharmacoepidemiological and biological analyses are warranted to ensure appropriate use is recommended.

Application of User-Centered Codesign Principles to Address Barriers in Therapeutic Drug Monitoring.

BACKGROUND: Different software applications have been developed to support health care professionals in individualized drug dosing. However, their translation into clinical practice is limited, partly because of poor usability and integration into workflow, which can be attributed to the limited involvement of health care professionals in the development and implementation of drug dosing software. This study applied codesign principles to inform the design of a drug dosing software to address barriers in therapeutic drug monitoring using vancomycin as an example. METHODS: Three workshops (face-to-face and online) were conducted by design researchers with pharmacists and prescribers. User journey storyboards, user personas, and prototyping tools were used to explore existing barriers to practice and opportunities for innovation through drug dosing software design. A prototype of the software interface was developed for further evaluation. RESULTS: Health care professionals (11 hospital pharmacists and 6 prescribers) with ≥2 years of clinical experience were recruited. Confidence and software usability emerged as the main themes. Participants identified a lack of confidence in vancomycin dosing and pharmacokinetic understanding and difficulty in accessing practice guidelines as key barriers that could be addressed through software implementation. Accessibility to information (eg, guidelines and pharmacokinetic resources) and information presentation (eg, graphical) within the dosing software were dependent on the needs and experience of the user. A software prototype with a speedometer-dial visual to convey optimal doses was well received by participants. CONCLUSIONS: The perspectives of health care professionals highlight the need for drug dosing software to be user centered and adaptable to the needs and workflow of end users. Continuous engagement with stakeholders on tool usability, training, and education is needed to promote the implementation in practice.

The effect of high-dose, short-term caffeine intake on the renal clearance of calcium, sodium and creatinine in healthy adults.

The consumption of caffeine has been linked to osteoporosis, believed to be due to enhanced bone resorption as a result of increased calcium excretion in the urine. However, the amount of calcium in the urine may not necessarily reflect the true effect of caffeine on calcium clearance. This study therefore examined the impact of high-dose, short-term caffeine intake on renal clearance of calcium, sodium and creatinine in healthy adults. In a double-blind clinical study, participants chewed caffeine (n = 12) or placebo (n = 12) gum for 5 minutes at 2-hour intervals over a 6-hour treatment period (800 mg total caffeine). Caffeine increased renal calcium clearance by 77%. Furthermore, the effect was positively correlated with sodium clearance and urine volume, suggesting that caffeine may act through inhibition of sodium reabsorption in the proximal convoluted tubule. This study confirmed that caffeine does increase renal calcium clearance and fosters further investigation into safe consumption of caffeine.

Extraskeletal Myxoid Chondrosarcoma of the Vulva Confirmed by EWSR1 FISH: A Case Report and Review of the Literature.

Extraskeletal myxoid chondrosarcoma of the vulva is a very rare tumor, with less than 10 cases reported in the literature. We report a case of a 45-yr-old woman with extraskeletal myxoid chondrosarcoma of the vulva confirmed by EWSR1 fluorescence in situ hybridization. Given the unusual site and prominent myxoid morphology, a broad differential diagnosis and a variety of ancillary testing was required. This article aims to review extraskeletal myxoid chondrosarcoma of the vulva, the differential diagnosis of a myxoid spindle cell neoplasm of the vulva, and the diagnostic importance of immunohistochemistry and EWSR1 fluorescence in situ hybridization.

Proton pump inhibitors may contribute to progression or development of chronic obstructive pulmonary disease-A sequence symmetry analysis approach.

WHAT IS KNOWN AND OBJECTIVE: Proton pump inhibitors (PPIs), used to treat and prevent gastro-oesophageal conditions, are well-tolerated but have been associated with risk including pneumonia. The extent to which initiation of PPIs can contribute to other respiratory conditions such as chronic obstructive pulmonary disease (COPD) is largely unknown. METHODS: A sequence symmetry analysis (SSA) approach was applied to the Australian Department of Human Services, Pharmaceutical Benefits Scheme 10% extract. Participants were aged 45 years and older and were dispensed PPIs (ATC Codes A02BC01, A02BC02, A02BC03, A02BC04 and A02BC05) and long-acting bronchodilators (LABDs) for COPD (ATC Codes R03BB04 (PBS Item Code 10509D and 08626B), R03BB05, R03BB06, R03BB07 and R03AC18 (PBS Item Code 05137J and 05134F)) between 2013 and 2019. The analysis included patients initiated on an LABD within 12 months before or after their first prescription of a PPI. The crude sequence ratio (cSR) was calculated as the number of patients prescribed their first LABD after starting a PPI divided by the number of patients prescribed their first LABD before starting a PPI. Calculation of the adjusted sequence ratio (aSR) accounted for prescribing trends over time in initiation of each of the medicines. A signal was identified where the aSR lower 95% confidence interval (CI) was greater than one. RESULTS AND DISCUSSION: Initiation of omeprazole was associated with a 29% increased risk of initiating a LABD (ASR = 1.29 95% CI 1.22-1.36). Initiation of esomeprazole, rabeprazole, pantoprazole or lansoprazole was associated with 25%, 15%, 8% and 8% increased risk, respectively. WHAT IS NEW AND CONCLUSION: There is an established association between gastro-oesophageal reflux disease and COPD which has been confirmed by implementation of a sequence symmetry-based approach which demonstrated that PPI initiation is potentially associated with progression or exacerbation of COPD. The impact PPI use has directly on this association requires further investigation.

Modifying the Interface Edge to Control the Electrical Transport Properties of Nanocontacts to Nanowires.

Selecting the electrical properties of nanomaterials is essential if their potential as manufacturable devices is to be reached. Here, we show that the addition or removal of native semiconductor material at the edge of a nanocontact can be used to determine the electrical transport properties of metal-nanowire interfaces. While the transport properties of as-grown Au nanocatalyst contacts to semiconductor nanowires are well-studied, there are few techniques that have been explored to modify the electrical behavior. In this work, we use an iterative analytical process that directly correlates multiprobe transport measurements with subsequent aberration-corrected scanning transmission electron microscopy to study the effects of chemical processes that create structural changes at the contact interface edge. A strong metal-support interaction that encapsulates the Au nanocontacts over time, adding ZnO material to the edge region, gives rise to ohmic transport behavior due to the enhanced quantum-mechanical tunneling path. Removal of the extraneous material at the Au-nanowire interface eliminates the edge-tunneling path, producing a range of transport behavior that is dependent on the final interface quality. These results demonstrate chemically driven processes that can be factored into nanowire-device design to select the final properties.

Effect of Garlic, Gingko, and St. John's Wort Extracts on the Pharmacokinetics of Fexofenadine: A Mechanistic Study.

The aim of this study was to determine the effects of garlic and ginkgo herbal extracts on the pharmacokinetics of the P-glycoprotein (P-gp)/organic anion-transporting polypeptides (Oatps) substrate fexofenadine. Male rats were dosed orally with garlic (120 mg/kg), ginkgo (17 mg/kg), St. John's wort (SJW; 1000 mg/kg; positive control), or Milli-Q water for 14 days. On day 15, rats either were administered fexofenadine (orally or i.v.), had their livers isolated and perfused with fexofenadine, or had their small intestines divided into four segments (SI-SIV) and analyzed for P-gp and Oatp1a5. In vivo, SJW increased the clearance of i.v. administered fexofenadine by 28%. Garlic increased the area under the curve0-∞ and maximum plasma concentration of orally administered fexofenadine by 47% and 85%, respectively. Ginkgo and SJW had no effect on the oral absorption of fexofenadine. In the perfused liver, garlic, ginkgo, and SJW increased the biliary clearance of fexofenadine with respect to perfusate by 71%, 121%, and 234%, respectively. SJW increased the biliary clearance relative to the liver concentration by 64%. The ratio of liver to perfusate concentrations significantly increased in all treated groups. The expression of Oatp1a5 in SI was increased by garlic (88%) and SJW (63%). There were no significant changes in the expression of P-gp. Induction of intestinal Oatp1a5 by garlic may explain the increased absorption of orally administered fexofenadine. Ginkgo had no effect on the expression of intestinal P-gp or Oatp1a5. A dual inductive effect by SJW on opposing intestinal epithelial transport by Oatp1a5 and P-gp remains a possibility.

The use of antipsychotics among people treated with medications for dementia in residential aged care facilities.

BACKGROUND: Antipsychotic agents have limited efficacy for Behavioral and Psychological Symptoms of Dementia (BPSD) and there are concerns about their safety. Despite this, they are frequently used for the management of BPSD. This study aimed to assess the use of antipsychotics among people on anti-dementia medicines in Australian residential aged care facilities. METHODS: Data were obtained from an individual patient unit dose packaging database covering 40 residential aged care facilities in New South Wales, Australia. Residents supplied an anti-dementia medicine between July 2008 and June 2013 were included. Prevalence of concurrent antipsychotic use was established. Incident antipsychotic users between January 2009 and December 2011 were identified. We examined initial antipsychotic dose, maximum titrated doses, type and duration of antipsychotic use, and compared use with Australian guidelines. RESULTS: There were 291 residents treated with anti-dementia medicines, 129 (44%) of whom received antipsychotics concomitantly with an anti-dementia medicine. Among the 59 incident antipsychotic users, risperidone (73%) was the most commonly used antipsychotic agent. Amongst the risperidone initiators, 43% of patients had initial doses greater than 0.5 mg/day and 6% of patients exceeded 2.0 mg/day for their maximum dose. 53% of concomitant users received daily treatment for greater than six months. CONCLUSIONS: Our study using records of individual patient unit dose supply, which represents the intended medication consumption schedule, shows high rates of concurrent use of antipsychotics and anti-dementia medicines and long durations of use. The use of antipsychotics in patients with dementia needs to be carefully monitored to improve patient outcomes.

Controlling the Electrical Transport Properties of Nanocontacts to Nanowires.

The ability to control the properties of electrical contacts to nanostructures is essential to realize operational nanodevices. Here, we show that the electrical behavior of the nanocontacts between free-standing ZnO nanowires and the catalytic Au particle used for their growth can switch from Schottky to Ohmic depending on the size of the Au particles in relation to the cross-sectional width of the ZnO nanowires. We observe a distinct Schottky to Ohmic transition in transport behavior at an Au to nanowire diameter ratio of 0.6. The current-voltage electrical measurements performed with a multiprobe instrument are explained using 3-D self-consistent electrostatic and transport simulations revealing that tunneling at the contact edge is the dominant carrier transport mechanism for these nanoscale contacts. The results are applicable to other nanowire materials such as Si, GaAs, and InAs when the effects of surface charge and contact size are considered.

Bimodal crystallization at polymer-fullerene interfaces.

The growth-kinetics of [6,6]-phenyl C61-butyric acid methyl ester (PCBM) crystals, on two different length-scales, is shown to be controlled by the thickness of the polymer layer within a PCBM-polymer bilayer. Using a model amorphous polymer we present evidence, from in situ optical microscopy and grazing-incidence X-ray diffraction (GIXD), that an increased growth-rate of nanoscale crystals impedes the growth of micron-sized, needle-like PCBM crystals. A combination of neutron reflectivity and GIXD measurements, also allows us to observe the establishment of a liquid-liquid equilibrium composition-profile between the PCBM layer and a polymer-rich layer, before crystallization occurs. While the interfacial composition-profile is independent of polymer-film-thickness, the growth-rate of nanoscale PCBM crystals is significantly larger for thinner polymer films. A similar thickness-dependent behavior is observed for different molecular weights of entangled polymer. We suggest that the behavior may be related to enhanced local-polymer-chain-mobility in nanocomposite thin-films.

ZnO nanowires with Au contacts characterised in the as-grown real device configuration using a local multi-probe method.

We demonstrate here a method using a multi-probe UHV instrument to isolate and measure individual metal contacts controllably fabricated on the tips of free standing ZnO nanowires (NWs). The measurements show Au can form reliable Ohmic and rectifying contacts by exercising control over the surface properties. In the as-grown state the Au contacts display low-resistance characteristics which are determined by the adsorbed species and defects on the NW surface. Subjecting the NWs to an oxidising agent (H2O2) increases the surface potential barrier creating more rectifying contacts. These developments are crucial for controllable NW array devices.

Use of secondary stroke prevention medicines in Australia: national trends, 2003-2009.

OBJECTIVE: To examine recent trends in the use of secondary stroke prevention medicines by transient ischaemic attack (TIA) and ischaemic stroke survivors. DESIGN, SETTING AND PARTICIPANTS: Retrospective observational study of patients aged ≥ 65 years who were hospitalised with a TIA or ischaemic stroke between January 2000 and December 2009. Use of antihypertensive, antithrombotic and lipid-lowering medicines by patients was determined monthly, using claims data from the Australian Government Department of Veterans' Affairs, commencing in January 2003. MAIN OUTCOME MEASURE: Monthly prevalence of use of secondary stroke prevention medicines. RESULTS: Between 2003 and 2009, small increases in use (less than 2% relative increase annually) were observed for antihypertensive and antithrombotic medicines among 19 019 patients. There was a 9% relative increase in use of lipid-lowering therapy each year. The proportion of patients dispensed all three recommended medicine classes nearly doubled over the 7-year period. By December 2009, about 80% of patients were dispensed an antihypertensive, 75% received an antithrombotic and 60% were dispensed lipid-lowering therapy. Almost half of the population were dispensed all three recommended classes by the end of the study period. CONCLUSIONS: Increased use of secondary stroke prevention medicines was shown in this study, in accordance with national stroke guideline recommendations and initiatives supporting quality use of medicines in Australia. There may be opportunity to further increase use of these medicines among older Australians who have had a TIA or ischaemic stroke.

Copper-doped CdSe/ZnS quantum dots: controllable photoactivated copper(I) cation storage and release vectors for catalysis.

The first photoactivated doped quantum dot vector for metal-ion release has been developed. A facile method for doping copper(I) cations within ZnS quantum dot shells was achieved through the use of metal-dithiocarbamates, with Cu(+) ions elucidated by X-ray photoelectron spectroscopy. Photoexcitation of the quantum dots has been shown to release Cu(+) ions, which was employed as an effective catalyst for the Huisgen [3+2] cycloaddition reaction. The relationship between the extent of doping, catalytic activity, and the fluorescence quenching was also explored.

Chronic Obstructive Pulmonary Disease Adverse Event Signals Associated with Potential Inhibitors of Glutathione Peroxidase 1: A Sequence Symmetry Analysis.

BACKGROUND AND OBJECTIVE: Prior molecular modelling analysis identified several medicines as potential inhibitors of glutathione peroxidase 1 (GPx1) which may contribute to development or progression of chronic obstructive pulmonary disease (COPD). This study investigates 40 medicines (index medicines) for signals of COPD development or progression in a real-world dataset. METHODS: Sequence symmetry analysis (SSA) was conducted using a 10% extract of Australian Pharmaceutical Benefits Scheme (PBS) claims data between January 2013 and September 2019. Patients must have been initiated on an index medicine and a medicine for COPD development or progression within 12 months of each other. Sequence ratios were calculated as the number of patients who initiated an index medicine followed by a medicine for COPD development or progression divided by the number who initiated the index medicine second. An adjusted sequence ratio (aSR) was calculated which accounted for changes in prescribing trends. Adverse drug event signals (ADEs) were identified where the aSR lower 95% confidence interval (CI) was greater than 1. RESULTS: Twenty-one of 40 (53%) index medicines had at least one ADE signal of COPD development or progression. Signals of COPD development, as identified using initiation of tiotropium, were observed for atenolol (aSR 1.32, 95% CI 1.23-1.42) and naproxen (aSR 1.14, 95% CI 1.06-1.23). Several signals of COPD progression were observed, including initiation of fluticasone propionate/salmeterol following initiation of atenolol (aSR 1.44, 95% CI 1.30-1.60) and initiation of aclidinium/formoterol following initiation of naproxen (aSR 2.21, 95% CI 1.34-3.65). CONCLUSION: ADE signals were generated for several potential GPx1 inhibitors; however, further validation of signals is required in large well-controlled observational studies.

Factors that determine and limit the resistivity of high-quality individual ZnO nanowires.

Knowing and controlling the resistivity of an individual nanowire (NW) is crucial for the production of new sensors and devices. For ZnO NWs this is poorly understood; a 10(8) variation in resistivity has previously been reported, making the production of reproducible devices almost impossible. Here, we provide accurate resistivity measurements of individual NWs, using a four-probe scanning tunnelling microscope (STM), revealing a dependence on the NW dimensions. To correctly interpret this behaviour, an atomic level transmission electron microscopy technique was employed to study the structural properties of the NWs in relation to three growth techniques: hydrothermal, catalytic and non-catalytic vapour phase. All NWs were found to be defect free and structurally equivalent; those grown with a metallic catalyst were free from Au contamination. The resistivity measurements showed a distinct increase with decreasing NW diameter, independent of growth technique. The increasing resistivity at small NW diameters was attributed to the dominance of surface states removing electrons from the bulk. However, a fundamental variance in resistivity (10(2)) was observed and attributed to changes in occupied surface state density, an effect which is not seen with other NW materials such as Si. This is examined by a model to predict the effect of surface state occupancy on the measured resistivity and is confirmed with measurements after passivating the ZnO surface. Our results provide an understanding of the primary influence of the reactive nature of the surface and its dramatic effect on the electrical properties of ZnO NWs.

Behavior of aluminum, arsenic, and vanadium during the neutralization of red mud leachate by HCl, gypsum, or seawater.

Red mud leachate (pH 13) collected from Ajka, Hungary is neutralized to < pH 10 by HCl, gypsum, or seawater addition. During acid neutralization >99% Al is removed from solution during the formation of an amorphous boehmite-like precipitate and dawsonite. Minor amounts of As (24%) are also removed from solution via surface adsorption of As onto the Al oxyhydroxides. Gypsum addition to red mud leachate results in the precipitation of calcite, both in experiments and in field samples recovered from rivers treated with gypsum after the October 2010 red mud spill. Calcite precipitation results in 86% Al and 81% As removal from solution, and both are nonexchangeable with 0.1 mol L(-1) phosphate solution. Contrary to As associated with neoformed Al oxyhydroxides, EXAFS analysis of the calcite precipitates revealed only isolated arsenate tetrahedra with no evidence for surface adsorption or incorporation into the calcite structure, possibly as a result of very rapid As scavenging by the calcite precipitate. Seawater neutralization also resulted in carbonate precipitation, with >99% Al and 74% As removed from solution during the formation of a poorly ordered hydrotalcite phase and via surface adsorption to the neoformed precipitates, respectively. Half the bound As could be remobilized by phosphate addition, indicating that As was weakly bound, possibly in the hydrotalcite interlayer. Only 5-16% V was removed from solution during neutralization, demonstrating a lack of interaction with any of the neoformed precipitates. High V concentrations are therefore likely to be an intractable problem during the treatment of red mud leachates.

CYP2C19-guided design of a proton pump inhibitor dose regimen to avoid the need for pharmacogenetic individualization in H. pylori eradication.

OBJECTIVE: It has been demonstrated that genetic variation in CYP2C19 has a significant influence upon H. pylori eradication rates. We have determined a dosage regimen of lansoprazole that will provide EMs with exposure approximately equivalent to that obtained by PMs treated with standard doses and determined the exposure that a PM would experience if they were to be treated with this 'EM optimised' lansoprazole dose. METHODS: Non-compartmental pharmacokinetic parameters (AUC, C(max), t(max)) for CYP2C19 genotypes were obtained from the literature. Primary pharmacokinetic parameters (CL, Vd, ka) for 200 virtual patients were calculated from the weighted non-compartmental variables and used to simulate a 7 day treatment course of twice daily lansoprazole, at standard and optimised doses for 1,000 patients. RESULTS: The administration of 180 mg twice daily to CYP2C19 EMs results in approximately equivalent exposure to lansoprazole as the administration of standard 30 mg twice daily doses to PMs. Administration of this six-fold dose increase to EMs is predicted to result in only a 2.5-fold increase in C(max) when compared with PMs receiving the standard 30 mg dose. CONCLUSION: We present a potential lansoprazole dosing regimen that should result in improved H. pylori eradication within CYP2C19 EMs and may not require individualization. Whilst the optimised dose represents a significant increase, it is below that reported in the chronic management of Zollinger-Ellison syndrome. On the basis that treatment is of limited duration and lansoprazole is generally well tolerated, such an approach warrants further in vivo evaluation to confirm drug exposure, efficacy and tolerability.

The Role of the Pharmacist in Optimizing Cancer Immunotherapy: A Retrospective Study of Nivolumab Adverse Events.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are an emerging treatment in cancer therapy for prolonging life, minimizing symptoms, and selectively targeting cancer. Program death 1 (PD-1) inhibitors, such as nivolumab, fall within this class, enabling the patient's immune system to detect and destroy cancer. The introduction of ICIs is changing cancer therapy, with new drugs and new toxicities-an evolving area encountered by pharmacists. OBJECTIVE: This study aims to compare the pattern of nivolumab-induced adverse events observed in practice, when compared with clinical trial and literature data. The secondary aim of the study is to identify the presentation and treatment modalities initiated in practice. METHODS: We performed a retrospective case note review across 2 South Australian hospitals to identify the common toxicities and symptomatic treatments experienced by patients receiving nivolumab. Results were compared with clinical trial data from product innovator Bristol-Myer Squib and other published literature. RESULTS: Seventy patients were included in the study; of these, 60 (86%) experienced any grade adverse event(s). A total of 59 (84%) of 70 experienced mild to moderate grade 1 to grade 2 adverse events and 10 (14%) of 70 patients experienced severe grade 3 to grade 4 adverse events, displaying some consistencies with clinical trial and published literature data. Together, the prevalence of adverse events with details on presentation and treatments illustrates possible pharmacy practice strategies and areas for intervention. CONCLUSIONS: The listed prevalence of adverse events and practice strategies identified throughout this study highlights how pharmacists may assist in the identification of predictable ICI toxicities associated with gastrointestinal, endocrine, dermatological toxicities, and fatigue.

A Role for SMARCB1 in Synovial Sarcomagenesis Reveals That SS18-SSX Induces Canonical BAF Destruction.

Reduced protein levels of SMARCB1 (also known as BAF47, INI1, SNF5) have long been observed in synovial sarcoma. Here, we show that combined Smarcb1 genetic loss with SS18-SSX expression in mice synergized to produce aggressive tumors with histomorphology, transcriptomes, and genome-wide BAF-family complex distributions distinct from SS18-SSX alone, indicating a defining role for SMARCB1 in synovial sarcoma. Smarcb1 silencing alone in mesenchyme modeled epithelioid sarcomagenesis. In mouse and human synovial sarcoma cells, SMARCB1 was identified within PBAF and canonical BAF (CBAF) complexes, coincorporated with SS18-SSX in the latter. Recombinant expression of CBAF components in human cells reconstituted CBAF subcomplexes that contained equal levels of SMARCB1 regardless of SS18 or SS18-SSX inclusion. In vivo, SS18-SSX expression led to whole-complex CBAF degradation, rendering increases in the relative prevalence of other BAF-family subtypes, PBAF and GBAF complexes, over time. Thus, SS18-SSX alters BAF subtypes levels/balance and genome distribution, driving synovial sarcomagenesis. SIGNIFICANCE: The protein level of BAF component SMARCB1 is reduced in synovial sarcoma but plays a defining role, incorporating into PBAF and SS18-SSX-containing canonical BAF complexes. Reduced levels of SMARCB1 derive from whole-complex degradation of canonical BAF driven by SS18-SSX, with relative increases in the abundance of other BAF-family subtypes.See related commentary by Maxwell and Hargreaves, p. 2375.This article is highlighted in the In This Issue feature, p. 2355.

Reducing Palivizumab Dose Requirements Through Rational Dose Regimen Design.

Palivizumab for respiratory syncytial virus (RSV) immunoprophylaxis in premature infants poses a significant economic challenge. Although standard dosing of palivizumab results in unnecessary drug accumulation without additional clinical benefit, some clinicians have moved outside of evidence-based practice by implementing untested dose modifications, potentially jeopardizing efficacy. Using an industry-developed population pharmacokinetic model, this study evaluated the previously published alternate dosing regimens and developed a revised regimen that minimizes palivizumab dose requirements while maintaining established therapeutic concentrations. All published dose modifications resulted in unacceptably high proportions of infants not attaining minimum protective concentrations, compromising efficacy. Through intelligent dose regimen design, a clinically practical palivizumab regimen was devised that reduces drug use by 25%, while enabling a greater proportion of infants attaining early season target concentrations, particularly those at greatest risk of the consequences of RSV infection. This novel regimen has the potential to substantially change clinical practice and increase drug availability.