Small Tablet Research Articles

The effect of material properties and process parameters on die filling at varying throughputs: A PLS-model-based analysis

When tablets are manufactured on a rotary tablet press and the throughput is increased, it leads to changes in powder dynamics during die filling due to formulation characteristics and changing powder flow in the feed frame. This may result, a.o. in increased tablet weight variability, poorer content uniformity, capping and lamination. This research focuses on explaining the die filling performance depending on material properties and process settings, including throughput for small and large tablets. It was concluded that throughput had a negative impact on die filling variability, which is related to reduced residence time and lower fill fraction of the feed frame and dies. Furthermore, the die filling mechanism was inherently different for large tablets in comparison to small tablets. Higher die filling consistency was observed for dense, less porous, less compressible and better flowing powders. As a result of this work, a model was developed to predict the impact of formulation properties and process settings on die filling variability and its dependency on changes in throughput. This model will benefit formulation development at an early stage when active ingredient availability may be challenging as it will avoid the need to conduct experiments at high throughputs.

Apixaban and clopidogrel in a fixed-dose combination: Formulation and in vitro evaluation

Fixed-dose combination (FDC) products represent a novel, safe, and cost-effective formulation. Combined use of anticoagulant and antiplatelet medications is common among comorbid cardiovascular patients. This study aimed to formulate FDC tablets for Apixaban and Clopidogrel, as prophylaxis and treatment of thrombo-embolic events. FDC tablets were developed by combining small tablets of Immediate-Release Clopidogrel 75 mg and Extend-Release Apixaban 5 mg through direct compression and wet granulation. Particularly, Apixaban tablets were developed using design expert software, and various types and concentrations of polymers were entered. For Clopidogrel tablets, various diluents were used to develop the formulation. Then, the dissolution profile for each formula was studied. Finally, the optimized formulations were encapsulated within hard gelatin capsules. Apixaban formulation followed zero-order with super case Ⅱ transport mechanism as the dominant mechanism of drug release. The Apixaban drug release rate was affected by the type and concentration of the polymers in the formulation (P < 0.05). As the HPMC concentration was increased, Apixaban release was retarded. For, Clopidogrel, the formulated tablets with spray-dried lactose filler and sodium stearyl fumarate lubricant were found to be stable with good properties. In conclusion, the optimum formulation yielded Clopidogrel and extended-release Apixaban for 24 h with the desired in vitro drug dissolution.

Long-term safety and decrease of pill burden by tenapanor therapy: a phase 3 open-label study in hemodialysis patients with hyperphosphatemia

Phosphate binders (PBs) generally have a high pill burden. Tenapanor selectively inhibits sodium/hydrogen exchanger isoform 3, reducing intestinal phosphate absorption. Tenapanor is a novel drug administered as a small tablet, twice daily. This multicenter, open-label, single-arm, phase 3 study aimed to evaluate the long-term safety of tenapanor and its efficacy in decreasing PB pill burden. Tenapanor 5 mg twice daily was administered to hemodialysis patients with serum phosphorus level 3.5–7.0 mg/dl at baseline; the dose could be increased up to 30 mg twice daily. Patients could also switch from PBs. The primary endpoint was safety during 52-week administration. The key secondary endpoint was a ≥ 30% reduction in the total pill number of daily PBs and tenapanor from baseline. Of 212 patients starting treatment, 154 completed the study. Diarrhea was the most frequent adverse event, occurring in 135 patients (63.7%); most events were classified as mild (74.8%). No clinically significant changes occurred other than serum phosphorus level. At Week 52/discontinuation, 158/204 patients (77.5%) achieved the key secondary endpoint. Complete switching from PBs to tenapanor was achieved in 50–76 patients (26.7%–41.5%), and 80 patients (51.9%) at Week 8–12 and Week 50, respectively. Serum phosphorus remained generally stable within the target range (3.5–6.0 mg/dl). These findings suggest the long-term safety and tolerability of tenapanor. Tenapanor could reduce or eliminate PB pill burden while controlling serum phosphorus levels.Trial registration: NCT04771780

Bictegravir/Emtricitabine/Tenofovir Alafenamide for HIV-1: What is the Hidden Potential of This Emerging Treatment?

Bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) is a single-tablet antiretroviral therapy regimen. B/F/TAF has become a popular treatment choice because of its small tablet size, high barrier to resistance, favorable tolerability, and limited drug-drug interaction profile. Continued research on B/F/TAF has revealed additional potential for this regimen. This review presents recent literature supporting the use of B/F/TAF as an option for consolidating therapy and maintaining virologic suppression in individuals despite M184V/I mutations. Additionally, children are a unique patient population with limited antiviral options. Standard dose B/F/TAF has demonstrated similar drug exposure in children and adolescents as adults, and low-dose B/F/TAF is approved for children living with HIV greater than two years of age and weighing at least 14 kg. Data supporting this recommendation is described in this review. Finally, despite a lack of prospective data, B/F/TAF may have a role in the future of pre- and post-exposure prophylaxis. This review discusses these discoveries and the continued exploration of the hidden potential of B/F/TAF.

OR21-03 Dose Responsiveness Of LUM-201 As Measured By Acute GH Response And IGF-1 And Annualized Height Velocity (AHV) Measured At 6 Months In The Interim Analysis Of The OraGrowtH212 Study In Idiopathic Pediatric Growth Hormone Deficiency (iPGHD)

Abstract Disclosure: F. Cassorla: Research Investigator; Self; Lumos Pharma, Inc. Speaker; Self; Lumos Pharma, Inc. R. Román: Research Investigator; Self; Lumos Pharma, Inc. M.L. Johnson: Consulting Fee; Self; Lumos Pharma, Inc. A. Avila: Research Investigator; Self; Lumos Pharma, Inc. G. Iñiguez: Research Investigator; Self; Lumos Pharma, Inc. I. Baier: Research Investigator; Self; Lumos Pharma, Inc. D. Said: Research Investigator; Self; Lumos Pharma, Inc. A. Bruchey: Employee; Self; Lumos Pharma, Inc. Stock Owner; Self; Lumos Pharma, Inc. C. Smith: Employee; Self; Lumos Pharma, Inc. Stock Owner; Self; Lumos Pharma, Inc. E.L. Brincks: Employee; Self; Lumos Pharma, Inc. Stock Owner; Self; Lumos Pharma, Inc. J.C. McKew: None. D.B. Karpf: Employee; Self; Lumos Pharma, Inc. Stock Owner; Self; Lumos Pharma, Inc. M.O. Thorner: Consulting Fee; Self; Lumos Pharma, Inc. Stock Owner; Self; Lumos Pharma, Inc. Objective: To evaluate acute GH, IGF-1, AHV at 6 mos of treatment of iPGHD subjects. Background: LUM-201 is an investigational oral GH secretagogue (GHS) currently in 3 Phase 2 iPGHD trials. The LUM-201 predictive enrichment marker (PEM) may be used to identify patients previously diagnosed with iPGHD who are likely to respond to LUM-201. PEM positivity is defined as a baseline IGF-1 level &amp;gt;30 ng/mL and a peak GH of ≥5 ng/mL in response to a single 0.8 mg/kg LUM-201 dose. LUM-201, a potent, durable oral GHS agonist, acts on the GHS Receptor 1a in the hypothalamus and anterior pituitary. LUM-201 enhances the amplitude of endogenous GH pulsatile release over 24 hrs, while also acting as a functional antagonist of the somatostatin receptor. The increased IGF-1 and GH reach the growth plates and promote linear growth. Three advantages of LUM-201 as a potential therapeutic for iPGHD are that it is a small oral tablet, it enhances natural GH pulses over 24 hr, and GH release is subject to the endogenous negative feedback mechanisms, so serum IGF-1 is expected to remain within the normal range. Method: Each subject is screened with the PEM test, which includes determining the max GH concentration in the first 90 min after a single 0.8 mg/kg dose of LUM-201. Additionally, each of these PEM positive subjects was assessed for increasing doses of LUM-201 to induce further acute GH secretion on their first day of therapeutic dosing with either a 1.6 or 3.2 mg/kg dose. The first 10 subjects with 6 months of growth on LUM-201 (5 subjects on each dose) were evaluated on their IGF-1 levels and AHVs. Results: The mean (+SD, n) peak GH for the 0.8 mg/kg dose was 26.04 ng/mL (+10.6, 22), at the 1.6 mg/kg dose 35.50 ng/mL (+17.5, 9), and at a 3.2 mg/kg dose 38.34 ng/mL (+10.4, 8). Serum IGF-1 levels of the 5 subjects in each cohort were monitored at baseline and at 6 months of treatment. The mean (+ SD) serum IGF-1 levels showed a change from baseline of 84.6 ng/mL (+30.1) at 6 months for the 1.6 mg/kg cohort and 113.8 (+49.9) at the 3.2 mg/kg dose. The pretreatment HV were 4.9 (+ 0.4) at 1.6 mg/kg and 4.3 (+ 0.9) cm/year at 3.2 mg/kg respectively and the respective mean AHVs (+ SD) at 6 months were 7.14 cm/year (+0.65) and 8.60 cm/year (+1.22). The acute GH response demonstrated a dose response between the 0.8 and 1.6 mg/kg doses, but the 1.6 and 3.2 mg/kg doses produced similar GH responses. These two doses of LUM-201 induced comparable changes from baseline values of IGF-1 after 6 months of treatment. In addition to these pharmacodynamic changes, the AHVs generated from each dose also appear similar. Conclusion: LUM-201 generated the expected AHV in this naive iPGHD population. The dose-response for GH secretion after an initial dose of LUM-201 and increases from baseline of serum IGF-1 after 6 months of treatment suggest that 1.6 mg/kg/day is the optimum dose for efficacy and durability. The results from this small study are corroborated by the larger OraGrowtH210 study data. Presentation: Saturday, June 17, 2023

Automated sample preparation of protein solid dosage forms: Novel application for the tablet processing workstation.

Biological macromolecule solid dosage forms represent the frontier of orally administered pharmaceuticals. Analysis of these drug products poses new challenges compared to traditional small molecule tablets. In this study we demonstrate the first, to our knowledge, automated Tablet Processing Workstation (TPW) sample preparation of large molecule tablets. Tablets containing a modified version of human insulin were tested for content uniformity and the automated method was successfully validated for recovery, carryover and displayed manual method equivalency in repeatability and in-process stability. Per TPW's ability to process one sample sequentially, the total analysis cycle time is, in fact, increased. In lieu, a net gain in scientist productivity is realized by enabling continuous operation reducing analytical scientist labor time by 71% compared to manually conducted sample preparation.

The application of Near-Infrared Spatially Resolved Spectroscopy in scope of achieving continuous real-time quality monitoring and control of tablets with challenging dimensions

In scope of achieving real-time release of tablets, quality attributes need to be monitored and controlled through Process Analytical Technology tools such as near-infrared spectroscopy (NIRS). The authors evaluated the suitability of NIR-Spatially Resolved Spectroscopy (NIR-SRS) for continuous real-time monitoring and control of content uniformity, hardness and homogeneity of tablets with challenging dimensions. A novel user-friendly research and development inspection unit was used as standalone equipment for the analysis of small oblong tablets with deep-cut break lines. A total of 66 tablets varying in hardness and Active Pharmaceutical Ingredient (API) content were inspected, with each tablet being analysed five times and measurements repeated on three different days. Partial Least Squares (PLS) models were developed to assess content uniformity and hardness, of which the former showed higher accuracy. The authors attempted to visualize tablet homogeneity through NIR-SRS spectra by regressing all spectra obtained during a single measurement using a content uniformity PLS model. The NIR-SRS probe demonstrated its potential towards real-time release testing through its ability to quickly monitor content uniformity, hardness and visualize homogeneity, even for tablets with challenging dimensions.

Tracking combustion behavior of copper monosulfide, ferrous sulfide, and chalcopyrite tablets by high-speed microscopic videography

A new suspended-combustion-test method involving high-speed digital microscopy and thermal measurements was developed to analyze small tablets of CuS, FeS, and CuFeS2 to elucidate their combustion behavior and phase changes in flash smelting. Moreover, the frequency of splash generation and homogeneous oxidation of the released gaseous sulfur from each sulfide were monitored. Microstructural analysis of quenched samples by X-ray diffraction, scanning electron microscopy, and energy-dispersive X-ray spectroscopy revealed that the combustion intensity could be related to the formation of an oxide layer, which blocked the O2 supply to the sample interior. Moreover, the gas formed at various oxygen concentrations agitated the samples. In particular, the generated solid-oxide shell could move, the sulfide was exposed to the surface again, and the combustion reaction proceeded further. Insufficient agitation at lower O2 concentrations resulted in a thick and dense oxide layer, which blocked the O2 supply and caused extinction.

Improving Quality Indicators of the Cloud-Based IoT Networks Using an Improved Form of Seagull Optimization Algorithm

The Internet of things (IoT) points to billions of devices located worldwide which are connected and share their data based on the Internet. Due to the new technologies that provide cheap computer chips and universal wireless networks, it is feasible that everything from a small tablet to a very large airplane will be connected to the Internet and will be a part of the IoT. In most applications, IoT network nodes face limitations in terms of energy source and cost. Therefore, the need for innovative methods to improve quality indicators that increase the lifespan of networks is evident. Here, a novel technique is presented to increase the quality of service (QoS) in IoT using an improved meta-heuristic algorithm, called the improved seagull optimization algorithm (ISOA), along with traffic management in these networks. Based on this subject, the traffic-aware algorithm can manage the sending of packets and increase the QoS provision in terms of time to a great extent. The performance evaluation of the proposed method and comparison with the previous methods demonstrated the accuracy and efficiency of this method and its superiority over the previous works.

The Effect of Cellulose Nanofibers on the Manufacturing of Mini-Tablets by Direct Powder Compression.

Mini-tablets (MTs) contain a small amount of active pharmaceutical ingredients in one small tablet. MTs are advantageous because they can be fine-tuned according to the age and weight of pediatric patients and they are easy for children and the elderly to swallow. However, there are manufacturing concerns such as the difficulty in achieving both hardness and disintegration of a small tablet and it is difficult to keep the tablet weight and drug content consistent in MTs because the mold used for its production is special. In this study, we aimed to determine if an additive such as cellulose nanofibers (CNF), which has been studied in various fields in recent years, could be used to manufacture MTs without difficulties. In this study, an MT was manufactured using a rotary tableting press with a compression force of 2, 5, and 8 kN, and the weight variation, drug content variation, tensile strength, friability, disintegration time, and drug dissolution were evaluated. Of note, the tensile strength of MTs produced with a compression force of ≥5 kN was ≥1.3 MPa, which was comparable to that of an ordinary tablet with an 8 mm diameter and a hardness of ≥30 N. The disintegration time of the MT which was 20-30% CNF was ≤30 s at any compression force. MTs with CNF showed similar disintegration to MTs with other common disintegrants. Therefore, we found that CNF is a functional additive capable of manufacturing MTs by direct powder compression which has both strength and disintegration.

Networked Fitness Management System Based on Internet of Things

In recent years, with the rapid development of Internet of things and other technologies, the digitalization, networking, and intelligence of sports have become the current research focus. In this paper, the fitness management system based on the Internet of things is studied. By analyzing the system function and performance requirements, the design of fitness client (small tablet) of networked fitness management system is based on Internet of things. Receiving the fitness data uploaded by the fitness device through Bluetooth, the fitness data can be processed and displayed in real time with graphics. After the exercise, the fitness data can be uploaded to the central computer through Wi-Fi wireless. Taking barbell as an example, by analyzing the movement characteristics of barbell, Bluetooth MPU6050 module is used for data acquisition; the data collected includes angle, number, etc.; the relevant functions of barb-dumbbell movement are analyzed and designed; and the Bluetooth communication module and Wi-Fi communication module in the small tablet software system are designed and implemented. The relevant experiments were carried out based on the developed software and hardware platform. Recognition experiments on 7 classes of actions show that the proposed deep neural network learns well on small datasets, achieving an action recognition accuracy of 97.61%, and the SVM also achieves a recognition accuracy of more than 96%. In the 50 action cycle calculation experiments, the number statistics algorithm reached 100% calculation accuracy, and the action cycle calculation results are also close to the real value, proving the effectiveness of the periodic calculation method.

Retrospective Analysis of Cataract Formation and Nutritional Etiology in a Managed Collection of Parakeet Auklets (Aethia psittacula).

The parakeet auklet (Aethia psittacula) is a piscivorous seabird with a natural diet of various invertebrate and teleost species, which is challenging to replicate in a managed collection. A high prevalence of early onset cataracts was observed in a managed collection of parakeet auklets at the North Carolina Zoo (Asheboro, NC, USA), which was hypothesized to be related to inappropriate vitamin A and E levels. From 1994 to 2002, these parakeet auklets were offered dietary supplementation comprising Vita-Zu small bird tablets. In June 2002, the birds were transitioned to only Thiamin-E paste (vitamin E and thiamin only). Plasma samples were collected from birds with and without cataracts from 1998 to 2005 and submitted for vitamin A (retinol) and vitamin E (α-tocopherol) analysis. Food items comprising the birds' diet were also evaluated for vitamin content. This information was combined with clinical and necropsy data from medical records from 1994 to 2015. A total of 78% of birds (39/50) developed cataracts, with a median age of onset of 7 years (range, 2-12 years). Cataracts ranged from incipient to hypermature during both routine ophthalmic examinations and postmortem evaluations. The median (range) of plasma retinol and α-tocopherol values were 1.99 µg/mL (0.20-6.68 µg/mL) and 15.39 µg/mL (3.40-96.27 µg/mL), respectively. There were no significant differences in plasma concentrations of vitamins based on the animals' sex, origin, presence of cataracts, or administered vitamin supplementation product. No other etiologies for cataract development were identified in the population. Further research in free-ranging parakeet auklet nutrition and cataract occurrence is warranted for continued species collection management.

Upotreba simulatora kompaktiranja za karakterizaciju kompresije praškova - prednosti i ograničenja

Compaction simulators are designed as machines which can provide an in-depth analysis of the powder compaction process. Characterization of the powder compression and compaction process, as well as material characterization, play an important role in the formulation and manufacturing process design and development, as well as in creating a strong knowledge basis for the scale-up of the tablet compression and troubleshooting in further stages of the product lifecycle. Although compaction simulators are designed to simulate the compression process on high-speed tablet-presses, with the advantages of a small quantity of material needed and highly sophisticated instrumentation, there are certain limitations in the extrapolation of the process parameters from these machines to high-speed rotary tablet presses. However, the advantage of the use of compaction simulators for studying basic compression and compaction mechanisms, identification of critical material attributes and critical process parameters ranges, and their relations with tablet characteristics and critical quality attributes of pharmaceutical products is clear, compared to the use of small excentre tablet presses, and complementary to the use of small rotary tablet presses. This scientific paper provides an overview and examples of the different advantages provided by the instrumentation of compaction simulators, including certain limitations in their exploitation.

The Brick Completion Receipts from the City of Pekasi, "Till Abu-Antik" “An Analytical Study of Unpublished Cuneiform Texts”

Between the finds discovered in the city of Pekasi and currently preserved in the treasuries of the Iraqi Museum was numbers of small tablet, its dimensions usually not exceeding three centimeters, with a dark black color, often invisible to the cuneiform signs written on it, all of it discovered during the excavations in Pekasi, "Till Abu-Antik" during five seasons. It seems that most of the tablets under study in this research belong to one person named (d MAR.TU-i-bi),that is meaning his own archive, as he hired workers in the Brick industry from different people, and it seems that he needed a large number of bricks, where we notice that he hired workers to manufacture brick throughout the month of July. The manufacture of bricks was of great importance from old Babylonian Period, as important information in this field reached us through cuneiform texts. It seems to us that these texts are daily diaries of ( d MAR.TU-i-bi), as we note that most of the texts of the study in this research date back to different days of The month of (July), without any indication of the duration of the lease or the materials received in return for their rent. In addition, it shows the urban movement witnessed by the city of Bekasi. As for the history of these texts that we have studied in this research, they go back to the twenty-fifth year (1724 BC) of the reign of King Samsu-iluna (1749-1712 BC).

The non-utilitarian objects from the initial Upper Paleolithic Ushbulak site in eastern Kazakhstan

The Middle to Upper Palaeolithic transition shows numerous indications for a manifestation of abstract thinking and symbolic behavior. In northern Central Asia this process is illustrated by the appearance and distribution of personal ornaments (pendants, beads, patterned items), as well as by evidence for the use of natural pigments and ritual activities. However, not only articles with distinctive functional features, but also finds of unknown purpose have been identified, such as small tablets and pebbles showing evidence of polish and/or irregular cut marks, as well as the fragmentary pigment remnants, and manuports. This publication discusses the results of use-wear analysis carried out for two such objects recovered from occupation layer 6 at the Ushbulak site, dating back to 45–40 ka BP (the Shilikty Valley in Eastern Kazakhstan), namely a tabular piece of talc, with a worked surface, and a small jasperoid pebble. Both artifacts show signs of being intensely treated, but their functional purpose is still unclear; these objects may be interpreted as non-utilitarian articles. Similar typologically indistinct artifacts were recovered from many IUP sites in the region (Denisova Cave, Kara-Bom, Podzvonkaya, Khotyk, Tolbor-4, 2). Their presence indicates that such a phenomenon should be regarded as a characteristic manifestation for the non-utilitarian human activity in the development of the Upper Palaeolithic tradition.

Formulation & assessment of combined antibiotics in a floating oblong tablet for treatment of H. pylori: (A) Radiological imaging to prove the floating of a high-weight oblong tablet

The floating drug delivery system (FDDS) is considered as a renewable technique in the pharmaceutical technology because the dreams of increasing the stomach residence time for local or systemic effect are continuously actual for different purposes. It was studied for small weight tablet, but it is not clearly studied for the high weight tablet which may be essential for high dose drugs or when combined drugs are needed. Sodium bicarbonate was only used as a gas generating agent to give the chance to increase the weight of the drugs. Factorial experimental design was utilized to statistically analyze factors affecting tablet buoyancy. The results showed that, all factors studied and their interactions have significant effect on the buoyancy lag time. The addition method of gas generating agent has the most significant effect on the buoyancy process regardless of concentration of sodium bicarbonate used. That is due to the gas generation process is an in-organic interaction between the moieties of strong acid normally present in the stomach and the base added to the tablet during formulation. F4 is selected as an optimum formula that achieves the lowest floating lag time (7 s) through intragranular addition of gas generating agent at the highest concentration for in-vivo radiological imaging. In-vivo study in mature human gastrointestinal tract shows that the gastric residence time has extended to 4 h after swallowing the optimum floated high weight tablet at 2 h after meal. Therefore, it is advisable that, such tablet formula should be administered after standard calorific meal since such meal delays the stomach evacuation.

BM 76829: A small astronomical fragment with important implications for the Late Babylonian Astronomy and the Astronomical Book of Enoch

BM 76829, a fragment from the mid-section of a small tablet from Sippar in Late Babylonian script, preserves what remains of two new unparalleled pieces from the cuneiform astronomical repertoire relating to the zodiac. The text on the obverse assigns numerical values to sectors assigned to zodiacal signs, while the text on the reverse seems to relate zodiacal signs with specific days or intervals of days. The system used on the obverse also presents a new way of representing the concept of numerical ‘zero’ in cuneiform, and for the first time in cuneiform, a system for dividing the horizon into six arcs in the east and six arcs in the west akin to that used in the Astronomical Book of Enoch. Both the obverse and the reverse may describe the periodical courses of the sun and moon, in a similar way to what is found in astronomical texts from Qumran, thus adding to our knowledge of the scientific relationship between the two cultures.

UTUKKŪ LEMNŪTU(UDUG-HUL) IN A NEW TEXT FROM THE IRAQ MUSEUM

A small tablet fragment acquired by the Iraq Museum raises interesting questions, although at first it appeared to be a simple duplicate manuscript from the large bilingual incantation series Udug-hul. Publishing this fragment has drawn attention to an interesting feature of Mesopotamian incantations, in which theāšipu-exorcist protects himself first, before addressing the patient. Although this practice has been known from Tablet 3 of Udug-hul incantations, it turns out that Assur exorcists occasionally inserted their own names into otherwise anonymous incantations and prayers, in order to ensure their own protection, which is a practice not known from other sites.

Patient-Centric Medicine Design: Key Characteristics of Oral Solid Dosage Forms that Improve Adherence and Acceptance in Older People.

Older people represent a very heterogeneous patient population and are the major user group of medication. Age-related changes mean that this population can encounter barriers towards taking medicines orally. The aim of this study was to investigate the characteristics of oral solid dosage forms that contribute to an age appropriate dosage design, with an aim to improve overall medication adherence and acceptance in older people. Fifty-two semistructured interviews were conducted with older people, informal (family) carers, and health and social care professionals. Formulation characteristics impacted three stages of the medication taking process: (1) medication identification and memorability, (2) medication handling and (3) swallowability. Small round tablets (≤7 mm) are least accepted amongst older people and their carers and had a negative impact on all stages. The use of bright, two-coloured preparations and interesting shapes improves identification and further aids memorability of indications and the timing of tablets. Palatability, while useful to enhance swallowability, also has an impact on the visual appeal and memorability of medication. Environmental, patient, medication and disease characteristics also determine preferences for formulation. Developing an age appropriate dosage design for older people, therefore, requires a holistic, patient-centric approach to improve adherence and acceptance.

Bictegravir, Emtricitabine, and Tenofovir Alafenamide Fixed-Dose Combination for Treatment of HIV in Adolescents and Children: Week 48 Results from an Open-Label, Multicentre, Phase 2/3 Paediatric Trial

Background: Bictegravir a potent integrase strand transfer inhibitor (INSTI) with a high barrier to resistance, coformulated with emtricitabine and tenofovir alafenamide, is a guidelines-recommended and preferred single-tablet regimen for adults and adolescents. The aim of this study was to evaluate the pharmacokinetics, safety, and efficacy of switching to this regimen in virologically suppressed children and adolescents living with HIV. Methods: In this prospective, multi-country, 48-week, Phase 2/3, single-arm, open-label trial (ClinicalTrials.gov, number NCT02881320), virologically suppressed children and adolescents (6 to <18 years of age) living with HIV were switched from their current regimen to bictegravir, emtricitabine, and tenofovir alafenamide (50/200/25 mg) once daily. Predicted systemic exposures (area under the curve and concentration at the end of the dosing interval [AUC tau and C tau ]) of bictegravir and safety assessments (adverse events) were co-primary outcomes and compared with adult values. Findings: Between September 29, 2016 and February 16, 2018, 102 participants were enrolled. One hundred received bictegravir, emtricitabine, and tenofovir alafenamide (6 to <12 years: n=50; 12 to <18 years: n=50). Bictegravir C tau was 35% lower in adolescents and bictegravir C max was 53% higher in children, compared to adults. However, no clinically relevant differences in bictegravir, emtricitabine, and tenofovir alafenamide exposures were observed in adolescents and children compared with adults. With median duration of exposure to study drug of 80 weeks, bictegravir, emtricitabine, and tenofovir alafenamide was well tolerated; most adverse events were <= grade 2 and there were no study drug-related serious adverse events. Only one individual discontinued study drug due to adverse events (grade 2 insomnia and anxiety). All 100 participants had HIV-1 RNA <50 copies per mL at week 24 and 98% (98/100) at week 48; no participant had treatment-emergent resistance. Interpretation: In adolescents and children living with HIV, the adult-strength bictegravir, emtricitabine, and tenofovir alafenamide single-tablet regimen was well tolerated and maintained virologic suppression. No clinically meaningful drug exposure differences comparing to phase 3 trials in adults were noted. Study data support the treatment of HIV in adolescents and children with bictegravir, emtricitabine, and tenofovir alafenamide. This single-tablet regimen offers an important regimen for adolescents and children living with HIV with the attractive attributes of having a high barrier to resistance, small tablet size, low potential for drug-drug interactions, and lack of food requirement. Trial Registration: This study is registered with ClinicalTrials.gov, number NCT02881320. Funding Statement: Gilead Sciences, Inc. Declaration of Interests: I was a stockholder and employee of Gilead Sciences at the time the clinical study described in the manuscript was conducted and when manuscript was written. Ethics Approval Statement: This trial was undertaken in accordance with the Declaration of Helsinki and approved by central or site-specific review boards or ethics committees. In the native language, all participants (7 to <18 years of age) were required to provide written or oral assent, and their parents/caregivers provided written informed consent.