Pill Burden Research Articles

Antiretroviral Therapy-Related Problems among Human Immunodeficiency Virus-Infected Patients

Background: There are problems associated with antiretroviral therapy despite its achievement. Poor medication adherence and inability to tolerate large pill burden are major problems facing patients with chronic illnesses. These drug therapy problems are under-studied among people living with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) in Nigeria. We evaluated adherence and pill burden among this set of patients in a tertiary hospital in Lagos. Methods: Data for eligible HIV-infected adults were documented from case notes and through interviews using a well-structured questionnaire. Important details extracted were sociodemographics, pills information, and CD4 counts. The main outcome measures were drug adherence, as assessed by the four-item Morisky Medication Adherence Scale and pill burden, as measured by daily pill >5. Results: Of the 296 patients, 219 (74%) were females. Median age (interquartile range) was 40 (35.0–47.7) years. Majority (262; 88.5%) were married, had at least a secondary education (142:48.0%), and CD4 count >500 cells/ml (215; 72.6%). Pill burden >5 pills/day was observed in 12.2% of the patients, while adherence was documented for 83.4% of the patients. Majority (259; 87.5%) were receiving fixed-dose combination of antiretroviral drugs. Forgetfulness (16.5%) and being too busy to take pills (10.5%) were the most common reasons for nonadherence. Pill burden in those who were not receiving fixed-dose combination was significantly associated with medication nonadherence. However, only pill burden was found to be an independent prognosticator of non-adherance. (Odd ratio = 0.67, confidence interval = 0.03–1.66, P < 0.00). Conclusion: Medication nonadherence and pill burden were observed in more than one-tenth of patients. These were the two major antiretroviral therapy-related problems reported in this study.

Gaps in TB preventive therapy for persons initiating antiretroviral therapy in Uganda: an explanatory sequential cascade analysis

BACKGROUND: The WHO recommends TB symptom screening and TB preventive therapy (TPT) for latent TB infection (LTBI) in persons living with HIV (PLWH). However, TPT uptake remains limited. We aimed to characterize and contextualize gaps in the TPT care cascade among persons enrolling for antiretroviral therapy (ART).SETTING: Four PEPFAR-supported facilities in Uganda.METHODS: We studied a proportionate stratified random sample of persons registering for ART when TPT was available. Patient-level data on eligibility, initiation, and completion were obtained from registers to determine proportion of eligible patients completing each cascade step. We interviewed providers and administrators and used content analysis to identify barriers to guideline-concordant TPT practices.RESULTS: Of 399 study persons, 309 (77%) were women. Median age was 29 (IQR 25-34), CD4 count 405 cells/µL (IQR 222-573), and body mass 23 kg/m² (IQR 21-25). Of 390 (98%) screened, 372 (93%) were TPT-eligible. Only 62 (17%) eligible PLWH initiated and 36 (58%) of 62 completed TPT. Providers reported hesitating to prescribe TPT because they lacked confidence excluding TB by symptom screening alone and feared promoting drug resistance. Although isoniazid was available, past experience of irregular supply discouraged TPT initiation. Providers pointed to insufficient TB-dedicated staff, speculated that patients discounted TB risk, and worried TPT pill burden and side effects depressed ART adherence.CONCLUSIONS: While screening was nearly universal, most eligible PLWH did not initiate TPT. Only about half of those who initiated completed treatment. Providers feared promoting drug resistance, harbored uncertainty about continued availability, and worried TPT could antagonize ART adherence. Our findings suggest urgent need for stakeholder engagement in TPT provision.

The Role of Patient-reported Outcomes and Medication Adherence Assessment in Patient-focused Drug Development for Solid Organ Transplantation.

The Role of Patient-reported Outcomes and Medication Adherence Assessment in Patient-focused Drug Development for Solid Organ Transplantation.

Factors Associated with Antidepressant Medication Non-adherence

Medication non-adherence is one of the major problems in treating patients with depression. Non-adherence results in an increased risk of relapse and reduced quality of life. The objective of this review was to review and summarize studies that focused on the factors associated with antidepressant medication non-adherence in patients with depression. Literature searches were performed using PubMed/Medline and Google Scholar. The search was limited to articles published in the English language in peer-reviewed journals between January 2000 and December 2019. Studies that analyzed factors of non-compliance in patients with depressive disorders were included in the review. Patient-related factors such as forgetfulness, comorbidities, and misconceptions about the disease and medication, medication-related factors, polypharmacy, side effects, pill burden and cost, healthcare system-related factors, including physician-patient interactions, sociocultural factors such religious and cultural beliefs and stigma, and logistic factors were found to be the major factors associated with antidepressant non-adherence. Efforts should be made to increase patient adherence to antidepressants by strengthening physician-patient relationships, simplifying medication regimens, and rectifying myths and beliefs held by patients with scientific information and explanations.

Enabling modular dosage form concepts for individualized multidrug therapy: Expanding the design window for poorly water-soluble drugs

Multidrug dosage forms (aka combination dosage forms, polypills, etc.) create value for patients through reduced pill burdens and simplified administration to improve adherence to therapy. Enhanced flexibility of multidrug dosage forms would provide further opportunities to better match emerging needs for individualized therapy. Through modular dosage form concepts, one approach to satisfy these needs is to adapt multidrug dosage forms to a wider variety of drugs, each with a variety of doses and release profiles. This study investigates and technically explores design requirements for extending the capability of modular multidrug dosage form concepts towards individualization. This builds on our recent demonstration of independent tailoring of dose and drug release, which is here extended towards poorly water-soluble drugs. The challenging design requirement of carrying higher drug loads in smaller volumes to accommodate multiple drugs at their clinical dose is here met regarding dose and release performance. With a modular concept, we demonstrate high precision (<5% RSD) in dose and release performance of individual modules containing felodipine or naproxen in Kollidon VA64 at both a wide drug loading range (5% w/w and 50% w/w drug) and a small module size (3.6 mg). In a forward-looking design-based discussion, further requirements are addressed, emphasizing that reproducible individual module performance is predictive of dosage form performance, provided the modules are designed to act independently. Therefore, efforts to incorporate progressively higher drug loads within progressively smaller module volumes will be crucial to extend the design window further towards full flexibility of future dosage forms for individualized multidrug therapy.

ACCESS TO SINGLE PILL COMBINATIONS IN NATIONAL HYPERTENSIVE CONTROL PROGRAMS: IS PRICING A BARRIER?

Objective: Most patients with hypertension require two or more medicines to control their blood pressure. Single pill combination (SPC) antihypertensive medicines facilitate simpler dosing schedules, decrease pill burden, increase patient medication adherence, simplify procurement and distribution. This study uses a private sector pharmaceuticals database to explore whether prices are a barrier to access SPCs in hypertension control programmes. Design and method: Trends in sales of anti-hypertensive medications in India were analysed in private sector pharmaceutical sales dataset from IQVIA Consulting. Price information was collated for medicines that attributed to 70% of sales in terms of number of tablets sold. Maximum Retail Prices of 11 SPCs and their associated Fixed Dose Equivalents (FDEs; same medications and doses as separate pills) were gathered through a publicly available website called “1mg” between November 2019-January 2020. Results: In India, the market share of 2-drug-SPCs and 3-or-more-drug SPCs increased from 2016–2018 at a compounded annual growth rate of 5.5% and 16.1% respectively. In 2018, 2-drug-SPCs (36.3%) had the highest market share in terms of quantity of medicines followed by FDE of SPC components, such as calcium channel blockers (18.3%), beta blockers (16.3%), angiotensin receptor blockers (14.6%), diuretics (5.3%), and ACE-Inhibitors (3.6%). Share of 3-or-more-drug SPCs (2.0%) was very small. While nine of 11 SPCs had an average price higher than sum of the average price of their component FDEs (Range 2.6% - 45.9% higher), a comparison of SPCs and FDEs by the same manufacturer showed that for eight 2-drug-SPCs there was at least one company for each molecule whose SPC was priced lower than the sum of the price of FDEs (Range -71.47% -124.73%). Conclusions: SPCs are increasingly preferred for hypertension treatment in the Indian private sector. The World Health Organization recently included four SPCs for hypertension management in its Essential Medicine List. India has a vibrant and competitive hypertensive medicines market. Examples discovered in this dataset of minimal-to-no price difference suggest that price need not be a barrier to accessing SPCs, and that market forces can further drive down prices with substantial advantages for patients and hypertension control programmes.

BOTH MEDICAL AND SURGICAL TREATMENT FOR UNILATERAL PRIMARY ALDOSTERONISM LEAD TO BLOOD PRESSURE IMPROVEMENTS

Objective: All patients with primary aldosteronism (PA) can be treated with medications but those with unilateral PA can be offered surgery (adrenalectomy). Since most patients confirmed to have unilateral PA by adrenal vein sampling undergo surgery, there is a paucity of data comparing the effects of medical versus surgical treatment in patients with unilateral PA. We applied a clinical prediction score to include patients with likely unilateral PA and assessed post-treatment blood pressure (BP) outcomes. Design and method: 214 patients diagnosed with PA managed in two major tertiary centres in Singapore from 2000 – 2019 were identified for this retrospective analysis. Patients with confirmed unilateral PA by adrenal vein sampling were included. Patients with indeterminate subtype were categorised using our previously validated clinical prediction score, Aldosterone-potassium ratio (APR), and patients with APR &gt; 10 (highly predictive of unilateral disease) were included. Results: Of 214 patients, 38 patients had confirmed unilateral PA on adrenal vein sampling, and another 78 patients had likely unilateral PA using APR score. Hence, 116 patients were included for analysis, median age 53 (46 – 60) yrs, 47 females (40.5%). 56 patients (48.3%) underwent adrenalectomy, and 60 patients (51.7%) were treated with medications (spironolactone, eplerenone or amiloride). In the surgical group, there was improvement in systolic and diastolic BP from 150 to 131 mmHg, P &lt; 0.001 and 87 to 76 mmHg, P &lt; 0.001 respectively, over a follow-up duration of 6.5 (3 – 9.25) yr. In the medical group, there was significant improvement in systolic and diastolic BP from 148 to 134 mmHg, P &lt; 0.001 and 85 to 76 mmHg, P &lt; 0.001 respectively, over a follow-up duration of 5 (2 – 11) yrs. In addition, post-surgery, there was a decrease in WHO-daily defined dose of antihypertensive medications from 1.8 to 0.8, P &lt; 0.001, whereas it did not change in the medical group, from 2.2 to 2.0 medications, P = 0.337. Conclusions: Both medical and surgical treatment for unilateral primary aldosteronism led to significant blood pressure improvements. However, surgical treatment reduces the pill burden of hypertension medications, and offers the possibility of complete cure of hypertension.

POS-791 EVALUATION OF EFFECTIVENESS OF AN ALTERNATIVE PRESCRIPTION PATTERN OF CINACALCET FOR BETTER CONTROL OF PARATHYROID HORMONE LEVELS IN HEMODIALYSIS PATIENTS

Due to the high pill burden, non-adherence (NA) to medications is highly prevalent among hemodialysis patients. NA to Cinacalcet in particular, poses a significant challenge in controlling parathyroid hormone (PTH) levels. Perhaps an effective way to improve adherence to Cinacalcet is to reduce the frequency of administration. There is limited knowledge of the effectiveness of controlling PTH level with three times per week (TIW) Cinacalcet compared with conventional daily dosing. The objective of this longitudinal retrospective single-center observational study was to evaluate the effectiveness of three times a week (TIW) Cinacalcet dosing compared with conventional daily dosing (DD) in subsequent levels of Parathyroid Hormone (PTH) in hemodialysis patients. All adult hemodialysis patients on Cinacalcet for secondary hyperparathyroidism (sHPT) for more than six months were selected. Patients who did not have any adherence issues continued oral Cinacalcet daily (QID) while patients who were suspected to be NA to Cinacalcet or suffered from intolerance were given oral Cinacalcet three times a week (TIW) on dialysis days under direct observation of the dialysis nurse. The dose of Cinacalcet was determined by the physician to maintain PTH levels within 130 - 600 pg/ml as per KDIGO guidelines. PTH levels were monitored every other month and the dose was titrated accordingly. All these patients also received intravenous alfacalcidol and phosphate binders at the discretion of the physician to maintain adjusted calcium and phosphate levels within the KDIGO recommendations. The primary endpoint of the study was to assess whether TIW dosing was more effective than QID dosing in terms of maintaining PTH levels within the KDIGO recommended range. Data regarding patients’ acceptability, tolerability, hypocalcemia, and required weekly cumulative Cinacalcet dose were also collected. Patients were followed up for 12 months. There were 40 patients in the QID group and 52 in the TIW group. All participants in the TIW group reported acceptability and improved tolerability and hence better adherence to the dosing regimen. Some in the TIW model even reported perceived improvement in their commitment to adherence. In terms of effectiveness, the TIW group showed better monthly PTH trends compared to the QID group as illustrated by the graph below. This appeared to be sustained over the 12 months follow up period. Concomitantly, the required cumulative dose of Cinacalcet per week was also much less in the TIW group (270 mg/week) compared to the QID group (420 mg/week) suggesting a significant healthcare cost saving in long run. While there were cases of hypocalcemia observed in the QID group no such events were noticed in the TIW group. Taken together, the results of our study confirm that patients on the TID model of prescription were able to achieve and sustain the PTH levels consistent with KDIGO recommendation with much lower cumulative Cinacalcet dose with consequent lower healthcare costs. Nevertheless, we do agree that this alternative model of prescription (TIW) needs to be further validated in a prospective study before drawing stronger conclusions.

Expanding the Repertoire for "Large Small Molecules": Prodrug ABBV-167 Efficiently Converts to Venetoclax with Reduced Food Effect in Healthy Volunteers.

Since gaining approval for the treatment of chronic lymphocytic leukemia (CLL), the BCL-2 inhibitor venetoclax has transformed the treatment of this and other blood-related cancers. Reflecting the large and hydrophobic BH3-binding groove within BCL-2, venetoclax has significantly higher molecular weight and lipophilicity than most orally administered drugs, along with negligible water solubility. Although a technology-enabled formulation successfully achieves oral absorption in humans, venetoclax tablets have limited drug loading and therefore can present a substantial pill burden for patients in high-dose indications. We therefore generated a phosphate prodrug (3, ABBV-167) that confers significantly increased water solubility to venetoclax and, upon oral administration to healthy volunteers either as a solution or high drug-load immediate release tablet, extensively converts to the parent drug. Additionally, ABBV-167 demonstrated a lower food effect with respect to venetoclax tablets. These data indicate that beyond-rule-of-5 molecules can be successfully delivered to humans via a solubility-enhancing prodrug moiety to afford robust exposures of the parent drug following oral dosing.

Long-acting cabotegravir plus rilpivirine for treatment in adults with HIV-1 infection: 96-week results of the randomised, open-label, phase 3 FLAIR study

There is a need for more convenient, less frequent treatment to help address challenges associated with daily oral HIV treatment in people living with HIV, including stigma, pill burden, drug-food interactions, and adherence. The phase 3 ATLAS and FLAIR studies showed non-inferiority of long-acting cabotegravir and rilpivirine dosed every 4 weeks compared with standard oral therapy for the maintenance of virological suppression in adults with HIV-1 over 48 weeks. We present the 96-week findings. FLAIR is a randomised, phase 3, open-label, multicentre study done in 11 countries investigating whether switching to long-acting cabotegravir and rilpivirine is non-inferior to daily dolutegravir, abacavir, and lamivudine in virologically suppressed adults living with HIV-1. Antiretroviral therapy (ART)-naive participants received induction therapy with daily oral dolutegravir (50 mg), abacavir (600 mg), and lamivudine (300 mg) for 20 weeks. After 16 weeks, participants with less than 50 HIV-1 RNA copies per mL were randomly assigned (1:1) to continue the standard of care regimen (standard care group) or switch to receive daily oral cabotegravir 30 mg and rilpivirine 25 mg for at least 4 weeks followed by long-acting cabotegravir 400 mg and rilpivirine 600 mg, administered as two 2 mL intramuscular injections, every 4 weeks for at least 96 weeks (long-acting group). Randomisation was stratified by baseline (preinduction) HIV-1 RNA (<100 000 or ≥100 000 copies per mL) and sex at birth and used GlaxoSmithKline-verified randomisation software (RandAll NG, version 1.3.3) for treatment assignment. The primary endpoint was the proportion of participants with plasma HIV-1 RNA of 50 copies per mL or more assessed as per the US Food and Drug Administration (FDA) Snapshot algorithm at week 48, which has been reported previously. Here, we report the proportion of participants with 50 or more HIV-1 RNA copies per mL using the FDA Snapshot algorithm at week 96 (intention-to-treat population; non-inferiority margin 6%). The trial is registered with ClinicalTrials.gov, NCT02938520. Between Oct 27, 2016, and March 24, 2017, 809 participants were screened. 631 (78%) participants entered the induction phase and 566 (70%) were randomly assigned to either the standard care group (283 [50%] participants) or the long-acting group (283 [50%]). Median age was 34 years (IQR 29 to 43), 62 (11%) were 50 years or older, 127 (22%) were women (sex at birth), and 419 (74%) were white. At week 96, nine (3%) participants in each arm had 50 or more HIV-1 RNA copies per mL, with an adjusted difference of 0·0 (95% CI -2·9 to 2·9), consistent with non-inferiority established at week 48. Across both treatment groups, adverse events leading to withdrawal were infrequent (14 [5%] participants in the long-acting group and four [1%] in the standard care group). Injection site reactions were the most common adverse event, reported by 245 (88%) participants in the long-acting group; their frequency decreased over time. Median injection site reaction duration was 3 days (IQR 2 to 4), and 3082 (99%) of 3100 reactions were grade 1 or 2. No deaths occurred during the maintenance phase. The 96-week results reaffirm the 48-week results, showing long-acting cabotegravir and rilpivirine continued to be non-inferior compared with continuing a standard care regimen in adults with HIV-1 for the maintenance of viral suppression. These results support the durability of long-acting cabotegravir and rilpivirine, over an almost 2-year-long period, as a therapeutic option for virally suppressed adults with HIV-1. ViiV Healthcare and Janssen Research and Development.

Assessment of Knowledge and reasons for Medication non-Adherence in Ambulatory Elderly Patients with Hypertension and Diabetes Mellitus in a Geriatric Centre in Nigeria

Abstract Introduction Hypertension and type 2 Diabetes mellitus are global health disorders afflicting millions of elderly patients worldwide with an ever-increasing incidence and prevalence. Non-adherence to medications affects the quality and length of life, and has been associated with negative health outcomes and increasing healthcare costs especially in the elderly [1]. Few empirical data exist on the knowledge and medication adherence among elderly patients in sub-Saharan Africa countries. Aim This study aimed to assess the knowledge, medication adherence, and the factors associated with patient’s knowledge on diabetes mellitus and hypertension. Methods A cross-sectional study of 423 elderly patients aged ≥60 years diagnosed with hypertension and diabetes mellitus, selected consecutively at the Geriatric centre in the University College Teaching Hospital, Ibadan was carried out between October 2019 and January 2020. Socio-demographic information, knowledge of the indication of the medications, possible side effects, and details of medication adherence level with reasons for non-adherence were obtained using interviewer-administered semi-structured questionnaire. Bivariate and multivariate analyses were carried out using SPSS 23. Alpha was set at 0.05. Results The mean age (±SD) of the older patients was 69.6 ± 6.4 years and 253 (59.8%) were females. About three-quarter of participants (320; 75.7%) were retired. Majority of the elderly (381; 90.1%) were hypertensive, while 270 (63.8 %) were diabetic, and 85 (20.1%) had multimorbidity of both hypertension and diabetes mellitus. Patients that were non-adherent with their medication were 138 (32.6%). The most common reasons reported for non-adherence included patient slept off (41; 56.6%), pre-occupation (24; 33.1%) and unavailability of medications (12; 16.6%). Thirty-seven (8.7%) participants intentionally missed doses, out of which 22 (59.5%) reported pill burden as its reason for medication non-adherence. All patients 423 (100.0%) knew the indication for their medications and 20 (4.7%) experienced medication-related side effects. Overall, 299 (70.6%) and 309 (73.0%) of patients with hypertension and diabetes mellitus showed good knowledge about their conditions. Adherence to medication was associated with good knowledge in hypertensive patients (p=0.002), while being male (p=0.002), age-group of 60–69 (p=0.001) and poor adherence (p=0.001) were associated with good knowledge in diabetes mellitus patients. Conclusion We found non-adherence was mainly as a result of patients’ behaviors, attitude, and unavailability of medications which could be the cause of low medication adherence among the elderly patients. A systematic review on factors associated with medication adherence in older patients reported medication review aimed at simplifying regimens and educating patients about their treatment as intervention to improve adherence [2]. Thus, we recommend educational intervention among the elderly patients. The elderly patients demonstrated good knowledge about their conditions and medication. However, the relatively good knowledge did not appear to have significant impact on patient’s adherence to medication. Improvement in medication adherence through interdisciplinary approach may improve clinical outcomes.

Deprescribing in Older Adults With Cancer and Limited Life Expectancy: An Integrative Review

Polypharmacy is common in older adults with cancer and deprescribing potentially inappropriate medications becomes very relevant when life expectancy decreases due to metastatic disease. Especially preventive medications may no longer be beneficial, because they may decrease quality of life and reduction in morbidity and mortality may be futile. Although deprescribing of preventive medication is common in the last period of life, it is still unusual during active cancer treatment for advanced disease, although life expectancy is often limited to less than 1 to 2 years in that stage. We performed a systematic search of the literature in Pubmed and Embase on the discontinuation of commonly utilized groups of preventive medication and evaluated the evidence of potential benefits and harms in patients aged 65 years or older with cancer and a limited life expectancy (LLE). From 21 included studies, it can be concluded that deprescribing lipid lowering drugs, antihypertensive drugs, osteoporosis drugs and antihyperglycemic drugs is feasible in a considerable part of patients with a LLE. Discontinuation may be performed safely, without the occurrence of serious adverse events or decrease of survival. The only study that addressed quality of life after deprescribing showed that discontinuation of statins improves quality of life in patients with a LLE. Recurrence of symptoms requiring reintroduction occurred in 0-13% of patients on antihyperglycemic treatment and 8-60% of patients using antihypertensive drugs. In order to reduce pill burden and futile treatment clinicians should discuss deprescribing of preventive medication with older patients with advanced cancer and a LLE.

Single centre experience with histaglobin as an adjunctive treatment of chronic urticaria: A post marketing surveillance study

Introduction: Chronic urticaria consists of itchy rash on most days for at least six weeks. It is caused by release of histamine and other mediators from degranulated cutaneous mast cells. Antihistamines, the current treatment mainstay, do not provide relief in many cases and necessitates the use of adjunctive treatment. Histaglobin, through the synthesis of histamine-neutralizing antibodies, can serve as an adjunct. The current study was aimed to evaluate the efficacy and safety of Histaglobin, as adjunctive therapy, in patients with chronic urticaria. Materials and Methods: Patients with chronic urticaria were enrolled in this single-centre, prospective open-label study. Patients were administered 3 injections of Histaglobin (1ml), subcutaneously, at intervals of 7 days. Efficacy was assessed by grading the change in disease activity, measured using urticarial activity score (UAS 7) on days 0, 7, 14, 28 and 42. Adverse events (AEs) and concomitant medications were also recorded at each study visit. Results: Thirty-seven of the 38 enrolled patients completed study by following-up on day 28. Thirtyfour (91.9%) patients showed improvement; 21 (56.8%) showed ‘moderate improvement’ and 13(35.1%) showed ‘clear cut improvement’. There was a significant (p 6.1) to Day 28(6.06.2). There was one patient who developed redness at injection site. Half the patients on antihistamines and all those on steroid treatment were able to reduce/stop these treatments at the end of study. Conclusion: Histaglobin treatment was found to be effective in the treatment of chronic urticaria. It was also well tolerated and reduced antihistamines and steroids pill burden. Histaglobin, is a safe, well-tolerated and valuable adjunct to antihistamines in the management of chronic urticaria.

Novel Physics-Based Ensemble Modeling Approach That Utilizes 3D Molecular Conformation and Packing to Access Aqueous Thermodynamic Solubility: A Case Study of Orally Available Bromodomain and Extraterminal Domain Inhibitor Lead Optimization Series

Drug design with patient centricity for ease of administration and pill burden requires robust understanding of the impact of chemical modifications on relevant physicochemical properties early in lead optimization. To this end, we have developed a physics-based ensemble approach to predict aqueous thermodynamic crystalline solubility, with a 2D chemical structure as the input. Predictions for the bromodomain and extraterminal domain (BET) inhibitor series show very close match (0.5 log unit) with measured thermodynamic solubility for cases with low crystal anisotropy and good match (1 log unit) for high anisotropy structures. The importance of thermodynamic solubility is clearly demonstrated by up to a 4 log unit drop in solubility compared to kinetic (amorphous) solubility in some cases and implications thereof, for instance on human dose. We have also demonstrated that incorporating predicted crystal structures in thermodynamic solubility prediction is necessary to differentiate (up to 4 log unit) between solubility of molecules within the series. Finally, our physics-based ensemble approach provides valuable structural insights into the origins of 3-D conformational landscapes, crystal polymorphism, and anisotropy that can be leveraged for both drug design and development.

Raltegravir in patients with tuberculosis

Treatment of patients with tuberculosis and HIV infection is complex, with pill burden and treatment adherence presenting major challenges. Rifampicin is a potent inducer of hepatic cytochrome P450 and uridine diphosphate glucuronosyl transferase 1A1 enzymes and the drug efflux pump P-glycoprotein, with potential for major drug–drug interactions with many antiviral drugs. Standard dose raltegravir or efavirenz-based antiretroviral treatment for patients co-infected with HIV and tuberculosis (ANRS 12 300 Reflate TB 2): an open-label, non-inferiority, randomised, phase 3 trialIn patients with HIV given tuberculosis treatment, non-inferiority of raltegravir compared with efavirenz was not shown. Raltegravir was well tolerated and could be considered as an option, but only in selected patients. Full-Text PDF

Cost-effectiveness of statins for primary prevention of atherosclerotic cardiovascular disease among people living with HIV in the United States.

BackgroundExpanding statin use may help to alleviate the excess burden of atherosclerotic cardiovascular disease in people living with HIV (PLHIV). Pravastatin and pitavastatin are preferred agents due to their lack of substantial interaction with antiretroviral therapy. We aimed to evaluate the cost‐effectiveness of pravastatin and pitavastatin for the primary prevention of atherosclerotic cardiovascular disease among PLHIV in the United States.MethodsWe developed a microsimulation model that randomly selected (with replacement) individuals from the Data‐collection on Adverse Effects of Anti‐HIV Drugs study with follow‐up between 2013 and 2016. Our study population was PLHIV aged 40 to 75 years, stable on antiretroviral therapy, and not currently using lipid‐lowering therapy. Direct medical costs and quality‐adjusted life‐years (QALYs) were assigned in annual cycles and discounted at 3% per year. We assumed a willingness‐to‐pay threshold of $100,000/QALY gained. The interventions assessed were as follows: (1) treating no one with statins; (2) treating everyone with generic pravastatin 40 mg/day (drug cost $236/year) and (3) treating everyone with branded pitavastatin 4 mg/day (drug cost $2,828/year). The model simulated each individual’s probability of experiencing atherosclerotic cardiovascular disease over 20 years.ResultsPersons receiving pravastatin accrued 0.024 additional QALYs compared with those not receiving a statin, at an incremental cost of $1338, giving an incremental cost‐effectiveness ratio of $56,000/QALY gained. Individuals receiving pitavastatin accumulated 0.013 additional QALYs compared with those using pravastatin, at an additional cost of $18,251, giving an incremental cost‐effectiveness ratio of $1,444,000/QALY gained. These findings were most sensitive to the pill burden associated with daily statin administration, statin costs, statin efficacy and baseline atherosclerotic cardiovascular disease risk. In probabilistic sensitivity analysis, no statin was optimal in 5.2% of simulations, pravastatin was optimal in 94.8% of simulations and pitavastatin was never optimal.ConclusionsPravastatin was projected to be cost‐effective compared with no statin. With substantial price reduction, pitavastatin may be cost‐effective compared with pravastatin. These findings bode well for the expanded use of statins among PLHIV in the United States. To gain greater confidence in our conclusions it is important to generate strong, HIV‐specific estimates on the efficacy of statins and the quality‐of‐life burden associated with taking an additional daily pill.

Investigation of Leftover Hyperphosphatemia Drugs in Hemodialysis Outpatients

Currently, various hyperphosphatemia drugs are administered orally to hemodialysis patients in order to lower serum phosphorus levels. However, it is known that medication adherence is poor, possibly due to greater pill burden taken each time and their complicated schedules. Therefore, large amounts of unused hyperphosphatemia drugs are likely to be leftover. The increase in leftover prescribed drugs leads to the unnecessary elevation of medical care costs. To date, however, the available information on leftover hyperphosphatemia drugs in hemodialysis outpatients is limited. In this study, we performed an interview survey of medication adherence to hyperphosphatemia drugs among 60 hemodialysis outpatients and evaluated the cost of the leftover drugs. Thirty-four patients showed good adherence. On the other hand, 19 patients self-adjusted to take hyperphosphatemia drugs according to their daily diet. When assessing the serum phosphorus levels for these patients over the past year, the values often exceeded the targeted range (3.5-6.0 mg/mL). Furthermore, 35 patients kept hyperphosphatemia drugs at their home. When estimating the cost derived from leftover drugs using the bootstrap method, main distribution of drug cost was shown to be in the range of 2000 to 2500 yen. This drug cost seemed to in part reflect preparation for an emergency. A serious problem was that 14 patients had previous experience in discarding hyperphosphatemia drugs. This study suggested that more appropriate pharmaceutical care according to each patient's situation is essential in improving phosphorus control in hemodialysis outpatients and in reducing the waste of medical resources.

Observations of Polypharmacy and Interactions on Varying COVID-19 Medication Regimens in Nursing Home Residents

Around 800,000 preventable medication-related errors occur yearly in nursing homes (NHs). With NHs susceptible to medication errors, COVID-19 can potentially increase their occurrence. No evidence-based regimen exists for COVID-19, yet different “cocktails” are prescribed at NHs as prophylaxis or treatment for COVID-19. Little is known regarding long-term consequences of such regimens, including increased pill burden, stable disease exacerbation, or adverse drug reactions. While preventing COVID-19 spread and decreasing mortality are important, doing so safely and effectively should be a priority. Pharmacists can play a pivotal role even with little information available regarding this issue. Student pharmacists performed a retrospective review of medication profiles of individuals living in a single nursing home chain who had an ICD-10 code for COVID-19 (U07.1) contained within their electronic health record from March 1to September 20, 2020. Medications started specifically for COVID-19 were collected, as were the number of scheduled medications +/-14 and +/-30 days from the COVID-19 diagnosis date. Drug interactions were screened via Lexi-Comp if new medications were started for COVID-19 and significant drug-disease interactions were based on clinical skills of the candidate and a review by the geriatrics-focused preceptor. Across 31 facilities, 759 patients were diagnosed with COVID-19. Out of 759 patients, 322 (42.4%) were treated pharmacologically following diagnosis. Interventions included antibiotics, antiplatelets, anticoagulants, nutritional supplements, and other medications. There were 164 patients (21.6%) prescribed antibiotics, 64 (8.4%) anticoagulants, 36 (4.7%) aspirin, 1 (0.1%) clopidogrel, 21 (2.8%) hydroxychloroquine, 124 (16.3%) corticosteroids, and 312 (41.4%) supplements. Nearly 1 in 5 individuals (n=148) were exposed to dangerous drug-drug interactions, with potential for increased bleeding risk and QTc prolongation the most common possible outcomes. Important drug-disease interactions were found in 221 patients with the most common being use of dexamethasone in diabetic patients. The average number of medications added for COVID-19 was 2.8 (range 1-10). The average increase in medications 30 days post-infection was 2.15 (range 1-13); however, 135 patients had fewer medications post-COVID-19, and 214 had no change. While anticoagulants and antibiotics typically did not persist long past infection resolution largely due to stop dates, supplements continued on profiles 30 days after diagnosis. Pharmacists have a vital role in recommendations of evidence-based medication regimens, as well as ensuring proper monitoring parameters are employed. Making certain stop dates are used can also greatly improve patient care and avoid unnecessary polypharmacy. Pharmacists should ensure when medications are being used for a COVID-19 infection, the indication is properly stated, as this will assist with classification of these individuals in other large database studies.

A randomized trial to examine the impact of food on pharmacokinetics of 4-phenylbutyrate and change in amino acid availability after a single oral administration of sodium 4-phenylbutyrarte in healthy volunteers

Urea cycle disorders (UCDs), inborn errors of hepatocyte metabolism, result in the systemic accumulation of ammonia to toxic levels. Sodium 4-phenylbutyrate (NaPB), a standard therapy for UCDs for over 20 years, generates an alternative pathway of nitrogen deposition through glutamine consumption. Administration during or immediately after a meal is the accepted use of NaPB. However, this regimen is not based on clinical evidence. Here, an open-label, single-dose, five-period crossover study was conducted in healthy adults to investigate the effect of food on the pharmacokinetics of NaPB and determine any subsequent change in amino acid availability. Twenty subjects were randomized to one of four treatment groups. Following an overnight fast, NaPB was administered orally at 4.3 g/m2 (high dose, HD) or 1.4 g/m2 (low dose, LD) either 30 min before or just after breakfast. At both doses, compared with post-breakfast administration, pre-breakfast administration significantly increased systemic exposure of PB and decreased plasma glutamine availability. Pre-breakfast LD administration attenuated plasma glutamine availability to the same extent as post-breakfast HD administration. Regardless of the regimen, plasma levels of branched-chain amino acids (BCAA) were decreased below baseline in a dose-dependent manner. In conclusion, preprandial oral administration of NaPB maximized systemic exposure of the drug and thereby its potency to consume plasma glutamine. This finding may improve poor medication compliance because of the issues with odor, taste, and pill burden of NaPB and reduce the risk of BCAA deficiency in NaPB therapy.

Adherence to, and patient convenience of, prolonged-release tacrolimus in stable kidney and liver transplant recipients after conversion from immediate-release tacrolimus in routine clinical practice in Switzerland.

Non-adherence to immunosuppressive therapy in patients following solid organ transplantation is associated with an increased risk of transplant rejection and graft loss. A high pill burden can adversely affect patients&rsquo; implementation of their treatment regimens and may lead to omitting doses of medication. The aim of this study was to investigate medication implementation adherence in liver and kidney transplant recipients converted from twice-daily, immediate-release tacrolimus to once-daily, prolonged-release tacrolimus. This multicentre, non-interventional, observational, 12-month study evaluated implementation adherence in routine practice at five hospitals in Switzerland. Patients attended four clinical visits: at baseline (pre-conversion), and then at week 2, month 6 and month 12 post-conversion. Implementation was defined as consistently taking medication at the correct time and at the correct dose in order to achieve target tacrolimus trough levels. Implementation adherence was evaluated in three ways: using the Basel Assessment of Adherence to Immunosuppressive Medications Scale (BAASIS) interview questionnaire (at baseline and month 12), investigator-rated patient adherence (recorded at all visits), and tacrolimus trough levels (assessed throughout the study; sub-therapeutic levels were predefined by the investigator on an individual patient basis, over-therapeutic levels were defined as tacrolimus trough levels &gt;15 ng/ml). The primary composite endpoint was non-adherence according to the BAASIS at month 12, any post-conversion investigator adherence rating of &ldquo;poor&rdquo;, or sub-therapeutic or over-therapeutic tacrolimus trough levels at month 6 or 12. Secondary endpoints included: individual components of the composite non-adherence primary endpoint, tacrolimus pill burden, patient satisfaction, and adverse drug reactions. Seventy-five patients received prolonged-release tacrolimus; 68 patients (46 kidney and 22 liver transplant recipients) completed the study. Of these 68 patients, 24 had missing data for at least one component of the primary endpoint; therefore, data for the primary composite endpoint were evaluable for 44 patients. Most (81.8%; 36/44) patients were non-adherent for the composite endpoint. Sub-therapeutic tacrolimus trough levels outside of the predefined therapeutic range were the largest contributor to the composite endpoint, and were detected in 62.0% (31/50) of patients. Overall non-adherence according to the BAASIS was similar pre-conversion (30.7%) and at 12 months post-conversion (28.3%). Investigators rated adherence as &ldquo;poor&rdquo; for two patients. Prolonged-release tacrolimus decreased tacrolimus pill burden in 66.7% of patients. All patients were very satisfied / satisfied with prolonged-release tacrolimus; 75.0% found it easier to remember to take prolonged-release versus immediate-release tacrolimus. Twenty percent of patients reported adverse drug reactions, with infections being the most frequently reported (9.3%). Overall, 1-year non-adherence rates were similar following conversion from immediate-release to prolonged-release tacrolimus; however, prolonged-release tacrolimus intake was more convenient. No new safety signals were detected.