Pharmacokinetic Interactions Between the Fixed-Dose Combination of Ezetimibe/Rosuvastatin 10/20 Mg and the Fixed-Dose Combination of Telmisartan/Amlodipine 80/5 Mg in Healthy Subjects.

Background: Management of hypertension and hyperlipidemia, which are common comorbid risk factors for cardiovascular diseases, require multiple medications. The development of a fixed-dose combination (FDC) containing ezetimibe, rosuvastatin, telmisartan, and amlodipine aims to enhance patient adherence and persistence, but the potential interactions among the four medications have not been studied. This study aimed to evaluate the pharmacokinetic (PK) interactions between the FDC of ezetimibe/rosuvastatin 10/20 mg (ER) and the FDC of telmisartan/amlodipine 80/5 mg (TA). Methods: An open-label, single-sequence, three-period, three-treatment crossover study was conducted in healthy male subjects. All subjects received ER for 7 days, TA for 9 days and ER combined with TA for 7 days during each treatment period. For PK analysis of total/free ezetimibe, rosuvastatin, telmisartan, and amlodipine, serial blood samples were collected for 24 hours at steady state. Safety profiles were assessed throughout the study. Results: Thirty-eight subjects were enrolled, and 34 subjects completed the study. The systemic exposure to each active ingredient after coadministration of the two FDCs was similar to that after each FDC alone. The geometric mean ratios and 90% confidence intervals for the maximum plasma concentration (µg/L) and the area under the plasma concentration-time curve (h·µg/L) of the combination therapy to monotherapy, assessed at steady state, were as follows: total ezetimibe, 1.0264 (0.8765-1.2017) and 0.9359 (0.7847-1.1163); free ezetimibe, 1.5713 (1.2821-1.9257) and 0.9941 (0.8384-1.1788); rosuvastatin, 2.1673 (1.7807-2.6379) and 1.1714 (0.9992-1.3733); telmisartan, 1.0745 (0.8139-1.4186) and 1.1057 (0.8379-1.4591); and amlodipine, 0.9421 (0.8764-1.0126) and 0.9603 (0.8862-1.0405). Both combination therapy and monotherapy were well tolerated by the subjects. Conclusion: The coadministration of ezetimibe/rosuvastatin 10/20 mg and ezetimibe/rosuvastatin 10/20 mg was well tolerated in healthy subjects, and the PK interaction between those two FDCs was not clinically significant.

Development of 3D-printed dual-release fixed-dose combination through double-melt extrusion.

This study aimed to develop a 3D-printed fixed-dose combination tablet featuring differential release of two drugs using double-melt extrusion (DME). The hot-melt extrusion (HME) process was divided into two steps to manufacture a single filament containing the two drugs. In Step I, a sustained-release matrix of acetaminophen (AAP) was obtained through HME at 190 °C using Eudragit® S100, a pH-dependent polymer with a high glass transition temperature. In Step II, a filament containing both sustained-release AAP from Step I and solubilized ibuprofen (IBF) was fabricated via HME at 110 °C using a mixture of hydroxy propyl cellulose (HPC-LF) and Eudragit® EPO, whose glass transition temperatures make them suitable for use in a 3D printer. A filament manufactured using DME was used to produce a cylindrical 3D-printed fixed-dose combination tablet with a diameter and height of 9 mm. To evaluate the release characteristics of the manufactured filament and 3D-printed tablet, dissolution tests were conducted for 10 h under simulated gastrointestinal tract conditions using the pH jump method with the United States Pharmacopeia apparatus II paddle method at 37 ± 0.5 °C and 50 rpm. Dissolution tests confirmed that both the sustained-release and solubilized forms of AAP and IBF within the filament and 3D-printed tablet exhibited distinct drug-release behaviors. The physicochemical properties of the filament and 3D-printed tablet were confirmed by thermogravimetric analysis, differential scanning calorimetry, powder X-ray diffraction, and Fourier-transform infrared spectroscopy. HME transforms crystalline drugs into amorphous forms, demonstrating their physicochemical stability. Scanning electron microscopy and confocal laser scanning microscopy indicated the presence of sustained AAP granules within the filament, confirming that the drugs were independently separated within the filament and 3D-printed tablets. Finally, sustained-release AAP and solubilized IBF were independently incorporated into the filaments using DME technology. Therefore, a dual-release 3D-printed fixed-dose combination was prepared using the proposed filament.

Improvement of corneal epithelial damage after switching from the concomitant use of brinzolamide and brimonidine to a brinzolamide/brimonidine fixed-dose combination.

PURPOSE: To assess the effectiveness of switching from the concomitant use of brinzolamide 1% (BZM) and brimonidine 0.1% (BMD) to a BZM/BMD fixed-dose combination (BBFC) for the reduction of corneal epithelial damage. STUDY DESIGN: Retrospective cohort study. METHODS: This study involved 52 eyes of 52 glaucoma patients (26 women, 26 men; mean age: 67.0 ± 14.0 years) followed for more than 3 months after being switched from concomitant BZM and BMD to BBFC. Superficial punctate keratitis (SPK) was assessed by fluorescein staining according to the National Eye Institute classification, with the cornea divided into 5 areas: center, superior, nasal, temporal, and inferior. SPK density was graded as 0 (no SPK), 1 (separate SPK), 2 (moderately dense SPK), and 3 (high SPK with overlapping lesions). SPK scores and intraocular pressure (IOP) at pre switching to BBFC (pre-BBFC) and at 3-months post switching to BBFC (post-BBFC) were then compared using the Wilcoxon signed-rank test. RESULTS: At pre-BBFC and post-BBFC, respectively, mean IOP was 12.4 ± 2.5 and 12.4 ± 2.7 mmHg, thus illustrating no significant difference in IOP between pre and post switch (p = 0.924), and the mean SPK score for center, superior, nasal, temporal, and inferior was 0.06 ± 0.24, 0.04 ± 0.19, 0.52 ± 0.67, 0.15 ± 0.36, and 0.92 ± 0.74, and 0.04 ± 0.19, 0.02 ± 0.14, 0.37 ± 0.56, 0.04 ± 0.19, and 0.75 ± 0.62, thus clearly showing a significant reduction in SPK scores for the nasal, temporal, and inferior areas at post-BBFC compared to those at pre-BBFC (p < 0.05). CONCLUSION: Our findings reveal that compared with the concomitant use of BZM and BMD, BBFC is effective in reducing corneal epithelial damage.

Corrigendum: Effectiveness of perindopril/amlodipine fixed-dose combination in the treatment of hypertension: a systematic review.

[This corrects the article DOI: 10.3389/fphar.2023.1156655.].

Pill Burden: A Major Barrier to HAART Adherence and Fixed Dose Combinations (FDCS) as its Solution - A Mini-Review.

HIV/ AIDS is a global pandemic and one of the most challenging; With no cure of the disease, various therapies available in form of regimens as Highly Active Anti-Retroviral Therapy (HAART) are the only way to manage the disease. Adherence to HAART is the most vital factor to ensure medication success and virologic suppression. However, adherence is faced with several barriers including adverse effects of Anti-Retroviral Therapy (ART) drugs, complexity of ART, social, cultural factors, and pill burden among others. Fixed Dose Combinations (FDC's) concept has been a well-recognised improvement in pharmacotherapy for treatment of a variety of chronic maladies like hypertension, diabetes, HIV/AIDS, and several FDC products consisting of HIV drugs are approved. This writing reviews the concept of adherence to ART, its barriers while stressing pill burden as a significant one which we suggest would be solved by use Fixed Dose Combinations (FDCs).

Comparison of the efficacy, safety, and tolerability of the FDC of telmisartan + bisoprolol with telmisartan + metoprolol succinate ER combination therapy for stage 1 and stage 2 hypertension: A double-blind, multicentric, phase-III clinical study.

AIM: The present study compared the safety, efficacy, and tolerability of the new fixed-dose combination (FDC) of telmisartan 40 mg + bisoprolol 5 mg (TBP) tablets with the existing comparator FDC telmisartan 40 mg + metoprolol succinate ER 50 mg (TMS) tablets in patients with stage 1 and stage 2 hypertension. METHODOLOGY: The multicentric, double-blind, parallel-group, comparative, prospective, phase-III clinical study involved 264 subjects with stage 1 and stage 2 hypertension from 10 centres across India. The selected subjects were randomized into two groups: group A received the TMS and group B received the new FDC TBP. The primary endpoint was the mean change in seated systolic blood pressure (SeSBP) and seated diastolic blood pressure (SeDBP) from baseline to week 12 in both the control and study arms. The secondary endpoint was achieving the target of SeSBP <140 mmHg and SeDBP <90 mmHg from baseline to week 12 in both groups. Safety and tolerability parameters were evaluated in both groups based on adverse effects (AEs) reported by the patients and the physician. RESULTS: Both treatment groups exhibited a reduction in BP after 2 weeks of treatment, which was sustained until 12 weeks. The mean change in SeSBP and SeDBP at weeks 2, 6, and 12 compared to the previous visit showed statistical significance (p < 0.001) in all cases for both groups A and B. The mean changes in SeSBP and SeDBP from baseline to study end were numerically higher in group B than in group A. The mean difference in SeSBP from baseline to study end was significantly higher in group B compared to group A (p = 0.029). By week 12, 88.28 % and 89.84 % of subjects in group B achieved SeSBP <140 mmHg and SeDBP <90 mmHg respectively, while 86.71 % and 91.40 % of subjects in group A achieved the same targets. Reported AEs were mostly mild to moderate in both treatment groups, and no serious AEs or deaths were reported. Tolerability was rated as 'excellent' by 93.75 % of subjects in group B and 91.40 % of subjects in group A. CONCLUSION: Both the new FDC TBP and the existing comparator TMS combination therapy have comparable efficacy, tolerability, and safety for the management of stage 1 and stage 2 hypertension. TRIAL REGISTRY NAME: Clinical Trials Registry of India (CTRI) TRIAL REGISTRATION NO: CTRI/2021/11/037,926 PROTOCOL NO: MLBTL/05/2021 PROTOCOL URL: https://ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=62069&EncHid=&userName=bisoprolol.

Dexketoprofen Trometamol and Tramadol Hydrochloride Fixed-Dose Combination in Moderate to Severe Acute Low Back Pain: A Phase IV, Randomized, Parallel Group, Placebo, Active-Controlled Study (DANTE).

INTRODUCTION: Dexketoprofen/tramadol 25/75 mg (DKP/TRAM) is a fixed-dose combination of a cyclooxygenase inhibitor and opioid receptor agonist. To better understand the efficacy and safety of DKP/TRAM in the treatment of moderate to severe acute lower back pain (LBP) with or without radiculopathy, we carried out a large explorative phase IV international, multicenter, prospective, randomized, double-blind, parallel group, placebo-controlled study (DANTE). METHODS: A total of 538 patients with or without a history of LBP and experiencing acute LPB of moderate to severe intensity [Numerical Rating Scale-Pain Intensity (NRS-PI) score > 5] were randomized 4:4:1:1 to DKP/TRAM 25/75 mg every 8 h (n = 211), tramadol (TRAM) 100 mg (n = 207), placebo-matched DKP/TRAM (n = 59), or placebo-matched TRAM (n = 61). RESULTS: The proportion of patients achieving the primary endpoint, defined as the time to first achieve NRS-PI score < 4 or pain intensity reduction ≥ 30% from drug intake up to 8 h after the first dose, was higher in the DKP/TRAM arm than in the placebo group, but the difference was not statistically significant (46.1% vs. 42.6%, respectively; hazard ratio 1.11; 95% confidence interval 0.775, 1.595; p = 0.566). DKP/TRAM achieved superiority over TRAM in total pain relief at 4, 6, and 8 h (p < 0.05). Conversely, in relation to the secondary endpoints, a significantly greater reduction in NRS-PI score was seen with DKP/TRAM versus placebo starting from 1 h, and this reduction remained numerically lower throughout 8 h. Summed pain intensity difference values were also significantly lower at 4, 6, and 8 h with DKP/TRAM compared to TRAM (p < 0.05). Overall, DKP/TRAM was well tolerated. CONCLUSION: Although the primary endpoint was not met, secondary efficacy analyses suggest the superiority of DKP/TRAM over placebo and TRAM alone in terms of total pain relief. DKP/TRAM can be considered to be an effective and safe option for the treatment of moderate to severe acute LBP. DANTE STUDY REGISTRATION: EudraCT number: 2019-003656-37; ClinicalTrials.gov Identifier: NCT05170841.

Cost effectiveness analysis of a fixed dose combination pill for primary prevention of cardiovascular disease from an individual participant data meta-analysis.

Background: Cardiovascular disease (CVD) continues to impart a large burden on the global population, especially in lower income countries where affordability limits the use of cardiovascular medicines. A fixed dose combination strategy of at least 2 blood pressure lowering medications and a statin with aspirin in a single pill has been shown to reduce the risk of incident CVD by 38% in primary prevention in a recent meta-analysis. We report the in-trial (median follow-up: 5 years) cost-effectiveness of a fixed dose combination (FDC) pill in different income groups based on data from that meta-analysis. Methods: Countries were categorized using World Bank economic groups: Lower Middle Income Countries (LMIC), Upper Middle Income Countries (UMIC) and High Income Countries (HIC). Country specific costs were obtained for hospitalized events, procedures, and non-study medications (2020 USD). FDC price was based on the cheapest equivalent substitute (CES) for each component. Findings: For the CES-FDC pill versus control the difference in cost was $346 (95% CI: $294-$398) per participant in Lower Middle Income Countries, $838 (95% CI: $781-$895) in Upper Middle Income Countries and $42 (95% CI: -$155 to $239) (cost-neutral) in High Income Countries. During the study period the CES-FDC pill was associated with incremental gain in quality-adjusted life years of 0.06 (95% CI: 0.04-0.08) resulting in an incremental cost-effectiveness ratio (ICER) of $5767 (95% CI: 5735-$5799), $13,937 (95% CI: $13,893-$14,041) and $700 (95% CI: $662-$738) respectively. In subgroups analyses, the highest 10 years CVD risk subgroup had ICERs of $2033, $7322 and -$6000/QALY. Interpretation: A FDC pill produced at CES costs is cost-neutral in HIC. Governments of LMI and UMI countries should assess these results based on the ICER threshold accepted in their own country and own specific health care priorities but should consider prioritizing this strategy for patients with high 10 years CVD risk as a first step. Funding: Population Health Research Institute.

Retrospective Observational Study on Assessing Sitagliptin and Dapagliflozin as a Fixed-Dose Combination in the Indian Population With Type 2 Diabetes Mellitus: The SIDAXA Study.

Introduction Type 2 diabetes mellitus (T2DM), a prevalent chronic metabolic disorder, necessitates multifaceted treatment approaches. Emerging studies highlight the cardiovascular advantages of sodium-glucose transport protein 2 (SGLT2) and dipeptidyl peptidase 4 (DPP-4) inhibitors in T2DM. This investigation delves into the synergistic effects of the fixed-dose combination (FDC) of sitagliptin and dapagliflozin, offering insights into its safety and efficacy for the Indian population. Methods This real-world, retrospective, observational study spanned 328 cases across 111 Indian centres, evaluating the safety, efficacy, and clinical utilization of the sitagliptin and dapagliflozin FDC in T2DM patients after obtaining ethical approval. Assessments at baseline, week four, and week 12 encompassed hemoglobin A1C (HbA1C), fasting plasma glucose (FPG), postprandial blood glucose (PPBG), low-density lipoprotein cholesterol (LDL-C), systolic blood pressure (SBP), diastolic blood pressure (DBP), and weight change. The statistical analysis was done using Statistical Package for Social Sciences (SPSS) version 29.0.1.0(171) (IBM Corp., Armonk, NY, USA) with a significance level p<0.05. Results Study participants [mean age: 51.14±5.55 years, 77.74% (n=255) males, 22.26% (n=73) females] exhibited prevalent risk factors like sedentary lifestyle (n=167, 50.91%) and smoking (n=147, 44.82%). Comorbidities included hypertension (n=235, 71.65%) and dyslipidaemia (n=139, 42.38%). Metformin (n=282, 85.98%) and sulfonylurea (n=134, 40.85%) were commonly prescribed concomitant oral antidiabetic agents (OADs). FDC administration significantly reduced HbA1c by 1.05 ± 0.83% (p < 0.0001) at week 12. FPG and PPBG showed significant reductions of 22.98 ± 22.23 mg/dL (p < 0.0001), 165.50 ± 37.02 mg/dL and 40.94 ± 36.04 mg/dL (p < 0.0001) at four weeks respectively. By week 12, significant reductions were noted in SBP (14.61±13.98mmHg reduction, p-value <0.0001), DBP (7.80±8.45mmHg reduction, p-value <0.0001), and LDL-C levels (18.14±23.95 mg/dL reduction, p-value <0.0001). In patients with established cardiovascular disease, there was reduction in HbA1c levels by 1.02 ± 0.63% after 12 weeks, with FPG decreasing by 54.52 ± 32.67 mg/dL and PPBG decreasing by 88.73 ± 44.90 mg/dL. Treatment-emergent adverse events included headache, changes in micturition, genital mycotic infection, and nausea and diarrhoea which were mild, transient, and necessitated no treatment discontinuation. Conclusion The FDC of sitagliptin and dapagliflozin significantly improved glycaemic control and lipid profiles in T2DM patients, particularly those with coronary artery disease. It demonstrated a favourable safety profile in the Indian population, signifying its potential as an effective and well-tolerated therapeutic option in patients with established cardiovascular disease.

Real-World Assessment of Personalized Approach With Voglibose Fixed-Dose Combination in Type 2 Diabetes Mellitus.

BACKGROUND: Post-prandial hyperglycemia (PPHG) remains a complex aspect in the management of type 2 diabetes mellitus (T2DM) in the Indian population due to uncertainty in the optimal utilization of alpha-glucosidase inhibitors (AGIs) either as standalone therapy or in combination, whether initiated initially or as a sequential therapy. METHODS: This was a post-approval, observational, multicentric clinical study conducted at 50 centers according to principles of the International Council for Harmonisation of Technical Requirements of Pharmaceuticals for Human Use Guideline for Good Clinical Practice (ICH-GCP) and Declaration of Helsinki and local ethics approval. Descriptive and analytical statistics were applied for conclusion and categorical variables using SPSS version 29.0.1.0 (171) (Armonk, NY: IBM Corp.). RESULTS: Protocol analyses of 515 cases revealed baseline demographics as follows: age 57.35±10.04 years, weight 72.86±10.92 kg, and BMI 28.33±6.07 kg/m2. Comorbidities included hypertension (N=169, 32.82%), thyroid disorders (N=99, 19.22%), and heart failure (N=92, 17.86%). Concomitant oral antidiabetics (OADs) prescribed as DPP4i (9.50%), SGLT2i (19.20%), and DPP4i+SGLT2i (7.20%). Study drug reduced glycosylated hemoglobin (HbA1c) by 13.77% (1.25% mean change, p<0.01), fasting blood glucose (FBG) by 23.69% (44.61 mg/dL mean change, p<0.01), post-prandial blood glucose (PPBG) by 24.57% (70.46 mg/dL mean change, p<0.01), and body weight by 4.43% (3.21 kg mean change, p<0.01) over 12 weeks. A total of 161 patients accomplished targeted PPBG of <180 mg/dL (119.13 mg/dL mean change, p<0.01). Regression analysis considering PPBG and HbA1c ≤7.5% showed a weak correlation between them (R-value=0.13, R-squared value=0.02), whereas between PPBG and HbA1c ≤9% yielded moderate positive correlation (R-value=0.53, R-squared value=0.28). There were no adverse events reported or analyzed during the observation period. CONCLUSION: Voglibose fixed-dose combination (FDC) demonstrates significant effectiveness at the initial dosage when started early in the management of T2DM and high PPBG levels. Moreover, it exhibits good tolerability, thereby contributing to higher compliance among Indian patients who consume a high-carbohydrate diet.

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.

Pharmacokinetic Comparison of a Fixed-Dose Combination of Candesartan Cilexetil/Amlodipine/Atorvastatin Versus Co-administration of Individual Formulations in Healthy Participants.

INTRODUCTION: Fixed-dose combinations (FDCs) of angiotensin II receptor blockers, calcium channel blockers, and statins are conventional therapeutic interventions prescribed for cardiovascular diseases. This study aimed at drawing a comparison between the pharmacokinetics and safety of an FDC and the corresponding individual formulations in healthy subjects. METHODS: A randomized, open-label, single-dose, three-sequence, three-period, partially repeated crossover study was conducted with a cohort of healthy volunteers. A 14-day washout period was maintained between each of the three periods. In this study, candesartan cilexetil, amlodipine, and atorvastatin was administered orally as FDCs of 16/10/40 mg in study 1 and 16/5/20 mg in study 2. The maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) of candesartan, amlodipine, and atorvastatin were estimated as the geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of the FDC to individual formulations. If the within-subject coefficient of variation (CVwr) of Cmax was greater than 0.3, the bioequivalence (BE) range calculated using the reference-scaled average bioequivalence was used to assess whether the 90% CI was within the BE range. RESULTS: The GMRs (90% CIs) for the AUClast for candesartan and amlodipine were 0.9612 (0.9158-1.0089)/0.9965 (0.9550-1.0397) and 1.0033 (0.9800-1.0271)/1.0067 (0.9798-1.0344), and the GMRs (90% CIs) for Cmax were 0.9600 (0.8953-1.0294)/0.9851 (0.9368-1.0359) and 1.0198 (0.9950-1.0453)/1.0003 (0.9694-1.0321) in studies 1 and 2, respectively. The extended BE ranges calculated from the CVwr of the Cmax of atorvastatin were 0.7814-1.2797 and 0.7415-1.3485, respectively. The GMRs (90% CIs) for the AUClast of atorvastatin were 1.0532 (1.0082-1.1003)/1.0252 (0.9841-1.0680), and the GMRs (90% CIs) for Cmax were 1.0630 (0.9418-1.1997)/0.9888 (0.8792-1.1120) in studies 1 and 2, respectively. CONCLUSION: The Cmax and AUClast values of candesartan cilexetil/amlodipine/atorvastatin 16/10/40 mg and 16/5/20 mg, respectively, were within the BE ranges. There were no clinically significant differences in safety between the two formulations. TRIAL REGISTRATION: ClinicalTrials.gov identifier, study 1: NCT04478097; study 2: NCT04627207.

Effectiveness of calcipotriol/betamethasone dipropionate aerosol foam in patients with small versus large plaque psoriasis in routine practice in South Korea.

Small plaque psoriasis is the typical form of chronic plaque psoriasis affecting adults in South Korea. The effectiveness of calcipotriol/betamethasone dipropionate (Cal/BD) aerosol foam for large and small psoriasis plaques has not previously been examined. We performed a post hoc analysis of a recent, 4-week observational study of Cal/BD aerosol foam use in routine clinical practice in South Korea. Investigator Global Assessment response ([IGA] 0/1 at week 4), Patient Global Assessment response ([PaGA] 0/1 at week 4), change in Psoriasis Area and Severity Index (PASI), changes in psoriasis symptom scores, change in the Dermatology Life Quality Index (DLQI), and the proportion of patients achieving DLQI ≤5 were analyzed for patients with small (≤5 cm; n = 131) or large (>5 cm; n = 35) baseline plaque size. IGA response rates were similar for patients with small and large plaques (59.5% and 51.4% respectively). Similarly, there was no significant difference between the small and large groups in mean change in PASI (-2.20 vs -3.34), the proportions of patients with DLQI ≤5 (62.3% vs 54.3%) or PaGA 0/1 (29.2% vs 40.0%). Mean improvements in DLQI (-4.04 vs -6.20) and in psoriasis symptoms including itching (-1.50 vs -2.83), sleep loss (-0.67 vs -1.89), dryness (-1.57 vs -2.97), scaling (-1.21 vs -3.57), and redness (-1.17 vs -3.11) were greater in patients with large plaques than those with small plaques. Itching and DLQI differences were not statistically significant after adjustment for baseline characteristics. Stratification by body surface area affected eliminated statistically significant differences between the groups for most outcomes. In conclusion, this analysis suggests that Cal/BD aerosol foam is an effective, well-accepted treatment for adult patients with the small plaques typical of chronic plaque psoriasis in South Korea, as well as for those with large plaques.

Assessment of swallowability and acceptability of scored darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) fixed-dose combination (FDC) tablets in HIV-1-infected children aged ≥6 to <12 years, using matching placebo tablets: A randomized study.

BACKGROUND: Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) fixed-dose combination (FDC) was developed as a once-daily, complete antiretroviral (ARV) regimen therapy to address the need for simplified protease inhibitor-based ARV regimens. This study assessed the swallowability and acceptability for long-term use of scored placebo tablets matching the D/C/F/TAF FDC tablets in children living with HIV-1. METHODS: This study (NCT04006704) was a Phase 1, open-label, randomized, single-dose, 2-period, 2-sequence crossover study in children living with HIV-1, aged ≥6 to <12 years and weighing ≥25 to <40 kg, on a stable ARV regimen for ≥3 months. Participants were asked to swallow whole (size, 21 × 11 × 7 mm) and split matching placebo D/C/F/TAF tablets. Swallowability of the matching placebo D/C/F/TAF tablets (primary endpoint) was assessed by observers. Acceptability of taking matching placebo D/C/F/TAF tablets and current ARVs was evaluated by participants using a 3-point questionnaire. Participants rated the acceptability for long-term daily use of the placebo D/C/F/TAF tablets, and observers assessed how easily caregivers could split a scored tablet by hand, using 3-point questionnaires. RESULTS: Among the 24 participants who enrolled and completed the study, 95.8% (23/24) were able to swallow the whole and split matching placebo D/C/F/TAF tablets after 1 or 2 attempts. Most participants (>70%) rated the acceptability of tablets for long-term daily use as acceptable or good to take. Breaking the tablets was considered easy or OK by 79.2% (19/24) of caregivers. CONCLUSION: Scored D/C/F/TAF FDC tablets are swallowable - with whole favoured over split - and considered at least acceptable for long-term daily intake in children living with HIV-1 aged ≥6 to <12 years. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04006704.

Mapping Advantages and Challenges in Analytical Development for Fixed Dose Combination Products, a Review.

Formulations containing more than one active ingredient are increasingly gaining popularity due to advantages with regard to patient convenience as well as reduced cost of production, packaging, and transportation. Such fixed-dose combinations (FDCs) demand for enhanced analytical methodologies and tools to efficiently achieve quality control of these complex products as compared to the conventional products containing only one active constituent. Highly efficient analytical methods can measure multiple constituents at once, improving their quality control. This review article discusses the challenges in the development of such methods due to the similarities or differences in the chemical identity of the participating drug molecules in an FDC. The latest developments in multiple analyte determination using various analytical techniques (HPLC, LC-MS, NMR, IR, powder XRD and DSC) are discussed, with a focus on special considerations in each case. The article discusses challenges with sample preparation of complex FDC products, and the use of Chemometrics and Quality by Design to develop efficient analytical methods. Lastly, an equation-based approach is proposed and demonstrated to arrive at a parameter referred to as "percentage efficiency gain" that would be useful in directly accessing the relevance and commercial benefits of a simultaneous method vis-a-vis separate methods for individual components.

A Comparative Analysis of the Efficacy and Safety of Nimesulide/Paracetamol Fixed-Dose Combination With Other NSAIDs in Acute Pain Management: A Randomized, Prospective, Multicenter, Active-Controlled Study (the SAFE-2 Study).

Objective In this study, we aimed to compare the efficacy and safety of the fixed-dose combination (FDC) of nimesulide (100 mg) + paracetamol (325 mg) [NP], ketorolac (10 mg) [Kt] alone, diclofenac (50 mg) + paracetamol (325 mg) [DP], and aceclofenac (100 mg) + paracetamol (325 mg) [AP] in patients with acute painful conditions. Methods This was a randomized, prospective, open-label, multicentre, active-controlled study involving patients aged ≥18 years, with acute painful conditions like low back pain, acute musculoskeletal disorders, and trauma such as tendinitis, tenosynovitis, bursitis, sprains and strains, migraine, dental pain, painful dental procedures, and post-surgical pain. Reduction in pain intensity and liver, renal, gastrointestinal, and cardiovascular safety were assessed on days seven and 14. Results A total of 600 patients were randomized into NP, Kt, DP, and AP groups in a 1:1:1:1 ratio. NP, DP, and AP were administered twice a day while Kt was given three times a day. The reduction of pain as measured by the numerical rating scale (NRS) scores at the end of day seven was 3.75 ± 1.58 in the NP group, 2.96 ± 1.18 in the Kt group, 3.42 ± 1.42 in the DP group, and 3.47 ± 1.30 in the AP group. The pain reduction in the NP group was significantly greater (p<0.001) as compared to the Kt group and non-inferior to the DP and AP groups on days seven and 14. Non-inferiority was concluded between the NP, DP, and AP groups as the lower limit of 95% CI of the difference in the change of pain intensity on both days seven and 14 was above the predefined margin of -1.0. All the drugs were well tolerated, but a significantly greater number of adverse events were reported in the DP group (32) as compared to the NP group (14) (p<0.05). The most common adverse events reported during the study were nausea, gastritis, and abdominal pain in all four groups. There was no significant alteration in liver and renal function tests except a rise in serum creatinine in the DP group. Conclusions The FDC of nimesulide with paracetamol is superior to ketorolac and non-inferior to the FDC of diclofenac with paracetamol and aceclofenac with paracetamol in the management of pain in patients with acute painful conditions. The tolerability profile of the FDC of nimesulide with paracetamol is similar to that of ketorolac but better than diclofenac with paracetamol and aceclofenac with paracetamol combinations.

Bioequivalence and the food effect of macitentan/tadalafil 10/20 fixed-dose combination tablets versus the use of single-component tablets in healthy subjects.

The primary aim was to demonstrate bioequivalence between the 10/20 mg fixed-dose combination (FDC) of macitentan/tadalafil in a single tablet and the free combination of both drugs, and to evaluate the food effect on the 10/20 mg FDC in healthy participants. In this single-center, randomized, open-label, 3-way crossover, single-dose Phase 1 study in healthy adult participants, macitentan/tadalafil was administered as a 10/20 mg FDC formulation and compared with the free combination of macitentan and tadalafil. The food effect on the FDC was also evaluated. Pharmacokinetic sampling (216 h) was conducted. The 90% confidence intervals (CIs) for the geometric mean ratios of maximum observed plasma analyte concentration (Cmax) and area under the plasma analyte concentration-time curves (AUCs) for Treatment A (FDC, fasted) versus C (free combination, fasted) were within bioequivalence limits demonstrating that the FDC formulation can be considered bioequivalent to the free combination. The 90% CIs for the geometric mean ratios of Cmax and AUC for Treatment B (FDC, fed) versus A (FDC, fasted) were contained within bioequivalence limits demonstrating that there was no food effect. The administration of the 10/20 mg FDC was generally safe and well tolerated in healthy participants. This study demonstrated bioequivalence between the FDC of macitentan/tadalafil (10/20 mg) in a single tablet and the free combination of both drugs in healthy participants, and that the FDC can be taken without regard to food, similarly to the individual components. The FDC was generally safe and well tolerated.

Drug Use Evaluation of Tenofovir/Lamivudine/Dolutegravir (TLD) Fixed-Dose Combination for Initiation and Transition Among HIV-Infected Individuals Attending Lumame Primary Hospital, North West Ethiopia.

Background: A key strategy for quality improvement is drug use evaluation, which looks at the safe, appropriate use of medication principles. Tenofovir/Lamivudine/Dolutegravir (TLD-FDC) usage has not yet been sufficiently examined in published literature. The purpose of this study was to assess how TLD were used by HIV-positive patients Using WHO drug use evaluation standards in Lumame Primary Hospital, North West Ethiopia. Methods: Using WHO drug use evaluation standards, a retrospective study design was used to evaluate the appropriateness of TLD use. Systematic random sampling was utilized to gather patient medical records containing TLD. Accordingly, 100 records that met the inclusion criteria were selected and reviewed between April 1 and 15, 2021. Five criteria, namely, indication, dose, contraindication, drug interaction, and TLD safety monitoring were used to evaluate the appropriateness of TLD utilization. Results: 80% of patients were transited to TLD from other regimens. The median time on TLD was found to be 13 months with 9 months to 18 months IQR. The latest CD4 count as well as CD4 count at the initiation or transition of TLD was not done for 75% and 89% of the patients, respectively. 3/4 (75%) of the patients were found to have a scheduled medication refill history. TLD dosing, indications, and contraindications were found to be 100% appropriate. No, TLD safety monitoring tests were done for 21% of the patients in this study. However, viral load, liver/kidney function, and serum creatinine tests were done for 77% (95% CI: 74%-79%), 5% (95% CI: 2%-8%), and 14% (95% CI: 11%-17%) of the patients, respectively. More over, In 93% (95% CI: 91%-95%) of the patients, the TLD interaction was appropriate; in 7%, it was not. All recording, documenting, and reporting technologies were available and used efficiently, except for the Electronic Dispensing Tool. Conclusion: Generally, good adherence to national and WHO guidelines was obtained regarding dose, indication, and contraindications. However, improvement in safety monitoring tests and CPT utilization is recommended. Drug interactions satisfied the majority of the criteria's threshold, while certain standards were not followed.

Clinical Benefit of Fixed-Dose Combination of Amlodipine and Potent Atorvastatin in Patients With Concomitant Hypertension and Hypercholesterolemia.

BACKGROUND: Hypertension and hypercholesterolemia are important risk factors for cardiovascular disease, and treatment with fixed-dose combination (FDC) regimens is recommended by current guidelines. However, the clinical outcomes of different FDC dosages remain unknown. This study aimed to examine the clinical outcomes of FDC regimens and the free combination of amlodipine and atorvastatin at different dosages. METHODS AND RESULTS: Patients with concurrent hypertension and hypercholesterolemia treated daily with an FDC of 5 mg amlodipine and 10 mg atorvastatin (5/10 fixed group), and FDC of 5 mg amlodipine and 20 mg atorvastatin (5/20 fixed group), or free combination of 5 mg amlodipine and 20 mg atorvastatin (5/20 free group) were identified from the National Health Insurance Research Database of Taiwan. The primary outcome was the composite cardiovascular outcomes, including cardiovascular death, acute myocardial infarction, stroke, and coronary intervention. A total of 9095 patients were eligible for inclusion. The incidence of primary outcome per 1000 person-years was 16.6 in the 5/10 fixed group, 12.6 in the 5/20 fixed group, and 16.5 in the 5/20 free group (5/20 fixed versus 5/20 free: hazard ratio [HR], 0.76 [95% CI, 0.64-0.91]; 5/20 fixed versus 5/10 fixed: HR, 0.76 [95% CI, 0.63-0.90]). CONCLUSIONS: Among patients with concomitant hypertension and hypercholesterolemia, treatment with an FDC of amlodipine and high-dose atorvastatin led to a lower risk of a composite of cardiovascular outcomes than treatment with the free combination or a similar FDC with a lower dose of atorvastatin.

Highly sensitive liquid chromatography-mass spectrometry method for the quantitative analysis of mometasone furoate in human plasma: Method validation and application to clinical pharmacokinetic studies.

We report the development and the validation of a sensitive liquid chromatography-mass spectrometry (LC-MS/MS) method for mometasone furoate (MF) analysis in human plasma. Plasma samples were processed through liquid-liquid extraction and analyzed using LC-MS/MS operating in positive mode using multiple reaction monitoring of transitions m/z 520.9 â†’ 355.0 and m/z 525.8 â†’ 355.0 for MF and the internal standard (IS), respectively. Separation was achieved at 1.0 mL/min on a C18 column using a gradient elution of mobile phase of 0.05% ammonia in water (phase A) and acetonitrile (phase B). The assay range was 0.250-100 pg/mL and proved to be accurate and precise MF. Normalized recoveries were consistent and reproducible with a coefficient of variation (CV%) value of 6.0. The CV (%) of the IS normalized matrix factor was not observed in normal, lipemic, and hemolyzed plasmas. Dilutions of 1:10 were accurately quantified. A cycle of three freeze and thaw and stabilities at room temperature and on the autosampler were demonstrated. In addition, MF in the presence of indacaterol and glycopyrronium was proven to be stable at -70°C for at least 157 days. The present method was successfully applied to quantify MF in patients receiving MF, indacaterol, and glycopyrronium as a fixed-dose combination.