Population pharmacokinetic modeling of dolutegravir/lamivudine to support a once-daily fixed-dose combination regimen in virologically suppressed adults living with HIV-1.

A fixed-dose combination (FDC) of 50 mg dolutegravir and 300 mg lamivudine is indicated for the treatment of HIV-1 infection. This analysis aimed to characterize the population pharmacokinetics (PK) of dolutegravir and lamivudine based on data from a phase 3 study (TANGO) in virologically suppressed adults living with HIV-1 switching to dolutegravir/lamivudine FDC. These analyses included 362 participants who contributed 2,629 dolutegravir and 2,611 lamivudine samples collected over 48 weeks. A one-compartment model with first-order absorption and elimination parameterized by apparent oral clearance (CL/F), apparent volume of distribution (V/F), and absorption rate constant (Ka) described dolutegravir PK. Covariate search yielded body weight, bilirubin, and ethnicity as predictors of CL/F, and weight was predictive for V/F. The estimates of CL/F, V/F, and Ka were 0.858 L/h, 16.7 L, and 2.15 h-1, respectively. A two-compartment model with first-order absorption and elimination parameterized by CL/F, apparent intercompartmental clearance (Q/F), apparent central volume of distribution (V2/F), apparent peripheral volume of distribution (V3/F), and Ka described lamivudine PK. Covariate search yielded eGFR and race as predictors of CL/F, and weight was predictive for V2/F. The estimated parameter values were CL/F = 19.6 L/h, Q/F = 2.97 L/h, V2/F = V3/F = 105 L, and Ka = 2.30 h-1. The steady-state prediction suggested that the effect of covariates dolutegravir and lamivudine exposures was small (<20%) and not clinically relevant. Therefore, no dose adjustments are recommended based on these analyses. The results support the use of dolutegravir/lamivudine FDC in the treatment of HIV-1 infection in adults.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT03446573.

Long-term intraocular pressure-lowering efficacy and safety of ripasudil-brimonidine fixed-dose combination for glaucoma and ocular hypertension: a multicentre, open-label, phase 3 study.

PURPOSE: To evaluate the long-term efficacy and safety of ripasudil-brimonidine fixed-dose combination (RBFC), a new intraocular pressure (IOP)-lowering medication for glaucoma and ocular hypertension (OHT). METHODS: This prospective, multicentre (23 sites in Japan), open-label study enrolled patients with primary open-angle glaucoma (POAG), OHT or exfoliative glaucoma and assigned them to one of four combination therapy cohorts, based on previous treatment(s) received: prostaglandin (PG) analogue (Cohort 1); PG analogue and beta-adrenoceptor blocker (ß-blocker) (Cohort 2); PG analogue, ß-blocker and carbonic anhydrase inhibitor (Cohort 3); or other/no treatment (Cohort 4). After a ≥ 4-week screening period, eligible patients received twice-daily RBFC for 52 weeks in addition to the treatments they were already receiving. Efficacy was assessed by change in IOP from baseline through week 52. Adverse events and adverse drug reactions (ADRs) were monitored throughout. RESULTS: In total, 179 patients from Cohort 1 (n = 48), Cohort 2 (n = 44), Cohort 3 (n = 41) and Cohort 4 (n = 46) entered the RBFC treatment period. For all cohorts, mean IOP was significantly reduced at 11:00 (2 h after instillation of RBFC) through week 52 with the changes from baseline at week 52 of - 2.7 to - 4.1 mmHg across cohorts; all p < 0.001. Common ADRs were conjunctival hyperaemia (58%), allergic conjunctivitis (18%) and blepharitis (17%), most of which were mild in severity. CONCLUSION: These data demonstrated the long-term efficacy and safety of RBFC, both alone and in combination with other anti-glaucoma agents. RBFC may offer a new treatment option for the long-term management of glaucoma and OHT. TRIAL REGISTRATION: Japan Registry of Clinical Trials Identifier: jRCT2080225063. DATE OF REGISTRATION: 17 February 2020.

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.

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.

Efficacy and safety of fixed-dose combination of Bilastine-Montelukast in adult patients with allergic rhinitis: a phase III, randomized, multi-center, double-blind, active controlled clinical study.

BACKGROUND: Histamine and cysteinyl leukotrienes (CysLTs) are potent inflammatory mediators in allergic rhinitis (AR). Studies involving other combinations of antihistaminics (Levocetirizine) and highly selective leukotriene receptor antagonist (LTA) (Montelukast) combination have shown additive benefits and are widely prescribed for AR. OBJECTIVE: Evaluate the efficacy and safety of Bilastine 20 mg and Montelukast 10 mg fixed-dose combination (FDC) therapy in patients with AR. METHODS: A randomized, double-blind, comparative, parallel, phase III study was conducted to evaluate efficacy and safety of Bilastine 20 mg and Montelukast 10 mg FDC at 16 tertiary care otolaryngology centres in India. Adult patients with AR for one year with IgE antibody positive and 12-h NSS score >36 in 3 days were randomized to receive either Bilastine 20 mg and Montelukast 10 mg or Montelukast 10 mg & Levocetirizine 5 mg tablets for 4 weeks. The change in total symptom score (nasal symptom scores (NSS) & non-nasal symptom scores (NNSS)) from baseline to week 4 was assessed as primary endpoint. Secondary endpoints included changes in TSS, NSS, NNSS, individual symptom scores (ISS), Rhinoconjunctivitis Quality of Life (RQLQ), discomfort due to rhinitis (VAS), and clinical global impression (CGI) scores. RESULTS: The change in mean TSS from baseline to week 4 in Test group (16.6 units) was comparable to reference group (17 units) (p= 0.8876). The difference in change in mean NSS, NNSS and ISS from baseline to day 7, 14, 28 were comparable. RQLQ improved from baseline to Day 28. Significant improvements were observed in discomfort due to AR measured by VAS and CGI scores from baseline to day 14 and 28. The safety and tolerability of patients were comparable between the groups. All adverse events (AEs) were mild to moderate in severity. No patient discontinued due to AEs. CONCLUSIONS: The FDC of Bilastine 20 mg and Montelukast 10 mg was efficacious and well tolerated in Indian patients with AR.

The effectiveness and tolerability of fixed-dose combination netarsudil 0.02%/latanoprost 0.005% at a tertiary glaucoma center.

PURPOSE: To assess real-world effectiveness and tolerability of fixed-dose combination netarsudil 0.02%/latanoprost 0.005% (FCNL) in management of glaucoma patients in a tertiary eye care center. METHODS: This retrospective cohort study included glaucoma patients initiated on FCNL from January 2018 to July 2021 with at least 1-month follow-up. Demographic and clinical data were collected at baseline and at follow-up visits through 12 months. Patient-solicited side effects were recorded at each visit. Maximum glaucoma pharmacotherapy was defined as surgery/laser being the next treatment option following an intensive pharmacotherapy regimen, or when pharmacotherapy could not be increased due to allergy/intolerance or all pharmacologic mechanisms already being in use. RESULTS: Seventy-nine eyes of 47 patients were included. Mean age was 67.7 ± 14.7 years. Baseline IOP was 18.7 ± 4.9 mmHg; mean change in IOP (∆IOP) each study visit compared to baseline ranged from - 1.6 ± 3.5 to - 4.4 ± 4.1 mmHg (all p < 0.05). The eyes on maximum glaucoma pharmacotherapy (73.4%) had similar ∆IOP compared to those on non-maximal therapy at each visit (p > 0.2 for all). Forty-three (54.4%) eyes were switched from a prostaglandin analog alone, producing a 1-month IOP reduction of - 4.7 ± 3.9 mmHg at 1 month which remained significant at each visit for the 12-month study period (all p < 0.05). Across all study visits, conjunctival hyperemia was documented in 26 (32.9%) eyes. Subjective blurry vision was reported in 22 (27.8%) eyes without significant worsening of visual acuity at any visit (all p > 0.05). Six (7.6%) and 7 (8.9%) eyes required further medical or surgical/laser intervention, respectively. Kaplan-Meier analysis revealed no significant difference in the need for subsequent medical or surgical intervention between those on maximum and non-maximal pharmacotherapy (p > 0.4). CONCLUSION: FCNL was well-tolerated and demonstrated a significant and sustained reduction in IOP, even as last-line therapy before incisional or laser surgery in those on maximum glaucoma pharmacotherapy. FCNL is a viable treatment option for glaucomatous eyes before consideration of surgical intervention.

The Indian registry on current patient profiles & treatment trends in hypertension (RECORD): One year interim analysis.

Background & objectives: In India, hypertension constitutes a significant health burden. This observational, non-interventional, prospective study was conducted in five centres across India to evaluate the current clinical practices for the management of hypertension. Methods: Participants were enrolled if they were newly diagnosed with essential hypertension or had pre-existing hypertension and were on the same therapeutic plan for the previous three months. At baseline, three months, six months, and one year, information on the patient and their treatment regimen was documented, and their quality of life (QoL) was evaluated. Results: A total of 2000 individuals were enrolled in this study, with a mean age of 54.45 yr. Of these, 55.7 per cent (n=1114) were males, and 957 (47.85%) were newly diagnosed with hypertension, while 1043 (52.15%) had pre-existing hypertension. Stage 2 hypertension (systolic blood pressure (BP) >140 or diastolic BP ≥90 mmHg) accounted for more than 70 per cent of the participants (70.76% of pre-existing and 76.29% of newly diagnosed); the average duration of pre-existing hypertension was 68.72 months. Diabetes (31.6%) and dyslipidaemia (15.8%) were the most common comorbidities. In 43.3 per cent of the participants, monotherapy was used, and in 56.7 per cent (70.55% fixed-dose combination), combination therapy was used. Telmisartan (31.6%), amlodipine (35.2%), and a combination of the two (27.1%) were the most commonly prescribed treatment regimens. At three months, six months, and one year, treatment modifications were observed in 1.4, 1.05, and 0.23 per cent of the participants receiving monotherapy and 2.74, 4.78 and 0.35 per cent receiving combination therapy, respectively. In both groups, the proportion of individuals with controlled hypertension (≤140/90 mmHg) increased by more than 30 per cent after a year. At one year, physical and emotional role functioning, social functioning, and health improved considerably. Interpretation & conclusions: Combination therapy for hypertension is increasingly preferred at the time of initial diagnosis. The efficacy, safety, and tolerance of the recommended medications were reflected by improvements in the QoL and the minimal changes in the therapeutic strategy required.

Polypill and Combination Therapy: Blood Pressure and Cardiovascular Risk Reduction.

PURPOSE OF REVIEW: The number of medications prescribed to patients has been progressively increasing, primarily driven by cardioprotective medications. The advent of pharmaceutical 3D printing technology holds the promise of reducing the burden of multiple pills by combining various medications with different release mechanisms into a single tablet. This development encourages a comprehensive review of the evidence supporting the use of combination pills. RECENT FINDINGS: Recent randomized studies have shown higher BP control rates in quadpill groups than in monotherapy groups and improved 6-month BP control rates with a low-dose triple fixed-dose combination (FDC) medication compared to usual care. Recent randomized controlled trials also support FDC use for primary and secondary prevention of cardiovascular disease. Three-dimensional printing technologies such as powder-based (PB) 3D printing, fused deposition modeling (FDM) 3D printing, and semisolid extrusion (EXT) 3D printing are examples of promising technologies that could be utilized to combine multiple medications with different release mechanisms into a single tablet. FDC therapy can provide patients with combination regimens with a reduced pill burden, which promotes improved adherence and efficacy. Recent randomized trials have shown that FDC can be used for primary and secondary prevention of cardiovascular disease with no significant difference in adverse events. Multidisciplinary approaches should be implemented to enhance long-term adherence, and further research on establishing affordable and effective initial dual antihypertensive therapy options is necessary. Pharmaceutical 3D printing technology may play an important role in enhancing the flexibility, affordability, and feasibility of clinical FDC utilization.

Masking the Taste of Fixed-Dose Combination Drugs: Particular NSAIDs Can Efficiently Mask the Bitterness of Famotidine.

This study aimed to evaluate the bitterness of famotidine (FAM) combined with each of three non-steroidal anti-inflammatory drugs (NSAIDs): ibuprofen (IBU), flurbiprofen (FLU), and naproxen (NAP), which have potential as fixed-dose combination (FDC) drugs. We evaluated the bitterness of FAM and each NSAID by taste sensor AN0 and C00, respectively. FAM showed high sensor output representing sensitivity to bitterness, whereas three NSAIDs did not show large sensor output, suggesting that the bitterness intensities of three NSAIDs were lower than that of FAM. The bitterness of FAM on sensor AN0 was suppressed in a concentration-dependent manner when mixed with IBU, FLU, or NAP. Among three NSAIDs, IBU most effectively inhibited bitterness on sensor output, and the gustatory sensation test confirmed that adding IBU to FAM reduced the bitterness of FAM in a concentration-dependent manner. MarvinSketch confirmed that the drugs were mostly present in an ionic solution when FAM was mixed with NSAIDs. The 1H-NMR spectroscopy analysis also revealed the presence of electrostatic interactions between FAM and NSAIDs, suggesting that the electrostatic interaction between FAM and NSAIDs might inhibit the adsorption of FAM on the bitter taste sensor membrane, thereby masking the bitter taste.

Development and Characterization of Different Dosage Forms of Nifedipine/Indomethacin Fixed-Dose Combinations.

Studies have shown that 40 individuals out of 100,000 are diagnosed with rheumatoid arthritis (RA) yearly, with a total of 1.3 million in the United States. Furthermore, the impact of RA in some cases can extend to cardiovascular diseases (CVD), as the studies showed that 84% of RA patients are at risk of developing hypertension. This study aims to design and develop different dosage forms (capsule-in-capsule and three-dimensional (3D) printed tablet) of nifedipine/indomethacin fixed-dose combination (FDC). The hot-melt extrusion (HME) was utilized alone and with fused deposition modeling (FDM) techniques The developed dosage forms were intended to provide delayed-extended and immediate release profiles for indomethacin and nifedipine, respectively. FDC dosage forms were successfully developed and characterized. Nifedipine formulations showed significant improvement in release profiles, having 94% of the drug release at 30 minutes compared with pure nifedipine, which had a percent release of 2%. Furthermore, the release of indomethacin was successfully delayed at a pH of 1.2 and extended at a pH of 6.8. Differential scanning calorimetry results showed endothermic crystalline peaks at 165 °C and 176 °C for indomethacin and nifedipine, respectively. Moreover, the thermal analysis of all formulations showed the absence of the endothermic peaks indicating complete solubilization of indomethacin and nifedipine in the polymeric carriers. All formulations had post-processing drug content in the range of 95% to 98%. Moreover, results from the stability study showed that all formulations were able to remain chemically and physically stable with no signs of recrystallization or degradation. The designed FDC dosage forms could improve the quality of life by enhancing patient compliance and preventing the need for polypharmacy.

Optimizing Dosing and Fixed-Dose Combinations of Rifampicin, Isoniazid, and Pyrazinamide in Pediatric Patients With Tuberculosis: A Prospective Population Pharmacokinetic Study.

BACKGROUND: In 2010, the World Health Organization (WHO) revised dosing guidelines for treatment of childhood tuberculosis. Our aim was to investigate first-line antituberculosis drug exposures under these guidelines, explore dose optimization using the current dispersible fixed-dose combination (FDC) tablet of rifampicin/isoniazid/pyrazinamide; 75/50/150 mg, and suggest a new FDC with revised weight bands. METHODS: Children with drug-susceptible tuberculosis in Malawi and South Africa underwent pharmacokinetic sampling while receiving first-line tuberculosis drugs as single formulations according the 2010 WHO recommended doses. Nonlinear mixed-effects modeling and simulation was used to design the optimal FDC and weight-band dosing strategy for achieving the pharmacokinetic targets based on literature-derived adult AUC0-24h for rifampicin (38.7-72.9), isoniazid (11.6-26.3), and pyrazinamide (233-429 mg ∙ h/L). RESULTS: In total, 180 children (42% female; 13.9% living with human immunodeficiency virus [HIV]; median [range] age 1.9 [0.22-12] years; weight 10.7 [3.20-28.8] kg) were administered 1, 2, 3, or 4 FDC tablets (rifampicin/isoniazid/pyrazinamide 75/50/150 mg) daily for 4-8, 8-12, 12-16, and 16-25 kg weight bands, respectively. Rifampicin exposure (for weight and age) was up to 50% lower than in adults. Increasing the tablet number resulted in adequate rifampicin but relatively high isoniazid and pyrazinamide exposures. Administering 1, 2, 3, or 4 optimized FDC tablets (rifampicin/isoniazid/pyrazinamide 120/35/130 mg) to children < 6, 6-13, 13-20. and 20-25 kg, and 0.5 tablet in < 3-month-olds with immature metabolism, improved exposures to all 3 drugs. CONCLUSIONS: Current pediatric FDC doses resulted in low rifampicin exposures. Optimal dosing of all drugs cannot be achieved with the current FDCs. We propose a new FDC formulation and revised weight bands.

One Pill, Once a Day: Simplified Treatment Regimens and Retention in HIV Care.

Simplified drug regimens may improve retention in care for persons with chronic diseases. In April 2013, South Africa adopted a once-daily single-pill human immunodeficiency virus (HIV) treatment regimen as the standard of care, replacing a multiple-pill regimen. Because the regimens had similar biological efficacy, the shift to single-pill therapy offered a real-world test of the impact of simplified drug-delivery mechanisms on patient behavior. Using a quasi-experimental regression discontinuity design, we assessed retention in care among patients starting HIV treatment just before and just after the guideline change. The study included 4,484 patients starting treatment at a large public sector clinic in Johannesburg, South Africa. The share of patients prescribed a single-pill regimen increased by over 40 percentage points between March and April 2013. Initiating treatment after the policy change was associated with 11.7-percentage-points' higher retention at 12 months (95% confidence interval: -2.2, 29.4). Findings were robust to different measures of retention, different bandwidths, and different statistical models. Patients starting treatment early in HIV infection-a key population in the test-and-treat era-experienced the greatest improvements in retention from single-pill regimens.

Long-term clinical outcomes of oral antidiabetic drugs as fixed-dose combinations: A nationwide retrospective cohort study.

AIM: To compare treatment patterns and clinical outcomes of single-pill fixed-dose combination (FDC) and two-pill combination (TPC) therapies using real-world data. METHODS: We conducted a nationwide retrospective cohort study using South Korea's healthcare database (2002-2015). We identified two cohorts of incident patients with type 2 diabetes who initiated FDC or TPC therapy within 4 months of their first prescription for metformin or sulphonylurea. We examined persistence and adherence patterns and the clinical outcome of a composite endpoint of death or hospitalization for acute myocardial infarction, heart failure or stroke and compared the differences in treatment patterns and clinical outcomes using Cox models. RESULTS: Of 5143 and 10 973 patients who initiated FDC and TPC therapy, respectively, we identified 5143 patient pairs after propensity score matching. The FDC group exhibited greater median time to treatment discontinuation (163 vs. 146 days), and proportion of days covered at 12 months (mean 0.60 vs. 0.57, P < .0001) and at 24 months (0.53 vs. 0.51, P = .014) than the TPC group. The FDC group, compared with the TPC group, had reduced risks of the composite clinical outcome (hazard ratio 0.86, 95% confidence intervals 0.77-0.97) and hospitalization for stroke (0.80, 0.67-0.96). CONCLUSION: FDC therapy may provide favourable cardiovascular benefits, especially reducing the risk of hospitalization for stroke, and has better medication adherence among patients with type 2 diabetes.

Pharmacokinetic profile of beclometasone dipropionate/formoterol fumarate administered through a novel dry-powder inhaler in Chinese healthy volunteers.

INTRODUCTION: An extrafine formulation of the inhaled corticosteroid beclometasone dipropionate (BDP) plus the long-acting ß2-agonist formoterol fumarate (FF) has been available for years via a pressurised metered-dose inhaler for the management of asthma and chronic obstructive pulmonary disease. More recently, the same extrafine BDP/FF formulation has become available in a multidose dry-powder inhaler (DPI) called the NEXThaler. The pharmacokinetics (PK) of BDP/FF via this DPI have previously been evaluated in a Caucasian population. The current study aimed to evaluate the PK profile of BDP/FF via DPI in healthy Chinese volunteers. The results were then compared to previous Caucasian data. METHODS: This open-label parallel group study randomised subjects to single-dose BDP/FF 200/12, 400/24, or 800/48 µg via DPI. Blood samples were taken up to 24 h post-dose for PK evaluation of BDP, beclometasone 17-monopropionate (B17MP, active metabolite of BDP) and formoterol. The primary objective of the study was to evaluate the PK of BDP/FF (BDP, B17MP and formoterol). The study is registered on the World Health Organization International Clinical Trials Registry Platform (ChiCTR1900021899). RESULTS: Of 36 subjects randomised, all completed the study. Following inhalation of all three doses, plasma concentration of formoterol and BDP increased rapidly, with peak mean values at the first post-dose timepoint (5 min), then rapidly decreasing; B17MP reached peak concentration slightly later. Plasma exposure to formoterol, BDP and B17MP increased broadly in a dose-proportional manner to BDP/FF dose, with tmax values similar across the dose range. All BDP/FF doses were generally well tolerated. CONCLUSIONS: Therapeutic and supra-therapeutic doses of BDP/FF administered via DPI resulted in approximately dose-proportional plasma exposure in healthy Chinese subjects, with PK profiles that were comparable to previous data from Caucasian subjects.

Aspirin, paracetamol (acetaminophen) and caffeine for the treatment of acute migraine attacks: A systemic review and meta-analysis of randomized placebo-controlled trials.

BACKGROUND AND PURPOSE: Many migraine patients rely on over-the-counter analgesics for the treatment of migraine attacks. Fixed-dose combinations of aspirin, paracetamol and caffeine (APC) have been used for treating migraine in many countries for a long time. We performed a meta-analysis for the comparison of APC versus placebo, which has not been done to date. METHODS: Randomized, blinded, placebo-controlled, parallel-group studies using APC to treat a migraine attack were included in a meta-analysis. We calculated the rate ratio (RRs) associated with APC versus placebo. RESULTS: Seven studies were included, with 3306 participants (2147 treated with APC and 1159 treated with placebo). For the primary efficacy outcome, being pain-free at 2 h, APC was superior to placebo (19.6% vs. 9.0%, RR 2.2, 95% confidence interval [CI] 1.4-3.3). For the co-primary efficacy outcome, pain relief at 2 h, APC was superior to placebo (54.3% vs. 31.2%, RR 1.7, 95% CI 1.6-1.9). Adverse events were more frequent in the APC than the placebo groups (10.9% vs. 7.8%, RR 1.7, 95% CI 1.3-2.2). CONCLUSIONS: Results showed that APC is superior to placebo in the treatment of acute migraine attacks. Efficacy, measured by pain-free response and pain relief at 2 h, was clinically relevant.

Safety and efficacy of a cardiovascular polypill in people at high and very high risk without a previous cardiovascular event: the international VULCANO randomised clinical trial.

BACKGROUND: Cardiovascular (CV) polypills are a useful baseline treatment to prevent CV diseases by combining different drug classes in a single pill to simultaneously target more than one risk factor. The aim of the present trial was to determine whether the treatment with the CNIC-polypill was at least non-inferior to usual care in terms of low-density lipoprotein cholesterol (LDL-c) and systolic BP (SBP) values in subjects at high or very high risk without a previous CV event. METHODS: The VULCANO was an international, multicentre open-label trial involving 492 participants recruited from hospital clinics or primary care centres. Patients were randomised to the CNIC-polypill -containing aspirin, atorvastatin, and ramipril- or usual care. The primary outcome was the comparison of the mean change in LDL-c and SBP values after 16 weeks of treatment between treatment groups. RESULTS: The upper confidence limit of the mean change in LDL-c between treatments was below the prespecified margin (10 mg/dL) and above zero, and non-inferiority and superiority of the CNIC-polypill (p = 0.0001) was reached. There were no significant differences in SBP between groups. However, the upper confidence limit crossed the prespecified non-inferiority margin of 3 mm Hg. Significant differences favoured the CNIC-polypill in reducing total cholesterol (p = 0.0004) and non-high-density lipoprotein cholesterol levels (p = 0.0017). There were no reports of major bleeding episodes. The frequency of non-serious gastrointestinal disorders was more frequent in the CNIC-polypill arm. CONCLUSION: The switch from conventional treatment to the CNIC-polypill approach was safe and appears a reasonable strategy to control risk factors and prevent CVD. Trial registration This trial was registered in the EU Clinical Trials Register (EudraCT) the 20th February 2017 (register number 2016-004015-13; https://www.clinicaltrialsregister.eu/ctr-search/search?query=2016-004015-13 ).

Treatment of open-angle glaucoma and ocular hypertension with preservative-free tafluprost/timolol fixed-dose combination therapy: 6 case reports and clinical outcomes.

BACKGROUND: Treatment of open angle glaucoma (OAG) and/or ocular hypertension (OHT) focuses on achievement of target intraocular pressure (IOP), with the objective of slowing disease progression. However, ocular surface health is an important consideration in the optimization of treatment. We report 6 patient cases in which enhanced IOP control was achieved following appropriate management of ocular surface inflammation and a therapeutic switch to the preservative-free (PF) tafluprost (0.0015%)/timolol (0.5%) fixed-dose combination (FC). CASE PRESENTATION: Six patient cases, aged 48-74 years, presented with OAG or OHT. Each patient had signs and symptoms of ocular surface disease (OSD). Cases 1-3 were each receiving maximal medical therapy for OAG; regimens comprising prostaglandin analogue (PGA), ß-blocker, carbonic anhydrase inhibitor (CAI) and α-2 agonist agents (including treatments containing preservative agent). Cases 1 and 2 reported IOP values ≥23 mmHg in each eye, and wide IOP fluctuations were identified when reviewing patient data concerning case 3 (11-20 mmHg). Maximal therapy was ceased and PF tafluprost/timolol FC was initiated, after which the signs and symptoms of OSD were improved and IOP was reduced (≤18 mmHg for cases 1-3) and stabilized. Cases 4 and 5 were diagnosed with OAG and case 6 had OHT. Each had symptoms and signs of OSD and were treated with a preserved PGA monotherapy (latanoprost 0.005% or bimatoprost 0.03%). At presentation, IOP was 24 mmHg in both eyes (case 4), ≥18 mmHg (case 5) and ≥ 22 mmHg (case 6). Following a switch to the PF tafluprost/timolol FC, OSD symptoms were improved and IOP was 14 mmHg (both eyes; case 4), ≤14 mmHg (case 5) and 16 mmHg (both eyes; case 6). CONCLUSIONS: In addition to IOP-lowering efficacy, approaches to the management of OAG and OHT should consider the impact of treatment tolerability and the susceptibility of these patients to OSD. The presence of ocular surface inflammation appears to be detrimental to adherence and therefore to the effectiveness of topical medications. Addressing OSD through the use of PF FC formations, such as the PF tafluprost/timolol FC, reduces exposure to potentially toxic agents and facilitates improvements in IOP control.

Fixed Dose Combination Tablets of Aripiprazole and Divalproex Sodium: a Pilot Pharmacokinetic Study in Human Volunteers.

A combination product of aripiprazole (antipsychotic) and divalproex sodium (mood stabilizer) was recently developed to establish their tolerability and safety in fixed dose combination (FDC). A pilot pharmacokinetic (PK) open-labeled parallel study on healthy human volunteers was carried out to assess the PK of FDC of aripiprazole/divalproex sodium in comparison with its individual components with a view to rationalize therapeutic regimen and potentially improve compliance of bipolar patients in future. A total of 24 volunteers were randomized to aripiprazole 5mg, divalproex sodium 500mg, and FDC (aripiprazole/divalproex sodium 5/500 mg) enteric-coated tablets. Peak plasma concentration (Cmax) and time to reach peak plasma concentration (Tmax) of aripiprazole increased, Cmax of valproic acid increased, and Tmax decreased. Half-life (t1/2) of both aripiprazole and valproic acid decreased. Area under the curve (AUC) of both aripiprazole and valproic acid increased while volume of distribution (Vd) and clearance (Cl) decreased when used in fixed combination. Increase in the AUC and decrease in the Vd of aripiprazole in the presence of valproic acid were found statistically significant while rest of the parameters were insignificant at level 0.05. Although not adequately powered, this pilot study gives an idea that FDC of aripiprazole and divalproex sodium has a PK profile comparable to its mono-component products. Thus, concomitant use of aripiprazole and valproate in FDC is possible which may prove to be a cost-effective and result-oriented substitute for conventional individual tablets to improve patients' compliance; however, further evaluation with positive control is required.

Beneficial Effects of Fixed-Dose Combination of Amlodipine and Atorvastatin in Patients with Concomitant Hypertension and Hypercholesterolemia: A Multi-Institutional Cohort Study.

Background: Blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) are important risk factors for cardiovascular (CV) diseases. Although treating these factors simultaneously is recommended by current guidelines, only short-term clinical results are available. Objectives: To examine the longer-term efficacy and safety of fixed-dose combination (FDC) versus free combination of amlodipine and atorvastatin in patients with concomitant hypertension and hypercholesterolemia. Methods: Patients with hypertension and hypercholesterolemia were stratified into three groups [FDC of amlodipine 5 mg/atorvastatin 10 mg (Fixed 5/10), FDC of amlodipine 5 mg/atorvastatin 20 mg (Fixed 5/20), and free combination of amlodipine 5 mg/atorvastatin 10 mg (Free 5/10)]. After inverse probability of treatment weighting, the composite CV outcome, liver function, BP, LDL-C and glycated hemoglobin (HbA1c) changes were compared. Results: A total of 1,788 patients were eligible for analysis, and the mean follow-up period was 1.7 year. There was no significant difference in the composite CV outcome among the three groups (Fixed 5/10 6.1%, Fixed 5/20 6.3% and Free 5/10 6.0%). The LDL-C level was significantly reduced in the Fixed 5/20 group (-35.7 mg/dL) compared to the Fixed 5/10 (-23.6 mg/dL) and Free 5/10 (-10.3 mg/dL) groups (p = 0.001 and < 0.001, respectively). The changes in HbA1c were similar among the three groups. Conclusions: FDC of amlodipine and atorvastatin, especially the regimen with a higher dosage of statins, significantly reduced the mid-term LDL-C level compared to a free combination in patients with concomitant hypertension and hypercholesterolemia. Blood sugar level was not significantly changed by this aggressive treatment strategy.

Impact of Simulated Intestinal Fluids on Dissolution, Solution Chemistry, and Membrane Transport of Amorphous Multidrug Formulations.

The solution behavior and membrane transport of multidrug formulations were herein investigated in a biorelevant medium simulating fasted conditions. Amorphous multidrug formulations were prepared by the solvent evaporation method. Combinations of atazanavir (ATV) and ritonavir (RTV) and felodipine (FDN) and indapamide (IPM) were prepared and stabilized by a polymer for studying their dissolution (under non-sink conditions) and membrane transport in fasted state simulated intestinal fluid (FaSSIF). The micellar solubilization by FaSSIF enhanced the amorphous solubility of the drugs to different extents. Similar to buffer, the maximum achievable concentration of drugs in combination was reduced in FaSSIF, but the extent of reduction was affected by the degree of FaSSIF solubilization. Dissolution studies of ATV and IPM revealed that the amorphous solubility of these two drugs was not affected by FaSSIF solubilization. In contrast, RTV was significantly affected by FaSSIF solubilization with a 30% reduction in the maximum achievable concentration upon combination to ATV, compared to 50% reduction in buffer. This positive deviation by FaSSIF solubilization was not reflected in the mass transport-time profiles. Interestingly, FDN concentrations remain constant until the amount of IPM added was over 1000 µg/mL. No decrease in the membrane transport of FDN was observed for a 1:1 M ratio of FDN-IPM combination. This study demonstrates the importance of studying amorphous multidrug formulations under physiologically relevant conditions to obtain insights into the performance of these formulations after oral administration.