Fixed-dose Formulation Research Articles

Separation of achiral anti-diabetic drugs using sub/supercritical fluid chromatography with a polysaccharide stationary phase: Thermodynamic considerations and molecular docking study

A simple, fast and environmental friendly supercritical fluid chromatography-photodiode array (SFC-PDA) method was developed for the simultaneous determination of metformin and three sodium-glucose co-transporter 2 (SGLT-2) inhibitors (canagliflozin, dapagliflozin and empagliflozin). The impact of different stationary phases, co-solvents, column temperature and outlet pressure was extensively evaluated for selective separation and quantitation of the drugs. Amongst several achiral and chiral stationary phases tested, the best results were obtained on amylose based Chiralpak IG column using CO2 and 0.1 % diethylamine in methanol and isopropanol 50:50 (v/v) in 60:40 ratios as the mobile phase. The separation efficiency was mainly dependent on the nature of stationary phase and the mobile phase composition. The limit of detection (LOD) and quantitation (LOQ) of the method were 0.155 and 0.469, 0.062 and 0.187, 0.015 and 0.045, 0.028 and 0.084 μg/mL for metformin, canagliflozin, dapagliflozin and empagliflozin, respectively. The chromatographic resolution between metformin-canagliflozin, metformin-dapagliflozin and metformin-empagliflozin pairs was 6.87, 3.44 and 6.47, respectively. The intra-batch and inter-batch precision of the method was ≤1.64 % while the accuracy was in the range of 96.2–103.3 %. The method was used to analyze metformin and SGLT-2 inhibitors in their binary fixed-dose formulations with acceptable accuracy (recovery) and precision. To support the experimental results, molecular docking was performed on Schrodinger software to provide a deeper insight into the interactions between the analytes and the chiral stationary phase and to understand their elution orders under optimized conditions.

Effectiveness comparison and incremental cost-per-responder analysis of calcipotriene 0.005%/betamethasone dipropionate 0.064% foam vs. halobetasol 0.01%/tazarotene 0.045% lotion for plaque psoriasis: a matching-adjusted indirect comparative analysis

Background: The fixed-dose combination foam formulation of calcipotriene 0.005% plus betamethasone dipropionate 0.064% (Cal/BD) has demonstrated efficacy and a favorable safety profile for the treatment of plaque psoriasis. Recently, a topical lotion of the combination of halobetasol 0.01% plus tazarotene 0.045% (HP/TAZ) was approved for treating adult plaque psoriasis. Currently, no head-to-head studies have compared Cal/BD foam with HP/TAZ lotion.Objective: Compare the effectiveness and drug incremental cost per responder (ICPR) of Cal/BD foam vs. HP/TAZ lotion in moderate-to-severe plaque psoriasis.Methods: An anchor-based, matching-adjusted indirect comparison was conducted for PGA treatment success (Physician’s Global Assessment of “clear” or “almost clear,” [PGA 0/1] with at least a 2-point improvement) using individual patient data from 3 randomized clinical studies of Cal/BD foam and published data from 2 randomized, Phase 3 clinical studies of HP/TAZ lotion. The number needed to treat and ICPR were also calculated.Results: After reweighting of patients in the Cal/BD foam studies to match summary baseline characteristics of the HP/TAZ lotion study patients and anchoring to vehicle effect, 4 weeks of Cal/BD foam produced a significantly greater rate of treatment success than 8 weeks of HP/TAZ lotion treatment (51.4 vs. 30.7%; treatment difference = 20.7%, p < .001). The number needed to treat with Cal/BD foam was also less than HP/TAZ lotion (1.9 vs. 3.3). Using US wholesale acquisition costs and equal weekly consumption rates, the incremental cost per PGA 0/1 responder relative to vehicle for Cal/BD foam was $3,988 and was 37% lower compared with HP/TAZ lotion ($6,294).Conclusions: The indirect comparison analyses showed that Cal/BD foam was associated with a greater rate of treatment success, lower ICPR, and quicker treatment response than HP/TAZ lotion in adult patients with moderate-to-severe plaque psoriasis.

Bioequivalence and Food Effect Assessment of 2 Fixed-Dose Combination Formulations of Dolutegravir and Lamivudine.

This single‐dose study evaluated the bioequivalence, food effect, and safety of 2 experimental, 2‐drug, fixed‐dose formulations of 50 mg dolutegravir and 300 mg lamivudine (formulation AH and formulation AK) as compared with coadministration of single‐entity tablets of 50 mg dolutegravir and 300 mg lamivudine (reference). In fasted subjects, formulation AH lamivudine exposure was similar to the reference; however, dolutegravir exposure was consistently higher in formulation AH, with area under the concentration‐time curve (AUC) and maximum concentration (Cmax) approximately 27% to 28% greater than reference. Formulation AK met bioequivalence standards to the reference for dolutegravir (AUC0‐∞ and Cmax) and lamivudine (AUC0‐∞ and AUC0‐t) exposure; however, dolutegravir AUC0‐t and lamivudine Cmax were approximately 16% and 32% higher than the reference, respectively. A high‐fat meal increased dolutegravir AUC and Cmax by up to 33% and 21%, respectively, and decreased lamivudine Cmax by approximately 30%. Both test and reference formulations were well tolerated. The results support further development of formulation AK as a novel, 2‐drug, fixed‐dose combination tablet treatment for patients with HIV.

Anthropometric and Genetic Factors Associated With the Exposure of Rifampicin and Isoniazid in Mexican Patients With Tuberculosis.

Tuberculosis (TB) remains a critical infectious, contagious disease worldwide with high prevalence and mortality rate. The directly observed treatment short-course therapy includes rifampicin (RMP) and isoniazid (INH) for at least 6 months. The purposes of this scheme are to interrupt the transmissibility of the Mycobacterium tuberculosis complex and to avoid secondary complications. Low plasma concentrations of these anti-TB drugs have been associated with extended treatment duration, therapeutic failure, and relapse. The determination of anthropometric, genetic, and clinical variables that may affect plasma concentrations of RMP and INH might facilitate the detection of patients at increased risk of therapeutic failure. A prospective observational study was performed in patients with TB diagnosis. A fixed-dose combined formulation was administered following clinical guidelines, and 12 venous blood samples were collected within 24 hours after dose for the quantification of plasma levels of RMP and INH by high-performance liquid chromatography-ultraviolet. The plasma concentrations versus time for each drug in each patient were assessed by a noncompartmental approach to obtain Cmax, and the area under the concentration-time curve to the last observation point (AUC0-24 h) was calculated by the linear trapezoidal rule. Genetic polymorphisms of the enzyme involved in INH metabolism (NAT2) and proteins involved in RMP transport (glycoprotein-P and OATP1B1) were determined. A total of 34 patients aged between 18 and 72 years with the diagnosis of TB were included in the current study. A multivariate analysis was performed to determine the anthropometric and genetic characteristics that modified the Cmax and AUC0-24 h of RMP and INH. Results indicated that RMP Cmax and AUC0-24 h were affected by sex, dose/weight, and single nucleotide polymorphism of MDR1. In addition, age, body mass index, and NAT2 acetylator genotype were shown to determine the Cmax and AUC0-24 h for INH. Anthropometric, genetic, and dosage characteristics of Mexican patients with TB are an important source of risk for subtherapeutic plasma concentrations of anti-TB drugs. Factors such as lower-than-recommended RMP dose, male patients with TB, and MDR1 3435 genotype, in addition to age group, body mass index, and INH acetylator phenotype based on NAT2 genotype, should be considered during treatment.

Challenges in simultaneous extraction and chromatographic separation of metformin and three SGLT-2 inhibitors in human plasma using LC–MS/MS

Optimization of extraction and chromatographic conditions is essential for the simultaneous analysis of drugs having different physico-chemical properties, especially for in vivo applications. The present work describes concurrent estimation of metformin (MET) and three sodium-glucose co-transporter 2 (SGLT-2) inhibitors namely canagliflozin (CANA), dapagliflozin (DAPA) and empagliflozin (EMPA) in human plasma by liquid chromatography-tandem mass spectrometry (LC–MS/MS). Sample clean-up was optimized using ion-pair solid-phase extraction with sodium lauryl sulphate on Strata-X extraction cartridges. Consistent recoveries were obtained by critically optimizing parameters such as washing and elution solvents during extraction. The extraction recovery ranged from 79 to 88% for all the analytes. Chromatographic separation were accomplished on a Cyano (150 × 4.6 mm, 5 μm) column within 5.0 min using acetonitrile and 10 mM ammonium formate buffer (75:25, v/v) as the mobile phase. The resolution factors between MET-EMPA, MET-DAPA, MET-CANA, DAPA-EMPA and CANA-DAPA were 4.92, 5.85, 7.13, 1.01 and 1.44, respectively. Calibration curves were linear in the concentration range of 2.00–2000, 3.00–3000, 0.20–200 and 1.50–1500 ng/mL for MET, CANA, DAPA and EMPA, respectively. Mass spectrometric analysis was performed using a polarity switching approach to achieve high sensitivity in multiple reaction monitoring mode. The method was validated using current regulatory guidelines and applied to study the pharmacokinetics of fixed-dose formulations of MET and SGLT-2 inhibitors in healthy subjects.

Emerging Fixed-Dose Combination Treatments for Hyperlipidemia.

Low-density lipoprotein cholesterol targets may not be achieved by statin monotherapy, especially in high-risk patients. Furthermore, in some patient subgroups, atherogenic dyslipidemia is observed. As a result, a combination of a statin with other hypolipidemic drugs may have additional benefits, especially in the form of a single tablet. The aim of this review is to present the novel fixed-dose drug combinations for the management of hyperlipidemia. Statins, ezetimibe, and fibrates have established their efficacy and safety in the treatment of hypercholesterolemia and hypertriglyceridemia. Clinical trials have shown that these hypolipidemic drug classes can be safely combined in order to augment the lipid-lowering efficacy. Furthermore, novel hypolipidemic drugs such as bembedoic acid and berberine have shown some promising initial results. The combination of different hypolipidemic regimens in a fixed-dose formulation can enhance the adherence to hypolipidemic treatment leading to improved outcomes. Moreover, complementary mechanisms of action of the combined hypolipidemic drugs may also provide additional benefits such as improvement in carbohydrate metabolism. As a result, fixed-dose combinations of hypolipidemic agents may provide an attractive option for the effective and safe management of hypercholesterolemia.

Impact of Ferroquine on the Solubilization of Artefenomel (OZ439) during in Vitro Lipolysis in Milk and Implications for Oral Combination Therapy for Malaria.

Milk is an attractive lipid-based formulation for the delivery of poorly water-soluble drugs to pediatric populations. We recently observed that solubilization of artefenomel (OZ439) during in vitro intestinal lipolysis was driven by digestion of triglycerides in full-cream bovine milk, reflecting the ability of milk to act as an enabling formulation in the clinic. However, when OZ439 was co-administered with a second antimalarial drug, ferroquine (FQ) the exposure of OZ439 was reduced. The current study therefore aimed to understand the impact of the presence of FQ on the solubilization of OZ439 in milk during in vitro intestinal digestion. Synchrotron small-angle X-ray scattering was used for in situ monitoring of drug solubilization (inferred via decreases in the intensity of drug diffraction peaks) and polymorphic transformations that occurred during the course of digestion. Quantification of the amount of each drug solubilized over time and analysis of their distributions across the separated phases of digested milk were determined using high-performance liquid chromatography. The results show that FQ reduced the solubilization of OZ439 during milk digestion, which may be due to competitive binding of FQ to the digested milk products. Interactions between the protonated FQ-H+ and ionized liberated free fatty acids resulted in the formation of amorphous salts, which removes the low-energy crystalline state as a barrier to dissolution of FQ, while inhibiting the solubilization of OZ439. We conclude that although milk could enhance the solubilization of poorly water-soluble OZ439 during in vitro digestion principally due to the formation of fatty acids, the solubilization efficiency was reduced by the presence of FQ by competition for the available fatty acids. Assessment of the solubilization of both drugs during digestion of fixed-dose combination lipid formulations (such as milk) is important and may rationalize changes in bioavailability when compared to that of the individual drugs in the same formulation.

Multicenter, randomized, double-blind clinical trial to evaluate efficacy and safety of combined glucosamine sulfate and chondroitin sulfate capsules for treating knee osteoarthritis

ObjectivesTo compare the efficacy and safety of a new fixed dose combination of glucosamine sulfate and chondroitin sulfate capsules (GS/CS) versus the fixed dose combination of glucosamine hydrochloride and chondroitin sulfate (Cosamin DS®) in capsules in patients with osteoarthritis (OA) of the knee.MethodsMulticenter, randomized, double-blind study. Participants with knee OA Kellgren-Lawrence grades 1 to 3 and VAS of symptoms ≥4 cm were randomized to receive GS/CS or Cosamin DS® over 12 weeks. The primary efficacy endpoint was the evaluation of the analgesic efficacy by the investigator. Secondary efficacy endpoints included: joint pain and swelling, investigator efficacy of the medication, and the use of rescue medication. Adverse events and drug tolerability were analyzed.ResultsOne hundred patients were randomized, and 50 patients were allocated to each group. The analgesic efficacy evaluated by the investigator in the GS/CS group was 88.9, 95%CI: 75.2, 95.8% and in the Cosamin DS® group was 85.4%; 95%CI: 70.1, 93.4%. The mean reduction in the pain intensity was significant in both groups (p < 0.001), with no difference between them. The primary efficacy analysis demonstrated the non-inferiority of the GS/CS group compared with the Cosamin DS® group; the lower limit of the 90% confidence interval (CI) between the two groups (− 8.39%) was higher than the established margin of non-inferiority of − 10.00%. Improvement in other efficacy outcomes was observed, again without differences between groups. Adverse events were similar between groups and both presented good tolerability.ConclusionsThe new fixed-dose formulation of GS/CS is effective in treating knee OA, presenting a good safety and tolerability profile. Trial Registration(https://clinicaltrials.gov/ct2/show/NCT00955552?term=NCT00955552&rank=1; ClinicalTrials.gov; register number NCT00955552; First randomized patient: 08/17/2010).

Inhaled Triple Therapy in Severe Chronic Obstructive Pulmonary Disease (COPD)

COPD (chronic obstructive pulmonary disease) is characterised by persistent airflow obstruction caused by exposure to irritants including cigarette smoke dust, and fumes. Long-acting beta-agonist (LABA) and long-acting muscarinic antagonist (LAMA) in fixed-dose combination inhalers are the pillars of modern COPD therapy. LABA/inhaled corticosteroids (ICS) inhalers have been proved to be particularly efficient in patients with ≥ 2 exacerbations per year. Until recently, although recommended in guidelines for severe and unstable COPD patients, the clinical usefulness of the LABA/LAMA/ICS combination was a matter of debate. Recent trials with fixed-dose combination inhalers containing fluticasonfuroate/vilanterol/umeclidinium or beclometasone/formoterol/glycopyrronium significantly reduced exacerbation rates and dyspnea scores and improved lung function as well as quality of life better than the LABA/ICS, LABA/LAMA comparators or the single compounds in selected COPD trial patients. Beclometasone/formoterol/glycolpyrronium and fluticasonfuroate/umeclidinium/vilanterol are the first triple combination therapies approved in a fixed-dose inhaler for COPD patients. The domains of triple fixed-dose formulations are COPD patients in groups C andD.

LIQUID CHROMATOGRAPHY TANDEM-MASS SPECTROMETRY METHOD DEVELOPMENT AND VALIDATION FOR SIMULTANEOUS ANALYSIS OF PARACETAMOL, GUAIFENESIN, PHENYLEPHRINE HYDROCHLORIDE, CHLORPHENIRAMINE MALEATE, AND AMBROXOL HYDROCHLORIDE IN BULK AND IN TABLET DOSAGE FORM

Objective: The objective is to study liquid chromatography tandem-mass spectrometry (LC/MS/MS) method for simultaneous quantification of paracetamol (PCM), guaifenesin (GUA), phenylephrine hydrochloride (PE), chlorpheniramine maleate (CPM), and ambroxol hydrochloride (AMB) in tablet dosage form developed and validated as per the International Conference on Harmonization Q2 (R1) guideline. Methods: The chromatograms were developed using a gradient mobile phase of WATER:methanol. Flow rate used was to 0.3 ml/min. Quantitation was performed using multiple reaction monitoring (MRM) mode to study parent to product ion transition, for paracetamol. (m/z 152.0 ≥ 110.0), guaifenesin (m/z 199.0 ≥163.0), phenylephrine hydrochloride (m/z 168.0≥ 150.0), chlorpheniramine maleate (m/z 275.0 ≥ 230.0) and ambroxol hydrochloride (m/z 379.0 ≥ 263.8). Results: The retention times were found to be 1.76, 1.81, 1.90, 2.10, and 2.33 min for PCM, GUA, PE, CPM, and AMB, respectively. The linearity of the method was found to be in the concentration range of 10–200 ng/ml for PCM, GUA, PE, CPM, and AMB. Percentage relative standard deviation values for repeatability and intermediate precision studies were below 2%. Conclusion: Developed method was found to be robust, precise, accurate, rapid and can be used to analyze fixed-dose tablet formulation used in the study.

Physico-chemical properties of co-formulated fast-acting insulin with pramlintide

Since the discovery of amylin its use has been discouraged by the inadequacy of the protocol involving multiple injections in addition to insulin. We aimed here to develop a combined fixed-dose formulation of pramlintide with fast-acting insulin. We have investigated the compatibility of regular and fast-acting insulin analogues (Aspart, AspB28, and LisPro, LysB28ProB29) with the amylin analogue pramlintide by using electrospray ionization - ion mobility spectrometry-mass spectrometry (ESI-IMS-MS), kinetic aggregation assays monitored by thioflavin T, and transmission electron microscopy (TEM) in the evaluation of the aggregation product. Insulin interacts with pramlintide, forming heterodimers as probed by ESI-IMS-MS. While their interaction is likely to delay the amyloid aggregation of pramlintide in phosphate-buffered solution pH 7.0, they do not prevent aggregation at this condition. At acidic sodium acetate solution pH 5.0, combination of pramlintide and the fast-acting insulin analogues become stable against amyloid aggregation. The co-formulated product at high concentration of both pramlintide (600 μg/mL,150 μM) and LisPro insulin (50 IU/mL, 300 μM) showed also stability against amyloid aggregation. These data indicate the physico-chemical short-term stability of the co-formulated preparation of LisPro insulin with pramlintide, which could bring benefits for the combined therapy.

Prevention and Treatment of Pediatric HIV Infection

The goal of this paper is to review the prevention of mother-to-child HIV transmission (PMTCT) research that informed World Health Organization (WHO) guidelines for PMTCT and describe the impact of worldwide scale-up of PMTCT programs and antiretroviral therapy (ART) coverage. The impact of these interventions on new pediatric infections and infected children’s morbidity and mortality in sub-Saharan Africa are reviewed. The IMPAACT PROMISE study demonstrated that triple therapy consisting of tenofovir (TDF), lamivudine (3TC), and lopinavir/ritonavir (LPVr) or zidovudine (AZT), 3TC, and LPVr initiated in the first trimester reduced vertical transmission at 2 weeks of age to 0.6% and 0.5%, respectively, supporting the current WHO Option B+ recommendation for PMTCT. However, increased adverse pregnancy outcomes in the AZT- and TDF-based triple therapy arms were reported when compared with the AZT prophylaxis arm (low birth weight [20.4% and 16.9% vs. 8.9%; p = 0.004] and premature deliveries [19.7% and 18.5% vs. 13.5%; p = 0.09], respectively). Implementation of Option B+ for PMTCT has led to significant reductions in vertical transmission rates, including elimination of new pediatric infections in some countries. The WHO declared elimination of mother-to-child HIV transmission (MTCT) in Cuba in 2015 and in Armenia, Belarus, and Thailand in 2016. Globally, new pediatric HIV infections have declined significantly since the introduction of effective antiretroviral regimens for PMTCT. Perinatal HIV prevention clinical trials conducted in sub-Saharan Africa informed WHO PMTCT guidelines which led to implementation of PMTCT programs worldwide, leading to a 47% reduction in new pediatric infections since 2009. Support from The United States President's Emergency Plan for AIDS Relief (PEPFAR), the Global Fund for AIDS, Tuberculosis and Malaria, and UN agencies has enabled scale-up of national PMTCT programs, and increased antiretroviral coverage (47% globally) for infected children has led to a decline in HIV/AIDS-related mortality in children. Implementation strategies that improve retention in care and adherence to ART in pregnant and breastfeeding HIV-infected women is critical to ensure that more countries achieve the elimination of MTCT (eMTCT) targets. Assessing the effectiveness of new antiretroviral drugs, including fixed-dose combinations and long-acting formulations, is key to improving ART adherence and reducing the emergence of viral resistance mutations. In addition, interventions to prevent HIV transmission in adolescents and young adults is critical for reducing new HIV infections worldwide. Innovative interventions to improve adherence to ART are required to further improve the survival of HIV-infected children and adolescents.

Concentrated and Fixed-Dose Insulin Formulations can Improve Outcomes in Patients with Type 2 Diabetes

Concentrated and Fixed-Dose Insulin Formulations can Improve Outcomes in Patients with Type 2 Diabetes

Concentrated and Fixed-Dose Insulin Formulations Can Improve Outcomes in Patients with Type 2 Diabetes Mellitus

The risk of developing long-term diabetes mellitus–related complications (retinopathy, nephropathy, neuropathy, cardiovascular disease, and stroke) increases as glycated hemoglobin (A1C) levels exceed 6.5%. All patients with diabetes should be provided with an individualized target A1C based on factors such as age, duration of disease, risk of hypoglycemia, existing comorbidities, available resources, life expectancy, and cardiovascular risk. A delay of therapeutic intensification of just 2 years from the time of diagnosis can expose a patient to “glycemic burden” and a 61% increased risk of cardiovascular complications.

Simultaneous determination of rifampicin, isoniazid, pyrazinamide and ethambutol in fixed-dose combination antituberculosis pharmaceutical formulations: a review

According to the World Health Organization, rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride are the first-line drugs used to treat tuberculosis – an infectious disease caused by Mycobacterium tuberculosis.

Core/shell microencapsulation of indomethacin/paracetamol by co-axial electrohydrodynamic atomization

Core/shell microparticles for development of drug delivery systems were prepared using co-axial electrohydrodynamic atomization technique in order to develop fixed dose combined formulations incorporating paracetamol and indomethacin as model drugs. The developed drug delivery systems offered successful co-encapsulation of paracetamol and indomethacin with high drug encapsulation efficiencies of 54% and 69% for paracetamol and indomethacin, respectively. The developed formulations were further characterised with respect to their morphology, drug release profile and possible interactions. In comparison to the release rate of the free indomethacin, the developed formulation resulted in enhanced dissolution rate of indomethacin. This study demonstrates a versatile polymeric platform where multiple drug encapsulation and co-delivery is made possible by utilizing co-axial electrohydrodynamic atomization. The proposed system offered high processing yield of 60–70%, as a single-step platform for preparation of fixed dose formulations for oral drug delivery, particularly in geriatric therapy.

Safety, efficacy, and pharmacokinetics of single-tablet elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in virologically suppressed, HIV-infected children: a single-arm, open-label trial

No once-daily single-tablet regimen is available for HIV-infected children under 12 years. The single-tablet, fixed-dose combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide is a once-daily, integrase strand transfer inhibitor-based regimen approved in the USA and European Union for individuals aged 12 years or older. In this study, we aimed to assess the pharmacokinetics, safety, and efficacy of this regimen in virologically suppressed, HIV-infected children. In this single-arm, open-label trial, we enrolled virologically suppressed, HIV-infected children from five hospital clinics in Uganda, the USA, and Thailand. Eligible participants were aged 6-11 years, weighed 25 kg or more, had virological suppression (<50 copies of HIV-1 RNA per mL) on a stable regimen for at least 6 months, CD4 count of more than 100 cells per μL, and no history of resistance to elvitegravir, emtricitabine, tenofovir alafenamide, or tenofovir. All participants received the available fixed-dose oral formulation of elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir alafenamide 10 mg once per day. Primary outcomes were the pharmacokinetic parameters area under the curve (AUC) concentration at the end of the dosing interval (AUCtau) for elvitegravir and the AUC from time zero to the last quantifiable concentration (AUClast) of tenofovir alafenamide, treatment-emergent serious adverse events, and all treatment-emergent adverse events. Results from baseline to week 24 are reported, unless specified otherwise. Primary and safety analyses included all enrolled participants who received one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01854775. Between July 27 and Sept 28, 2015, we screened 26 children, of whom 23 were enrolled and initiated treatment. Median age was 10 years (IQR 8-11), median weight was 30·5 kg (IQR 27·5-33·0), and all participants had virological suppression. The mean AUCtau of elvitegravir was 33 814 ng × h/mL (coefficient of variation 58%), and the mean AUClast of tenofovir alafenamide was 333 ng × h/mL (45%). Exposures to elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide were higher, but modestly so, than those previously reported in adults. All 23 participants tolerated the regimen well; there were no serious adverse events or adverse event-related discontinuations. All participants maintained virological suppression (HIV-1 RNA <50 copies per mL) at week 24. CD4 count decreased by a median of -130 cells per μL (range -472 to 266) with little change in CD4 cell percentage (-2·1%, range -8·4 to 5·9). The fixed-dose combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide was efficacious and well tolerated in virologically suppressed, HIV-infected children. Although plasma exposure of all components was higher than has been reported in adults, there were no safety concerns and the overall bone and renal safety profile was favourable. These data support the use of this regimen in children at least 25 kg in weight. Gilead Sciences.

Pharmacokinetics and Placental Transfer of Elvitegravir, Dolutegravir, and Other Antiretrovirals during Pregnancy.

The integrase inhibitors elvitegravir (EVG) and dolutegravir (DTG) rapidly decrease the plasma HIV-1 viral load, a key factor in the prevention of maternal-to-fetal transmission of HIV-1. No data have been reported on the concentrations of these drugs in cord blood, maternal peripheral blood mononuclear cells (PBMCs), or placental tissue in pregnant women. We present in vivo pharmacokinetic data on antiretrovirals (ARV) within maternal and cord blood and within placentae from HIV-1-infected pregnant women. Maternal blood and cord blood were obtained from women receiving EVG, cobicistat, tenofovir disoproxil fumarate, and emtricitabine as a single fixed-dose combination formulation or DTG as part of a combination regimen. Plasma and PBMCs from maternal and cord blood were obtained along with villous placental samples. Drug concentrations were simultaneously determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Utilizing medians and ranges to interpret our data, we compared the drug concentration ratios between different matrices (maternal and cord blood plasma, PBMCs, and placenta). All five agents transferred from maternal into fetal circulation via the placenta. Concentration ratios for EVG, cobicistat, tenofovir, and emtricitabine (n = 10) and DTG (n = 3) were determined between cord plasma and placenta, cord and maternal plasma, and cord PBMCs and maternal PBMCs. TFV moves from maternal plasma through the placenta to the cord blood and then into cord PBMCs, where it is phosphorylated into its active forms (TFV diphosphate). These five ARVs were detected in each of the compartments, highlighting transfer of these agents from the maternal into the fetal circulation.

The effectiveness of a fixed-dose combination pour-on formulation of 1.25% fipronil and 2.5% fluazuron against economically important ectoparasites and associated pharmacokinetics in cattle

The present work consisted of eight studies to evaluate the ectoparasiticidal spectrum and determine the pharmacokinetic parameters of a pour-on combination of fipronil 1.25mg/kg+fluazuron 2.5mg/kg for cattle against Rhipicephalus microplus, Haematobia irritans and the larvae of Dermatobia hominis and Cochliomyia hominivorax. The analysis fipronil and fluazuron were performed by liquid chromatography using a mass detector for the detection and quantification of analytes (LC-MS/MS). Additionally, in two of these studies, the animals were artificially infested with R. microplus ticks (stall tests), and the efficacy of this formulation was compared with that of two other standalone pour-on formulations of fipronil 1.0mg/kg and fluazuron 2.5mg/kg. In the two stall studies, 28 calves were artificially infested with 5000 R. microplus (different strains), and daily collections of all of the engorged female ticks that detached from each calf were performed until 60 and 100days post-treatment (dpt). For the R. microplus field trials, 20 bovines were selected by counting the semi-engorged females, and the therapeutic and residual efficacy was evaluated by taking tick counts at 3, 7, 14, 21, 28, 35, 42, 49 and 56dpt. Forty bovines that were naturally infested with Dermatobia hominis larvae were selected, and the numbers of larvae were counted by visual and tactile inspection on 3, 7, 14, 28, 35, 42 and 49dpt. To address the efficacy on C. hominivorax larvae, two circular skin incisions (one on each side of the body) measuring approximately 4cm in diameter each were made in 12 crossbred calves, and the natural exposure of the lesions to C. hominivorax infestations was then allowed. The incisions from the 12 animals were carefully examined daily from 1 to 10dpt. Based on the PK results obtained for this pour-on combination containing fipronil 1.25mg/kg+fluazuron 2.5mg/kg, the maximum concentrations (Cmax) and the half-lives (T1/2) of these two active ingredients were detected on days 2, 5/6 and 19 (±2)/24, 4 (±3.5) days for fipronil and fluazuron, respectively. Furthermore, the combination showed higher therapeutic and residual efficacy against R. microplus (P≤0.05) when compared with commercial standalone formulations that were administered separately. A high efficacy for this new combination was also found against C. hominivorax and D. hominis larvae (efficacy≥99%). This study's results show that the combination of these two active ingredients, as opposed to their separate use, could represent a tool for extending the life cycle of these two molecules against cattle ectoparasites, especially R. microplus. Further studies would be desirable to further confirm this.

Trifluridine/tipiracil in metastatic colorectal cancer: a guide to its use

Trifluridine/tipiracil (Lonsurf®; also known as TAS-102), an oral antimetabolite agent, is a welcome addition to the options available to treat metastatic colorectal cancer in patients who are refractory to, or are not considered candidates for, currently available therapies. This novel fixed-dose formulation combines trifluridine, which inhibits cell proliferation after being incorporated into DNA via phosphorylation, with tipiracil, which increases systemic exposure to trifluridine by potently inhibiting thymidine phosphorylase. In clinical trials, the addition of trifluridine/tipiracil (35 mg/m2 twice daily on days 1–5 and 8–12 of each 28-day cycle) to best supportive care significantly improved overall survival, progression-free survival and disease control relative to placebo. Adverse events associated with trifluridine/tipiracil can generally be managed with dose modification and/or supportive measures.