Fixed-dose Combination Tablet Research Articles

An LC-MS/MS Method for Determination of Triple Drugs Combination of Valsartan, Amlodipine and Hydrochlorothiazide in Human Plasma for Bioequivalence Study

Background: Current guidelines for the treatment of hypertension recommend combination therapy, which intends to control blood pressure and enhance cardiovascular protection. Materials and Methods: A sensitive, reliable and selective tandem mass spectrometry (LC-MS/MS) method has been developed for simultaneous quantification of amlodipine (AML), valsartan (VAL) and hydrochlorothiazide (HCTZ) in human plasma. The chromatographic system was equipped with ACE 5 C8 (50 X 2.1 mm) column and utilized a mobile phase composition of 0.5 mM Ammonium Chloride & 0.04% FA-Methanol (45:55% v/v). The method used three internal standards; AML-D4, HCTZ-D2 C13 and VAL-D3 with 10% intra- and inter-day precision, and 6% bias for all the analytes. Results: The assay was found to be linear with R-2 > 0.998, and the limits of quantification for AML, VAL and HCTZ were 0.2, 50.0 and 2.0 ng/mL, respectively. The analytes were found to be stable in plasma samples over short and long term storage. : The developed method is rapid with a run time of 3.5 min and cost-effective since the simple sample preparation method is adopted. This method was successfully applied for the bioequivalence study of AML, VAL, and HCTZ in human plasma after administration of the fixed-dose combination tablet of (10/160/25 mg). Pharmacokinetic parameters (Cmax and AUC0-72) for AML and (Cmax, AUC0-t, AUC0-∞) for VAL and HCTZ were used for bioequivalence assessment. These were determined by noncompartmental analysis of concentration data. Conclusion: The result showed 90% confidence intervals (obtained by ANOVA) which were within the predefined ranges. As a consequence, this method can be successfully applied for measuring and quantifying a large number of samples.

The comparison of two different direct acting antiviral regimens in treatment of chronic hepatitis C virus

Aim: Chronic hepatitis C virus (HCV) is considered a critical threat to the public health in the world. We compared treatment outcomes of Ombitasvir, Paritaprevir and Ritonavir with Dasabuvir (PrOD) and Ledipasvir (LDV) and Sofosbuvir (SOF) in real world patients with chronic HCV in treatment-naive and pre-treated patients with chronic HCV.MaterialS and Methods: 91 adult patients enrolled in our study and were divided in two groups. The first group; consisted of 53 patients, who orally received a fixed-dose combination tablet comprised of LDV and SOF once daily for 24 weeks. The second group; consisted of 38 patients, who orally received a fixed-dose combination tablet comprised of PrOD twice daily for 12 weeks without regard to fat or calorie content. Results: The results showed that sustained virologic response (SVR) rates were 100% in the both groups analyzed. 76 adverse events were occurred in total. 46 of overall adverse events were found on patients in the first group and 30 of those events were found on patients in the second group. Weakness (13.1%), pruritus (5.5%), myalgia (1.1%) nausea (5.5%), dry mouth (1.1%) and insomnia (1.1%) were observed among the patients. Twelve weeks after initiating treatment, virologic suppression was accomplished for all patients in the both groups. Additionally, laboratory analysis concluded that HCV-RNA levels of the overall patients were negative after 48 weeks of the onset of the treatment.Conclusion: The real world comparative analysis of two distinct treatment regimens concluded that administration of PrOD and LDV/SOF on the patients with chronic HCV has an extremely effective outcome. SVR12 rates of 100% were obtained in both treatment regimens for all treatment naive and treatment-experienced patients regardless of cirrhosis occurrence and of HCV genotype.

Fixed Drug Eruption: A Rare Case of Polysensitivity between Two Unrelated Fixed Dose Combination Preparations - A Case Report

Background: A fixed drug eruption is a type IV hypersensitivity reaction to a medication that characteristically re-emerges on the same site each time the specific drug is taken. Antimicrobials (including fixed dose combinations) are frequently implicated in fixed drug eruption while gliptins (as separate drugs or as combined preparations) on the other hand are infrequent triggers. Drugs belonging to similar classification and having similar chemical structures can show cross reactivity, but here we describe a case of cross reactivity between unrelated drug classes, also known as polysensitivity.
 The Case: A 58-year-old man presented with painful, burning, and pruritic blisters with ulcerations on the oral mucosa of lips, hard palate, and tip of the tongue. The patient had been on vildagliptin - metformin fixed dose combination tablets for one year. He was asked to stop the drug and lesions started improving thereafter. A week later he suffered from gastroenteritis for which he took a combined preparation of ofloxacin and ornidazole and lesions re-appeared at the same site as before with severe itching and burning.
 Conclusion: This case highlights polysensitivity amongst chemically unrelated drugs, especially available in fixed-dose combination. It is an extremely rare occurrence (less than 0.2%). Moreover, there have only been a few cases of such delayed reactions occurring to gliptins, especially vildagliptin. A clinician must keep a high index of suspicion to identify this phenomenon.

Tackling quantitative polymorphic analysis through fixed-dose combination tablets production. Pyrazinamide polymorphic assessment

Pyrazinamide (PZA), Rifampicin (RIF), Isoniazid (ISH) and Ethambutol (ETB) form the core for the treatment of Tuberculosis, today a devastating disease in low-income populations around the world. These drugs are usually administrated by fixed-dose combination (FDC) products, to favour the patient compliance and prevent bacterial resistance.PZA exists in four enantiotropically-related polymorphs (Forms α, δ, β and γ), but only Form α is considered suitable for pharmaceutical products due to its stability and bioavailability properties. The classical approaches to address solid-state (microscopy, X-ray diffraction and calorimetry) shows limitations for quantification of polymorphs in the presence of excipients and other active components, as in the case of FDC tablets.In this work, an overall strategy was developed using near infrared spectroscopy (NIR) coupled to partial least squares regression (PLS) to quantify Form α of PZA in drug substance (raw material) and PZA/RIF/ISH-FDC tablets. For this purpose, two PLS models were constructed, one for drug substance preparing training (n = 30) and validation (n = 18) samples with a ternary composition (Form α/Form δ/Form γ), and other for FDC drug products, also including the appropriate amount of RIF, ISH and the matrix of excipients in order to simulate the environment of PZA/RIF/ISH association.The NIR-PLS models were optimized using a novel smart approach based on radial optimization (full range, 3 L V and MSC-D’ and SNV-D’ as pre-treatment, for raw material and FDC tablets, respectively).During the validation step, both methods showed no bias or systematic errors and yielded satisfactory recoveries (102.5 ± 3.1 % for drug substance and 98.7 ± 1.5 % for FDC tablets). When commercial drug substance was tested, NIR-PLS was able to predict the content of Form α (0.98 ± 0.01 w/w). The model for FDC tablets allowed estimating polymorphic purity in intact (0.984 ± 0.003 w/w), sectioned (0.986 ± 0.002 w/w), and powered (0.985 ± 0.004 w/w) tablets, showing the methodology could be applied to a different stage of the process (i.e premixed-powders or granulates). The suitability of the method was also verified when Form α was satisfactorily analysed in FDC fortified with Form δ and Form γ to reach 0.78, 0.88 and 0.98 w/w, Form α. This strategy results in an excellent alternative to ensure the polymorphic purity of PZA throughout the overall pharmaceutical manufacturing process.

Green reversed-phase HPLC development strategy: Application to artesunate and amodiaquine analysis.

A green analytical chemistry strategy is described to develop a reversed-phase high-performance liquid chromatography method for amodiaquine and artesunate analysis using ethanol-based mobile phases. This method development was particularly challenging due to the basicity of amodiaquine and low UV absorption of artesunate, leading to peak asymmetry and detection issues, respectively. UV detection concern was even more challenging due to the baseline drift observed with ethanol in gradient mode. Several green pH modifiers were selected for their ecofriendly character and their impact on peak shape and detection was investigated. The screening of various stationary phases (19 columns) appeared as a relevant and necessary approach to reach satisfactory peak shape of basic compounds. To support the results of this study, some additional compounds related to artesunate and amodiaquine structures were included. Methods were optimized and validated using total error approach with a mobile phase composed of ethanol and 10mM formic acid using three different stationary phases from different manufacturers, providing flexibility of the quality control approach. Method greenness was assessed using the National Environmental Methods Index, the Green Analytical Procedure Index, and the Analytical Eco-Scale. Finally, artesunate and amodiaquine were successfully analyzed in fixed dose combination tablets.

Application of MEKC and UPLC with Fluorescence Detection for Simultaneous Determination of Amlodipine Besylate and Bisoprolol Fumarate.

Two chromatographic methods were described for simultaneous determination of the antihypertensive drugs amlodipine besylate (AML) and bisoprolol fumarate (BIS). Method I applies micellar electrokinetic capillary chromatography using a deactivated fused silica capillary (25 cm effective length × 50 μm internal diameter). The background electrolyte consisted of 0.01 M borate buffer (pH 9.2) containing 0.025 M sodium dodecyl sulphate and methanol in the ratio of 80:20 (v/v). Valsartan (VAL) was used as an internal standard. Diode array detector was set at 238, 224, and 210 nm for measuring AML, BIS, and VAL, respectively. Method II involves using ultra-performance liquid chromatography with fluorescence detection. Zorbax SB-C8 column (2.1 × 100 mm, 1.8 μm particle size) was used with isocratic elution of the mobile phase composed of 0.1% trifluoroacetic acid, acetonitrile, and methanol in the ratio of 55:35:10 (v/v) at a flow rate of 0.6 mL/min. Fluorescence detection was done using excitation wavelengths 230 and 370 nm and emission wavelengths 305 and 450 nm for BIS and AML, respectively. Validation parameters were carefully studied including linearity, ranges, precision, accuracy, robustness, detection, and quantification limits. Method I showed good linearity over the range 10-100 μg/mL for both dugs. Method II's linear ranges were 0.001-0.1 and 0.02-1 µg/mL for BIS and AML, respectively. The proposed methods were successfully validated and applied for assay of the studied drugs in their fixed-dose combination tablets. To the best of our knowledge, this study suggests the first electro-chromatographic and LC with fluorescence detection methods for simultaneous determination of amlodipine and bisoprolol.

Process Control of Drug Product Continuous Manufacturing Operations\u2014a Study in Operational Simplification and Continuous Improvement

PurposeThe purpose of this manuscript is to demonstrate that implementation of gravimetric measurements provides the same assurance of product quality and process control as spectroscopic measurements (1) for control of drug content in a fixed-dose combination (FDC) tablet and (2) for identification of non-conforming material.MethodsA wet granulation continuous tableting line was used to make the FDC drug product batches. Comparative data was generated for ten batches using near-infrared (NIR) spectroscopy for core tablets, and gravimetric in-process control measurements (IPCs) applied to the ratio control of intra- and extra-granular blend (IG and EG). HPLC reference data were collected to further demonstrate uniformity at each stage of the production process, including IG, final blend, and core tablets. All possible sources of variation not directly detectable by the gravimetric measurements were considered and quantified.ResultsThe two IPC measurement techniques showed excellent agreement where both were within 2% of the target drug concentrations and within 2% of each other for the ten comparative batches. The NIR was more sensitive to material and process variations than the gravimetric IPCs; thus, it was more variable within and across batches. Gravimetric IPCs were demonstrated as an effective replacement for spectroscopic measurements for continuous tableting operations, capable of ensuring on target manufacturing and detection of non-conforming material.ConclusionsAs pharmaceutical companies continue to push toward operational simplicity and sustainable manufacturing processes, soft-sensor and gravimetric controls as alternatives to their spectroscopic counterparts will be applied more broadly for process monitoring and control.

Drug exposure of first-line anti-tuberculosis drugs in China: A prospective pharmacological cohort study.

Exploring the need for optimization of drug exposure to improve tuberculosis (TB) treatment outcome is of great importance. We aimed to describe drug exposure at steady state as well as the population pharmacokinetics (PK) of rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA) in Chinese TB patients. A prospective multicentre PK study of RIF, INH and PZA was conducted in China between January 2015 and December 2017. Six blood samples were collected from each subject for drug concentration measurement. Nonlinear mixed effect analyses were used to develop population PK models. In total, 217 patients were included. Positive correlations between body weight, clearance and volume of distribution were identified for RIF and PZA, whereas body weight only influenced clearance for INH. In addition, males had higher RIF clearance and thus lower RIF exposure than women. Acetylator status was significantly associated with INH clearance as INH exposure in intermediate and fast acetylators was significantly lower than in slow acetylators, especially in low-weight bands. Simulations also showed significantly lower drug exposures in low-weight bands for all three drugs. Patients weighing <38 kg were respectively exposed to 30.4%, 45.9% and 18.0% lower area under the concentration-time curve of RIF, INH and PZA than those weighing ≥70 kg. Higher doses by addition of one fixed-dose combination tablet or 150 mg INH were simulated and found to be effective in improving INH drug exposures, especially in low-weight bands. PK variability of first-line anti-TB drugs is common in Chinese TB patients. The developed population PK models can be used to optimize drug exposures in Chinese patients. Moreover, standard dosing needs to be adjusted to increase target attainment.

Pharmacokinetics of Efavirenz 600 mg Once Daily During Pregnancy and Post Partum in Ghanaian Women Living With HIV

PurposeThe updated World Health Organization guidelines recommend efavirenz (EFV) 400 mg as the preferred alternate first-line antiretroviral therapy to dolutegravir, with EFV 600 mg recommended only in special situations. We examined the pharmacokinetic (PK) properties of EFV 600 mg/d during pregnancy and post partum to inform EFV dosing decisions in pregnant women. MethodsGhanaian pregnant women with HIV infection initiating tenofovir disoproxil fumarate 300 mg/lamivudine 300 mg/EFV 600 mg fixed-dose combination tablet once daily were enrolled. Efavirenz concentrations were measured at 4 weeks of antiretroviral therapy initiation during pregnancy and 6 weeks post partum using validated LC-MS/MS assays. Efavirenz PK parameters were calculated using noncompartmental analysis, and within-group parameters between the 2 periods were compared. FindingsOf 25 enrolled women, 19 completed PK sampling during pregnancy and post partum. The Cmax, Cmin, AUC0–24h, and CL/F for EFV during pregnancy were similar to values at 6 weeks post partum. The pregnancy/postpartum geometric mean ratios for EFV Cmax, Cmin, AUC0–24, and CL/F were 1.10 (95% CI, 0.93–1.31), 0.88 (95% CI, 0.67–1.17), 0.84 (95% CI, 0.71–0.98), and 1.20 (95% CI, 1.02–1.40), respectively. Viral load suppression (HIV RNA <200 copies/mL) was achieved in 16 of 17 participants (94%) by the time of delivery. There was 1 maternal-to-child transmission. ImplicationsWe found that the PK parameters of EFV 600 mg once daily during pregnancy were similar to those in the postpartum period. Our findings suggest that EFV dose adjustment during pregnancy is not necessary in our study population.

Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study

AbstractThis phase 2 study was designed to compare systemic decitabine exposure, demethylation activity, and safety in the first 2 cycles with cedazuridine 100 mg/decitabine 35 mg vs standard decitabine 20 mg/m2 IV. Adults with International Prognostic Scoring System intermediate-1/2- or high-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) were randomized 1:1 to receive oral cedazuridine/decitabine or IV decitabine in cycle 1, followed by crossover to the other treatment in cycle 2. All patients received oral cedazuridine/decitabine in subsequent cycles. Cedazuridine and decitabine were given initially as separate capsules in a dose-confirmation stage and then as a single fixed-dose combination (FDC) tablet. Primary end points: mean decitabine systemic exposure (geometric least-squares mean [LSM]) of oral/IV 5-day area under curve from time 0 to last measurable concentration (AUClast), percentage long interspersed nuclear element 1 (LINE-1) DNA demethylation for oral cedazuridine/decitabine vs IV decitabine, and clinical response. Eighty patients were randomized and treated. Oral/IV ratios of geometric LSM 5-day AUClast (80% confidence interval) were 93.5% (82.1-106.5) and 97.6% (80.5-118.3) for the dose-confirmation and FDC stages, respectively. Differences in mean %LINE-1 demethylation between oral and IV were ≤1%. Clinical responses were observed in 48 patients (60%), including 17 (21%) with complete response. The most common grade ≥3 adverse events regardless of causality were neutropenia (46%), thrombocytopenia (38%), and febrile neutropenia (29%). Oral cedazuridine/decitabine (100/35 mg) produced similar systemic decitabine exposure, DNA demethylation, and safety vs decitabine 20 mg/m2 IV in the first 2 cycles, with similar efficacy. This study is registered at www.clinicaltrials.gov as #NCT02103478.

A fast and green reversed-phase HPLC method with fluorescence detection for simultaneous determination of amlodipine and celecoxib in their newly approved fixed-dose combination tablets.

A fast, green, sensitive, and accurate analytical method using high-performance liquid chromatography couple with fluorescence detection was established and validated for the simultaneous determination of amlodipine besylate and celecoxib in their recently approved fixed-dose combination tablets (1:20). Separation of the two drugs was achieved on C18 reversed-phase column (Thermo ODS Hypersil, 4.6 × 250mm, particle size 5µm) using acetonitrile:potassium phosphate buffer (50mM; pH 5.5, 60:40 v/v) as a mobile phase at 40°C, which eluted at a rate of 1mL/min. Detection was carried out with excitation and emission wavelengths of 360 and 446nm for amlodipine and 265 and 359nm for celecoxib, respectively. The method was linear over a concentration range of 0.05-2 and 0.05-10 µg/mL and limit of detection reached to 0.017 and 0.0167 µg/mL for amlodipine and celecoxib, respectively. The developed method was successfully applied to assess the cited drugs in their newly FDA approved fixed-dose combination tablet dosage form. Furthermore, the method was found to be sensitive and eco-friendly green alternative to the reported methods as it was evaluated according to the green analytical procedure index tool guidelines and analytical Eco-Scale.

Pharmacokinetic similarity demonstrated after crushing of the elbasvir/grazoprevir fixed-dose combination tablet for HCV infection.

BackgroundFinding a suitable treatment for HCV patients with swallowing disorders is still a major challenge. In practice, direct-acting antivirals are crushed without knowledge of adequate absorption. Crushing can alter drug exposure, possibly leading to treatment failure, development of resistance or toxicity. Currently, there is no information about crushing of the fixed-dose combination tablet of elbasvir/grazoprevir; therefore, crushing of this tablet is not recommended.ObjectivesTo investigate the influence of crushing on the pharmacokinetics of the elbasvir/grazoprevir fixed-dose combination tablet.MethodsWe conducted an open-label, two-period, randomized, cross-over, Phase I, single-dose trial in 11 healthy adult volunteers. Subjects randomly received whole-tablet elbasvir/grazoprevir or crushed and suspended elbasvir/grazoprevir in a fasted state. Pharmacokinetic similarity criteria (90% CIs lie within 70%–143% acceptance range) were used for AUC0–∞ and AUC0–72.ResultsMean plasma concentration–time curves of elbasvir and grazoprevir showed similar pharmacokinetic profiles. The primary pharmacokinetic parameters AUC0–∞ and AUC0–72 of elbasvir and grazoprevir after intake of a crushed tablet were on average 12%–16% higher compared with the whole tablet, but 90% CIs were all within the predefined boundaries of pharmacokinetic similarity. Crushing leads to a higher Cmax of grazoprevir (42%); no significant difference was found between treatments with regard to the Cmax of elbasvir. No serious adverse events were reported during the trial.ConclusionsPharmacokinetic similarity could be demonstrated for a crushed and suspended tablet compared with a whole tablet, without impacting drug safety or efficacy. Crushed and suspended administration of elbasvir/grazoprevir can be used in patients with swallowing disorders.

Electroanalytical investigation and determination of hepatitis C antiviral drug ledipasvir at a non-modified boron-doped diamond electrode

This study is about the use of the boron-doped diamond electrode pretreated electrochemically (anodic and subsequent cathodic) in the voltammetric determination of hepatitis C antiviral drug ledipasvir. Cyclic voltammetric measurements revealed that the compound yielded two well-separated irreversible oxidation peaks (PA1 and PA2) in acidic medium. The dependence of intensities of currents and potentials on electrode pretreatment, pH and nature of the supporting electrolyte, and other variables was investigated by square-wave voltammetry. Determination of ledipasvir was performed in Britton-Robinson buffer (pH 2.0) on the basis of both PA1 and PA2, which offered linear concentration ranges 0.5–60.0 μg mL−1 (5.6 × 10−7–6.8 × 10−5 mol L−1) and 5.0–60.0 μg mL−1 (5.6 × 10−6–6.8 × 10−5 mol L−1), respectively, with detection limits of 0.12 μg mL−1 (1.4 × 10−7 mol L−1) and 0.76 μg mL−1 (8.6 × 10−7 mol L−1). The practical applicability of developed methodology was tested by the assay of a fixed-dose combination tablet with sofosbuvir.

The Effect of Moderate- and High-Fat Meals on the Bioavailability of Dolutegravir/Rilpivirine Fixed-Dose Combination Tablet.

Dolutegravir 50 mg (DTG) and rilpivirine 25 mg (RPV) are a newly approved 2-drug regimen for the treatment of HIV in virally suppressed patients. A 2-part study evaluated the relative bioavailability and food effect of five experimental fixed-dose combination (FDC) tablet formulations of DTG/RPV. When given with a moderate- or high-fat meal, the absorption of both DTG and RPV was increased, resulting in higher exposures. As per product labelling, DTG/RPV FDC should be taken with a meal.

Tuberculosis in children: screening, diagnosis and management.

The present review focuses on recent advances and current challenges in screening, diagnosis and management of tuberculosis (TB) in children, encompassing TB infection and TB disease, and public health priorities for screening and family engagement. Although awareness has improved in recent years that children in TB endemic areas suffer a huge disease burden, translation into better prevention and care remains challenging. Recent WHO guidelines have incorporated screening of all household contacts of pulmonary TB cases, but implementation in high incidence settings remains limited. Improved tests using noninvasive samples, such as the lateral flow urinary lipoarabinomannan assay and the new Xpert Ultra assay applied to induced sputum or stool in young children, are showing promise and further assessment is eagerly awaited. From a treatment perspective, child-friendly dispersible fixed dose combination tablets are now widely available with excellent acceptability and tolerance reported in young children. High-level government commitment to TB control as a public health priority and feasible strategies to achieve this are required to contain the global epidemic, whereas strong engagement of local TB clinics and affected families in TB prevention is essential to limit secondary cases and protect exposed children.

Bioequivalence of macitentan and tadalafil given as fixed-dose combination or single-component tablets in healthy subjects.

AimsTo demonstrate the bioequivalence of macitentan/tadalafil fixed‐dose combination (FDC) tablets with single‐component tablets of macitentan and tadalafil in healthy subjects.MethodsStudies AC‐077‐101 and AC‐077‐103 were single‐centre, open‐label, single‐dose, 2‐period, randomized, crossover Phase 1 studies conducted in healthy subjects. Two FDCs were investigated: FDC‐1 and FDC‐2 in Study AC‐077‐101 and FDC‐2 in Study AC‐077‐103. Both FDCs contained 10 mg/40 mg of macitentan/tadalafil and differed in excipients and coating materials used. In both studies, pharmacokinetic sampling over 216 hours was conducted, and pharmacokinetic parameters were derived using noncompartmental methods.ResultsBioequivalence of macitentan, its active metabolite ACT‐132577, and tadalafil was established for FDC‐2 in both studies AC‐077‐101 and AC‐077‐103 in which tadalafil as a single component was sourced from the USA and EU, respectively, to fulfil regional regulatory requirements. The area under the plasma concentration–time curve and maximum plasma concentration with 90% confidence intervals of all components were entirely within the bioequivalence limits (0.8000–1.2500). No subject died and no serious adverse events were reported in either studies.ConclusionThe FDC‐2 tablet containing 10 mg/40 mg of macitentan/tadalafil was bioequivalent to the free combination of 10 mg macitentan and 40 mg tadalafil (both US and EU sourced). Macitentan and tadalafil were well tolerated when administered as FDC or as a free combination.

Triple fixed-dose combination empagliflozin, linagliptin, and metformin for patients with type 2 diabetes

ABSTRACT Objectives Fixed-dose combination (FDC) therapy can improve outcomes in type 2 diabetes (T2D). We evaluated the bioequivalence of 2 doses of an FDC of extended-release metformin (metformin XR), empagliflozin, a sodium-glucose co-transporter 2 inhibitor, and linagliptin, a dipeptidyl peptidase-4 inhibitor, versus corresponding free tablet combinations. Methods Two randomized, open-label, two-way crossover studies in healthy adults compared: 2 FDC tablets of empagliflozin 5 mg/linagliptin 2.5 mg/metformin XR 1000 mg (Study 1; N = 30), 1 FDC tablet of empagliflozin 25 mg/linagliptin 5 mg/metformin XR 1000 mg (Study 2; N = 30) versus corresponding dose of free combinations. Subjects received study medication under fed conditions; washout was ≥35 days between treatments. Primary endpoints: area under the plasma concentration–time curve (AUC) from time 0 to last quantifiable data point for empagliflozin and metformin; AUC from time 0 to 72 hours for linagliptin, and peak plasma concentration (Cmax) for empagliflozin, linagliptin, and metformin. Bioequivalence was defined as adjusted geometric mean ratios (FDC: free combination) and two-sided 90% confidence intervals (CIs) of AUC and Cmax for each component within 80.00–125.00%. Results Study 1: 27/29 and 28/30 treated participants were included in the pharmacokinetic analysis for the FDC and free combination periods, respectively. Study 2: 29/29 treated participants were included in the pharmacokinetic analysis for both periods. The adjusted geometric mean ratios of FDCs to their respective free tablet combinations and two-sided 90% CIs were all within the predefined range. The shapes of the mean plasma concentration–time profile of empagliflozin, linagliptin, and metformin XR were similar for subjects in the FDC and free combination groups in both studies. No serious adverse events were reported. Conclusion The evaluated doses of empagliflozin/linagliptin/metformin XR FDC tablets were bioequivalent to the corresponding free combinations. Based on these two bioequivalence studies and existing phase 3 data, the FDA has recently approved this triple FDC to improve glycemic control in adults with T2D.

Preexposure Prophylaxis for Prevention of HIV Acquisition Among Adolescents: Clinical Considerations, 2020.

SummaryPreexposure prophylaxis (PrEP) with antiretroviral medication has been proven effective in reducing the risk for acquiring human immunodeficiency virus (HIV). The fixed-dose combination tablet of tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) was approved by the U.S. Food and Drug Administration (FDA) for use as PrEP for adults in 2012. Since then, recognition has been increasing that adolescents at risk for acquiring HIV can benefit from PrEP. In 2018, FDA approved revised labeling for TDF/FTC that expanded the indication for PrEP to include adolescents weighing at least 77 lb (35 kg) who are at risk for acquiring HIV. In 2019, FDA approved the combination product tenofovir alafenamide (TAF)/FTC as PrEP for adolescents and adults weighing at least 77 lb (35 kg), excluding those at risk for acquiring HIV through receptive vaginal sex. This exclusion is due to the lack of clinical data regarding the efficacy of TAF/FTC in cisgender women.Clinical providers who evaluate adolescents for PrEP use must consider certain topics that are unique to the adolescent population. Important considerations related to adolescents include PrEP safety data, legal issues about consent for clinical care and confidentiality, the therapeutic partnership with adolescents and their parents or guardians, the approach to the adolescent patient’s clinical visit, and medication initiation, adherence, and persistence during adolescence. Overall, data support the safety of PrEP for adolescents. PrEP providers should be familiar with the statutes and regulations about the provision of health care to minors in their states. Providers should partner with the adolescent patient for PrEP decisions, recognizing the adolescent’s autonomy to the extent allowable by law and including parents in the conversation about PrEP when it is safe and reasonable to do so. A comprehensive approach to adolescent health is recommended, including considering PrEP as one possible component of providing medical care to adolescents who inject drugs or engage in sexual behaviors that place them at risk for acquiring HIV. PrEP adherence declined over time in the studies evaluating PrEP among adolescents, a trend that also has been observed among adult patients. Clinicians should implement strategies to address medication adherence as a routine part of prescribing PrEP; more frequent clinical follow-up is one possible approach.PrEP is an effective HIV prevention tool for protecting adolescents at risk for HIV acquisition. For providers, unique considerations that are part of providing PrEP to adolescents include the possible need for more frequent, supportive interactions to promote medication adherence. Recommendations for PrEP medical management and additional resources for providers are available in the U.S. Public Health Service clinical practice guideline Preexposure Prophylaxis for the Prevention of HIV Infection in the United States — 2017 Update and the clinical providers’ supplement Preexposure Prophylaxis for the Prevention of HIV Infection in the United States — 2017 Update: Clinical Providers’ Supplement (https://www.cdc.gov/hiv/clinicians/prevention/prep.html).

IDENTIFICATION OF DRUG-RELATED PROBLEMS IN ADULTS WITH TUBERCULOSIS AT THE TEBET SUBDISTRICT HEALTH CENTER FROM JULY TO DECEMBER 2018

Objective: Tuberculosis (TB) is a highly prevalent infectious disease caused by Mycobacterium tuberculosis. The recommended TB treatment is acombination of various antibiotics in the form of a fixed-dose combination tablet or kombipak; however, this increases the prevalence of drug-relatedproblems. Therefore, this study aimed to identify drug-related problems of patients receiving TB therapy at the Tebet Subdistrict Health Center fromJuly 2018 to December 2018.Methods: The study was designed as a cross-sectional study using the retrospective data retrieval method from prescriptions of patients withTB from July 2018 to December 2018. The classification system prepared by Cipolle, Strand, and Morley was used for the classification of drugrelatedproblems; this system includes unnecessary drug therapy, required additional drug therapy, ineffective drug, dosage error, and druginteraction.Results: The percentage of unnecessary drug therapy, required additional drug therapy, ineffective drug, dosage error, and drug interaction was2.85%, 6.89%, 1.54%, 12.46%, and 66.18%, respectively, with the occurrence of drug-related problems being the highest.Conclusion: The administration of anti-TB drugs can potentially cause drug-related problems. Therefore, the assessment needs to be optimizedbefore the administration of medications to patients and medications should be prescribed and monitored regularly to achieve rational drug use

Formulation and Evaluation of Fixed Dose Combination Tablets of Antifungal Drugs for Candida albicans Resistant to Fluconazole

Background: The emergence of Candida albicans strains resistant to fluconazole (FLZ) had raised interest on combining other antifungals with FLZ. In vitro and clinical studies had indicated synergistic interaction between terbinafine and FLZ against strains resistant to FLZ and improved therapeutic efficacy. Objective: Formulation and evaluation of fixed dose combination (FDC) tablets of terbinafine HCl (TH) and FLZ for avoidance of resistance and improved therapeutic efficacy against C. albicans infections. Method: The compatibility of TH and FLZ together and with excipients was determined by FTIR spectroscopy. A UV-visible spectroscopic Q-absorbance ratio method was developed and validated for linearity, accuracy, precision, LOD and LOQ for simultaneous estimation of TH and FLZ. The FDC tablets was prepared by wet granulation using hydroxy propyl cellulose (1%, 2%, 3%, 4% and 5%) as binder and evaluated for pre-compression and post-compression parameters. Result and Discussion: The TH and FLZ were compatible together and with excipients used in FDC. The linearity range was found to be 0.5-3.0 µg/ml and 80-400 µg/ml for TH and FLZ, respectively. Percent RSD was less than 2% indicating good accuracy and precision for proposed method. The hardness and disintegration time of tablets increased and friability decreased with increased binder concentration. Formulation F2 and F3 showed more than 80% drug release within 30 minutes. Conclusion: The TH and FLZ were compatible and can be formulated as a FDC tablet. The UV-Visible spectrophotometric method developed for simultaneous estimation was simple, accurate and sensitive.&#x0D; Keywords: Terbinafine, Fluconazole, Q-absorbance, Fixed Dose Combination, Candida albicans