Fixed-dose Combination Tablet Research Articles

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.
 Keywords: Terbinafine, Fluconazole, Q-absorbance, Fixed Dose Combination, Candida albicans

Simultaneous separation of artesunate and mefloquine in fixed-dose combination tablets by CZE-UV.

A novel method was proposed for simultaneous determination of artesunate (ATS) and mefloquine (MFQ) in fixed-dose combination tablets by capillary zone electrophoresis with simultaneous direct and indirect detection by ultraviolet (CZE-UV). The background electrolyte, consisting of 30/15 mmol L-1 TRIS/3,5-dinitrobenzoic acid buffer at pH 8.2, a chromophore buffer, was selected taking into account a detailed study involving the effective mobility vs. pH curves of the analytes and electrolyte compounds in association with the very low molar absorptivity of ATS. Suitable separation conditions, considering voltage, temperature and buffer concentration as factors, were achieved through the 33 Box-Behnken design investigation. The optimum baseline separation conditions were: injection pressure of 30 mbar for 10 s, cartridge temperature of 22.5 °C and positive voltage of +30 kV. The method proved to be rapid (5 minutes), simple, selective, linear (r2 > 0.98), precise (relative standard deviation (RSD): ATS < 2.9% and MFQ < 2.2%) and accurate (recoveries: ATS 98.13-102.96% and MFQ 98.75-106.77%), proving to be suitable for routine quality control analysis.

Quantificação simultânea de efavirenz, lamivudina e fumarato de tenofovir desoproxila em comprimidos de dose fixa combinada por cromatografia a líquido de alta eficiência

The therapeutic regimen for the treatment of AIDS using efavirenz, lamivudine and tenofovir disoproxil fumarate has demonstrated efficacy and safety. In this work, an analytical method was developed and validated for simultaneous quantitation of efavirenz (EFV), lamivudine (3TC) and tenofovir disoproxil fumarate (TDF) in fixed-dose combination tablet. Analysis by high performance liquid chromatography was performed using a reversed phase column Sun Fire® C18 (250 mm x 4,6 mm; 5 μm) at 30 °C, 20 μL injection volume and detection at 260 nm. The mobile phase, composed of acetate buffer pH 5.4 and methanol, was employed at 1.0 mL/min flow rate and gradient elution. Adequate linearity was obtained in the range from 66 to 198 μg/mL for EFV, 66 to 198 μg/mL from 3TC and 33 to 99 μg/mL for TDF. Relative standard deviation values were lower than 5% and mean recoveries were within 98% to 102%, confirming the precision and accuracy of the method, respectively. In addition, the developed method showed to be selective and robust and can be successfully applied for routine quality control analysis.

Pharmacokinetics and pharmacodynamics of a fixed-dose combination of gemigliptin/metformin sustained release 25/500 mg compared to the loose combination in healthy male subjects.

A fixed-dose combination (FDC) of gemigliptin/metformin can improve the medication adherence in patients with type 2 diabetes mellitus (T2DM). In this study, the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of gemigliptin and metformin were compared between FDC and the corresponding loose combination under fasted and fed states. A two-part, randomized, open label, single-dose, two-way crossover study was conducted in healthy male subjects. Under fasted (part 1) or fed (part 2) state, 2 FDC tablets of gemigliptin/metformin sustained release (SR) 25/500 mg or loose combination with one tablet of gemigliptin 50 mg and two tablets of metformin extended release (XR) 500 mg were orally administered in each period with a 7-day washout. Serial blood samples were collected up to 48 hours to determine the drug concentration and the dipeptidyl peptidase 4 (DPP-4) activity. The concentration-time profiles of gemigliptin and metformin were similar between FDC and loose combination in both the fasted and fed states. Geometric mean ratios and 90% confidence intervals of FDC to loose combination for area under the concentration-time curve and maximum plasma concentration of gemigliptin and metformin were within the bioequivalence range (0.8–1.25) in both states. DPP-4 activity-time profiles of FDC were comparable to that of the loose combination, showing similar area under the DPP-4 inhibition-time curve and maximum DPP-4 inhibition between FDC and loose combination, regardless of the fasted or fed state. In conclusion, the PK/PD characteristics of gemigliptin and metformin were similar in FDC tablets and loose combination both in fasted and fed states.Trial RegistrationClinicalTrials.gov Identifier: NCT03355014

Formulation of dispersible isoniazid/pyridoxine fixed-dose combination tablets for isoniazid preventive therapy in pediatrics

Objective: Oral dispersible isoniazid 50 mg/pyridoxine 6.25 mg fixed-dose combination (FDC) tablets were formulated for Isoniazid Preventive Therapy in pediatrics weighing less than 5 kg. Significa...

Rifampicin Can Be Given as Flat-Dosing Instead of Weight-Band Dosing.

BackgroundThe weight-band dosing in tuberculosis treatment regimen has been implemented in clinical practice for decades. Patients will receive different number of fixed dose combination tablets according to their weight-band. However, some analysis has shown that weight was not the best covariate to explain variability of rifampicin exposure. Furthermore, the rationale for using weight-band dosing instead of flat-dosing becomes questionable. Therefore, this study aimed to compare the average and the variability of rifampicin exposure after weight-band dosing and flat-dosing.MethodsRifampicin exposure were simulated using previously published population pharmacokinetics model at dose 10–40 mg/kg for weight-band dosing and dose 600–2400 mg for flat-dosing. The median area under the curve (AUC0–24 h) after day 7 and 14 were compared as well as the variability of each dose group between weight-band and flat-dosing.ResultsThe difference of median AUC0–24 h of all dose groups between flat-dosing and weight-band dosing were considered low (< 20%) except for the lowest dose. At the dose of 10 mg/kg (600 mg for flat-dosing), flat-dosing resulted in higher median AUC0–24h compared to the weight-band dosing. A marginal decrease in between-patient variability was predicted for weight-band dosing compared to flat-dosing.ConclusionsWeight-band dosing yields a small and non-clinically relevant decrease in variability of AUC0–24h.

Formulation, Development and Scale-Up of Fixed-Dose Combination Tablets Containing Zidovudine, Lamivudine and Nevirapine.

The development of antiretroviral associations in a single dosage form aims to ensure improved efficacy, low costs and better adherence to treatment. This work performed the pharmacotechnical development, coating, and stability studies of fixed-dose combination tablets of zidovudine, lamivudine and nevirapine (300 + 200 + 150 mg, respectively). Qualitative and quantitative planning of diluents (101 and 250 microcrystalline cellulose, spray-dried monohydrate lactose and corn starch) and coating polymers (Opadry white II HP® and Instacoat Aqua Moistshield II®) were analyzed, and direct compression (DC) and wet granulation (WG) methods were tested aiming the development of the pharmaceutical form. Quality control was carried out according to the specifications set by official compendia. The chosen formulation was scaled-up and the industrial batches were submitted to accelerated and long-term stability studies. The batches obtained by WG met the requirements, using 101 microcrystalline cellulose, corn starch and Opadry white II HP® as excipients. The DC trial was not possible due to the need of a greater ratio of excipients to improve formulation properties. Thus, this study brings a new therapeutic alternative for HIV treatment, contributing to the development of another possibility to simplify drug administration.

Elexacaftor/Ivacaftor/Tezacaftor: First Approval.

A fixed-dose combination tablet of the cystic fibrosis transmembrane conductance regulator (CFTR) corrector tezacaftor and the CFTR potentiator ivacaftor with the next-generation CFTR corrector elexacaftor (hereafter referred to as elexacaftor/ivacaftor/tezacaftor) [Trikafta™] has been developed by Vertex Pharmaceuticals Inc. to treat patients with the most common cystic fibrosis mutation (F508del). Its use has been associated with statistically significant and/or clinically meaningful improvements in lung function and respiratory-related quality of life compared with comparator regimens (placebo or ivacaftor/tezacaftor) in multinational phase II and III studies, and in October 2019 elexacaftor/ivacaftor/tezacaftor was approved by the US FDA for the treatment of cystic fibrosis in patients aged ≥ 12years who have ≥ 1F508del mutation in the CFTR gene. A regulatory assessment for elexacaftor/ivacaftor/tezacaftor as a treatment for cystic fibrosis is underway in the EU. This article summarizes the milestones in the development of elexacaftor/ivacaftor/tezacaftor leading to this first approval for the treatment of cystic fibrosis in patients aged ≥ 12years who have ≥ 1 F508del mutation in the CFTR gene.

Ultra-short duration direct acting antiviral prophylaxis to prevent virus transmission from hepatitis C viremic donors to hepatitis C negative kidney transplant recipients.

We conducted an adaptive design single-center pilot trial between October 2017 and November 2018 to determine the safety and efficacy of ultra-short-term perioperative pangenotypic direct acting antiviral (DAA) prophylaxis for deceased hepatitis C virus (HCV)-nucleic acid test (NAT) positive donors to HCV negative kidney recipients (D+/R-). In Group 1, 10 patients received one dose of SOF/VEL (sofusbuvir/velpatasvir) pretransplant and one dose on posttransplant Day 1. In Group 2A (N=15) and the posttrial validation (Group 2B; N=25) phase, patients received two additional SOF/VEL doses (total 4) on Days 2 and 3 posttransplant. Development of posttransplant HCV transmission triggered 12-week DAA therapy. For available donor samples (N=27), median donor viral load was 1.37E+06IU/mL (genotype [GT]1a: 70%; GT2: 7%; GT3: 23%). Overall viral transmission rate was 12% (6/50; Group 1:30% [3/10]; Group 2A:13% [2/15]; Group 2B:4% [1/25]). For the 6 viremic patients, 5 (83%) achieved sustained virologic response (3 with first-line DAA therapy; and two after retreatment with second-line DAA). At a median follow-up of 8months posttransplant, overall patient and allograft survivals were 98%, respectively. The 4-day strategy reduced viral transmission to 7.5% (3/40; 95% confidence interval [CI]: 1.8%-20.5%) and could result in avoidance of prolonged posttransplant DAA therapy for most D+/R-transplants.

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.

Oral Azacitidine and Cedazuridine Approximate Azacitidine Efficacy in a Murine Model

Background: DNA methyltransferase inhibitors (DNMTi) induce remissions and improve survival for patients with MDS and those with AML unable to receive standard cytotoxic chemotherapy. Accordingly, DNMTi therapy is the backbone of SOC treatment for MDS and AML. Given the inconvenience, pain, and general detriments to QOL with SQ or IV therapy daily for 5-7 days every month with azacitidine (AZA) or decitabine (DAC), many have attempted to provide the therapy orally, but encountered difficulties with this method of administration given rapid first-pass clearance via the enzyme cytidine deaminase (CDA) which is ubiquitous in the gut and liver. Recently, DAC was combined with cedazuridine (CDZ), an oral CDA inhibitor, in a fixed-dose (35mg/100mg) combination tablet (ASTX727) to approximate the pharmacokinetics of IV DAC (Savona et al Lancet Haematology 2019). To determine if a similar strategy might be feasible with AZA, we attempted to increase the bioavailability of oral AZA with CDZ in a murine tumor model. Methods: We measured GI50 in AML cell lines treated with vehicle (DMSO), AZA, and AZA/CDZ combination. Although cancer cell lines produce CDA, total levels are negligible in comparison CDA in the gut and liver. For this reason, we then studied CDZ, AZA, and the AZA/CDZ combination in a systemic model of AML in immunocompromised mice. NSGS mice were sub-lethally irradiated and administered MOLM-13 AML cells via tail vein injection. At day seven post-transplant, engrafted mice were randomized to receive 2.5 mpk i.p. AZA(n=8), 2.5 mpk oral AZA(n=8), 3 mpk CDZ + oral AZA(n=6), or CDZ alone at 30 mpk (n=7). All oral AZA and CDZ was administered via oral gavage daily for 7 consecutive days; i.p. therapy was similarly given for 7 consecutive days. During treatment, the kinetics of MOLM-13 expansion was defined by detection of human AML in the blood as detected by flow cytometry. At approximately three weeks after transplant, CDZ-only treated mice became moribund, and all experimental groups were sacrificed for analysis of chimerism. Results: After 72 hour of treatment, no differences were noted in viability of cell lines between AZA and AZA+ CDZ in vitro. In the xenograft model, as expected, i.p. AZA-treated mice had significant decreases in leukemic expansion in the bone marrow and spleen, whereas CDZ alone did not (AZA i.p. vs CDZ, p = 0.004 and &amp;lt;0.001). More importantly, whereas oral AZA alone failed to decrease AML expansion in both the bone marrow and spleen of treated mice (oral AZA vs CDZ., p = 0.677 and 0.249, respectively), the addition of CDZ to oral AZA led to significant decreases in AML in both bone marrow and spleen (Oral AZA + CDZ vs CDZ, p = 0.012 and 0.004, respectively). Likewise, addition of CDZ to oral AZA showed no significant differences in activity against AML compared to traditional AZA i.p. dosing in either bone marrow or splenic tissue (p= 0.204 and 0.224, respectively). Furthermore, in a Kaplan-Meier survival analysis, mice treated with CDZ alone die within 21 days of transplant, but both i.p. AZA and oral AZA + CDZ treated mice had a 50% extended survival with no significant difference in survival between i.p. AZA and oral AZA + CDZ treated mice (p= 0.502). H&amp;E staining revealed no significant bone marrow toxicity in treated mice, suggesting that AZA preferentially effected transplanted MOLM-13 AML cells. Conclusion: Consistent with previous preclinical and clinical studies with ASTX727, the oral AZA approximated AZA anti-tumor activity when co-treated with CDA-inhibitor CDZ. These preliminary data provide rationale for the development of CDZ + oral AZA therapy as a fixed dose combination (ASTX030) in myeloid disease. Clinical trials evaluating ASTX030 are being planned. Figure Disclosures Oganesian: Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Savona:TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Patents &amp; Royalties; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Selvita: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding.

2508. Virologic Suppression in Patients Switched to BIC/TAF/FTC with Baseline NRTI and/or INSTI Resistance

BackgroundBIC/TAF/FTC is the first fixed-dose combination tablet to contain both a second-generation INSTI and TAF and has therefore become a popular treatment option for HIV. Historically, patients with NRTI mutations were placed on four-drug, NRTI-retaining regimens or two-drug, NRTI-sparing regimens. Recently, data have emerged supporting the use of second-generation INSTIs with tenofovir/FTC in the setting of the M184V mutation alone. There is a paucity of data, however, evaluating the use of BIC/TAF/FTC in the setting of NRTI and/or INSTI mutations. This study assessed the role of BIC/TAF/FTC in patients with baseline NRTI and/or INSTI mutations.MethodsThis was an observational retrospective study conducted at an inner city HIV clinic. Patients were eligible if they were switched to BIC/TAF/FTC with confirmed adherence and had either the M184V mutation alone, M184V plus another NRTI mutation(s), an INSTI mutation alone, or both NRTI and INSTI mutation(s) at the time of ART switch. We evaluated virologic response (HIV RNA < 200 copies/mL) and duration of BIC/TAF/FTC therapy.ResultsThere were 16 patients eligible for analysis. Among the patients, 69% were male and 31% were female. The majority of patients were Black (81%). The mean age was 63 years (SD ± 8.6). Thirteen patients were virologically suppressed (HIV RNA < 200 copies/mL) at baseline. The mean CD4 count at baseline was 630.4 cells/mm3 (SD ± 297.1). Mutations at baseline were as follows: M184V alone (25%), M184V plus another NRTI mutation(s) (56.25%), INSTI mutation alone (12.5%), NRTI and INSTI mutation(s) (6.25%). BIC/TAF/FTC mean duration of therapy was 10.5 months (range 6–14 months). The mean CD4 count of the patients switched to BIC/TAF/FTC was 687 cells/mm3 (SD ± 20.7). All patients switched to BIC/TAF/FTC achieved or maintained virologic suppression (HIV RNA < 200 copies/mL) with a mean HIV RNA of 26.25 copies/mL (SD ± 14.1). Fifteen of those switched to BIC/TAF/FTC had an undetectable HIV RNA level (HIV RNA < 50 copies/mL).ConclusionWhile a larger cohort and longer follow-up period is needed, BIC/TAF/FTC may maintain virologic suppression in patients with select baseline NRTI and/or INSTI mutations.Disclosures All authors: No reported disclosures.

Using electronic medication monitoring to guide differential management of tuberculosis patients at the community level in China

BackgroundIn settings such as China, where universal implementation of directly observed therapy (DOT) is not feasible, innovative approaches are needed to support patient adherence to TB treatment. The electronic medication monitor (EMM) is one of the digital technologies recommended by the World Health Organization (WHO), but evidence from implementation studies remains sparse. In this study, we evaluated acceptance of the EMM among health care workers and patients while implementing the device for differential TB patient management at the community level.MethodsZhenjiang City in Jiangsu Province was purposively selected for the study. All participating patients were allowed to select their preferred management approach. If patients declined to use the EMM, DOT was offered. The EMM was designed to hold 1 month of anti-TB drugs for once-daily dosing of fixed-dose combination (FDC) tablets. Patient EMM records were monitored monthly by a physician; if 20 to 50% of doses were missed twice, or more than 50% of doses were missed once, the patient was switched to DOT. The four physicians and five nurses involved in the study at four designated hospitals were surveyed using a structured questionnaire to assess their acceptance of the EMM.ResultsFrom October 2017 through January 2018, 316 pulmonary TB patients were notified in the TB information management system, and 231 (73.1%) met the study enrollment criteria. Although 186 patients (80.5%) initially consented to use the EMM, 17 later refused to use it. Among the 169 patients who used the EMM, 15 (8.9%) were switched to DOT due to poor adherence, and the other 154 completed the treatment course. The median adherence rate was 99.3%. Surveyed health care workers from designated hospitals found the EMM acceptable, although eight of nine felt use of the device moderately increased their workload. However, the EMM program significantly reduced the workload of community physicians by reducing patient visits by 87.9%.ConclusionsThis study demonstrated the acceptability of using an indigenously developed EMM for differential management of TB patients at the community level. However, more operational research should be conducted before introducing and scaling the technology throughout China.

Erratum to: SD1000: High Sustained Viral Response Rate in 1361 Patients With Hepatitis C Genotypes 1, 2, 3, and 4 Using a Low-cost, Fixed-dose Combination Tablet of Generic Sofosbuvir and Daclatasvir: A Multicenter, Phase III Clinical Trial.

Erratum to: SD1000: High Sustained Viral Response Rate in 1361 Patients With Hepatitis C Genotypes 1, 2, 3, and 4 Using a Low-cost, Fixed-dose Combination Tablet of Generic Sofosbuvir and Daclatasvir: A Multicenter, Phase III Clinical Trial.

Fixeddose combination of rosuvastatin + ezetimibe: ease of use, safety and efficacy

Today, cardiovascular diseases remain the leading cause of morbidity and mortality globally. Hyperlipidemia and dyslipidemia are key points in the occurrence and progression of CVDs, as well as the development of its complications. Elevated low density lipoprotein cholesterol (LDL-C) is the target of lipid-lowering therapy. The LDL-C target level is often not achieved in everyday clinical practice, which is especially important for patients at high and very high risk for cardiovascular complications. Furthermore, in some patient subgroups, atherogenic dyslipidemia is observed. Due to use of intensive and prolonged lipid-lowering therapy, the problem of its tolerability and patient adherence to the treatment becomes a live issue today. In addition, the use of drugs with effect that complements and enhances the effect of statin helps to achieve targets and improve long-term prognosis. Statins and ezetimibe are effective and widely used drugs to treat dyslipidemia. Clinical studies show that ezetimibe can be safely co-administered with statins to enhance lipid-lowering activity. In this regard, a statin and non-statin drug fixed-dose combination tablet may have additional advantages both for enhancing the lipidlowering effect and for greater patient convenience. Rosuvastatin is more effective than other statins in reducing low density lipoprotein cholesterol. The article provides a rationale for the possibility, efficacy, safety and convenience of using an ezetimibe and rosuvastatin fixed-dose combination tablet in patients with a high and very high risk and unattained target level of low density lipoprotein cholesterol.

&lt;p&gt;Bioequivalence Study Of A Fixed-Dose Combination Tablet Containing Melitracen 10 mg And Flupentixol 0.5 mg In Healthy Chinese Volunteers Under Fasted And Fed Conditions&lt;/p&gt;

PurposeA fixed-dose combination (FDC) tablet of melitracen/flupentixol has been widely used for depression. The purpose of this study was to assess the safety profile and the relative bioavailability of two FDC products containing 10 mg melitracen and 0.5 mg flupentixol from two different manufacturers, in order to acquire adequate pharmacokinetic evidence for registration approval of the test formulation.MethodsThe study was designed as a single-dose, randomized, open-label, 2-period crossover study under fasted or fed conditions in healthy Chinese subjects. Twenty-four subjects (16 men and 8 women) were selected for fasted study, and another 24 cases (16 men and 8 women) were in fed study. Each subject was randomized at the beginning to receive either a single dose of the reference FDC or the test FDC tablet during the first period. Following two-week washout period, all subjects received the alternate formulation during the second period. Blood samples were collected up to 144 hrs after administration. Pharmacokinetic parameters, including Cmax, Tmax, AUC0-t, AUC0-∞, t½, CL/F, and Vd/F were acquired based on the time versus concentration profiles. Then, the geometric mean ratios (GMR) and corresponding 90% CIs were calculated for the determination of bioequivalence analysis. Safety assessment included changes in vital signs and laboratory tests, physical examination findings, and incidence or reports of adverse events (AEs).ResultsThe present study has clearly indicated the test and the reference FDC products are bioequivalent in terms of rate and extent of drug absorption. GMR of Cmax, AUC0–t, and AUC0-∞ for both flupentixol and melitracen between the two formulation FDC products, and corresponding 90% CIs, were all within the range of 80% to 125% under fasted or fed conditions. Both the test and the reference FDC products indicated good tolerance in all volunteers. Chinese Clinical Trials Registry identifier: CTR20171256.

Trifluridine/Tipiracil: A Review in Metastatic Gastric Cancer.

Trifluridine/tipiracil (Lonsurf®) is a fixed-dose combination tablet comprising trifluridine, an antineoplastic nucleoside analogue, and tipiracil, a thymidine phosphorylase inhibitor. Trifluridine/tipiracil has recently been granted an additional indication in the USA for the treatment of metastatic gastric cancer, including gastroesophageal junction adenocarcinoma, in patients who have been previously treated with at least two systemic treatment regimens, and has received a positive opinion for this indication in the EU. In the large pivotal phase III TAGS trial, trifluridine/tipiracil plus best supportive care (BSC) significantly prolonged overall survival (OS; primary endpoint) compared with placebo plus BSC in this patient group. Progression-free survival (PFS) and the disease control rate were also improved with trifluridine/tipiracil relative to placebo. Health-related quality of life was not adversely affected by the addition of trifluridine/tipiracil to BSC and time to deterioration of Eastern Cooperative Oncology Group (ECOG) performance status was significantly delayed. The most common adverse events were mainly haematological (neutropenia, leucopenia and anaemia) and gastrointestinal (nausea, vomiting and diarrhoea), and were generally manageable with dosage modifications and/or supportive care. Adverse events ≥ Grade 3 were most frequently haematological in nature. Thus, trifluridine/tipiracil provides a valuable and much needed treatment option for patients with metastatic gastric or gastroesophageal junction adenocarcinoma that has progressed on at least two prior therapies.

Clinical Pharmacodynamics, Pharmacokinetics, and Drug Interaction Profile of Doravirine.

Doravirine is a novel non-nucleoside reverse transcriptase inhibitor(NNRTI) that has demonstrated good efficacy, tolerability, and safety for the treatment of patients with human immunodeficiency virus (HIV)-1 infection in phase III clinical trials. Doravirine achieved non-inferiority when compared with efavirenz- and darunavir/ritonavir-based regimens. Fewer adverse effects, including neuropsychiatric effects were observed with doravirine compared with efavirenz. Key pharmacodynamic and pharmacokinetic characteristics as well as drug-drug interactions and the resistance profile were assessed in this clinical review. Doravirine is a pyridinone NNRTI with potent antiviral activity against wild-type HIV-1 virus and common NNRTI variants. Studies in healthy volunteers and HIV-infected individuals have shown that doravirine has a favorable pharmacokinetic profile for once-daily dosing, with an elimination half-life of around 15h, median time to maximum plasma concentrations of 1-4h, and time to steady-state concentration of 7days. The pharmacokinetics of doravirine arenot greatly influenced by sex, age, race, or hepatic impairment. Although no dose adjustment is required for doravirine in renal impairment when given as a single tablet, the fixed-dose combination tablet of doravirine/lamivudine/tenofovir disoproxil fumarate is not recommended in patients with a creatinine clearance of < 50mL/min. Doravirine has a low potential for drug-drug interactions and does not impact on the pharmacokinetics of other drugs. However, it is metabolized via cytochrome P450 (CYP) 3A enzymes and is thus susceptible to interactions with CYP3A inhibitors and inducers. Strong CYP3A inhibitors can significantly increase doravirine exposure; however, this is not considered to be clinically relevant. Conversely, strong CYP3A inducers, such as rifampin, are contraindicated with doravirine owing to a significant reduction in exposure with potential for impaired virological efficacy. Moderate CYP3A inducers, such as rifabutin, may be co-administered if the doravirine dose is increased to 100mg twice daily. Doravirine has a unique resistance profile and has demonstrated in vitro activity against some of the most common, clinically relevant NNRTI-resistant mutations. Prevalence of baseline NNRTI resistance to doravirine appears to be low in treatment-naïve cohorts. Further data on the efficacy of doravirine in patients with previous treatment experience and/or transmitted NNRTI resistance are required to further inform its place in the current armamentarium of drugs for the treatment of HIV infection.

Optimization of a paediatric fixed dose combination mini-tablet and dosing regimen for the first line treatment of tuberculosis

We aim to optimize the paediatric dosing regimen of isoniazid, rifampicin and pyrazinamide for the first-line treatment of tuberculosis, based on a fixed dose combination (FDC) mini-tablet using simulations. An optimization problem was set up to determine the 3 strengths of the drugs of the mini-tablet and 4 cutoff points that define the weight bands of a dosing chart, simultaneously. Using Monte Carlo simulations, first, exposure targets were determined for the 3 drugs, from published population pharmacokinetic models for adults, assuming that the approved doses for adults are de facto efficacious. Then optimal strengths and cutoff points were determined by matching children exposures generated from population pharmacokinetic models to the adults targets. The optimal dosing strengths of the FDC tablet were found to be 95 mg of rifampicin, 200 mg of pyrazinamide and 75 mg of isoniazid, and the 4 body weight bands for 1 to 4 mini-tablets, respectively were: 4 to 8 kg, 8 to 12 kg, 12 to 18 kg and 18 to 28 kg. Children with body weight ≥ 28 kg will be treated with adult dosages. The higher doses proposed were evaluated to be much closer to the adult targets compared to the existing recommended by WHO paediatric doses.

Alternative dosing guidelines to improve outcomes in childhood tuberculosis: a mathematical modelling study

Malnourished and young children are particularly susceptible to severe forms of tuberculosis and poor treatment response. WHO dosing guidelines for drugs for tuberculosis treatment are based only on weight, which might lead to systematic underdosing and poor outcomes in these children. We aimed to assess and quantify the population effect of WHO guidelines for drug-susceptible tuberculosis in children in the 20 countries with the highest disease burden. We used an integrated model that linked country-specific demographic data at the individual level from the 20 countries with the highest disease burden to pharmacokinetic, outcome, and epidemiological models. We estimated tuberculosis treatment outcomes in children younger than 5 years following WHO guidelines (children are dosed by weight bands corresponding to the number of fixed-dose combination tablets [75 mg rifampicin, 50 mg isoniazid, 150 mg pyrazinamide]) and two alternative dosing strategies: one based on a proposed algorithm that uses age, weight, and available formulations, in which underweight children would receive the same drug doses as would normal weight children of the same age; and another based on an individualised algorithm without dose limitations, in which derived doses results in target exposure attainment for the typical child. We estimated that 57 234 (43%) of 133 302 children younger than 5 years who were treated for tuberculosis in 2017 were underdosed with WHO dosing and only 47% of children would reach the rifampicin exposure target. Underdosing and subtherapeutic exposures were more common among malnourished children than among age-matched healthy children. The proposed dosing approach improved estimated rifampicin target exposure attainment to 62% and equalised outcomes by nutritional status. An estimated third of unfavourable treatment outcomes might be resolved with this dosing strategy, saving the lives of a minimum of 2423 children in these countries annually. With individualised dosing approaches, almost all children could achieve adequate exposure for cure. This work shows that a simple change in dosing procedure to include age and nutritional status, requiring no additional measurements or new drug formulations, is one approach to improve tuberculosis treatment outcomes in children, especially malnourished children who are at high risk of mortality. Eunice Kennedy Shriver National Institute of Child Health and Human Development and UK Medical Research Council.