Elexacaftor-Tezacaftor-Ivacaftor and Ivacaftor (Trikafta)

CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class. The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec. This review assesses ELX-TEZ-IVA (Trikafta) and ELX 100 mg, TEZ 50 mg, IVA 75 mg (combination tablet), and 150 mg IVA (tablet); oral. Indication: Treatment of cystic fibrosis in patients aged ≥ 12 years who have at least 1 F508del mutation in the cystic fibrosis transmembrane conductance regulator gene.

Co-Spray Drying of Paracetamol and Propyphenazone with Polymeric Binders for Enabling Compaction and Stability Improvement in a Combination Tablet

Paracetamol (PCT) and propyphenazone (PRP) are analgesic drugs that are often combined in a single dosage form for enhanced pharmacological action. In this work, PCT and PRP were co-spray dried separately with hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC) using drug suspensions in polymer solutions as feed liquids. It was thought that because of polymer adherence to the surface of drug particles, the risk of PCT–PRP contact and interaction could be reduced. Such interaction may be caused by localized temperature gradients due to frictional forces during tableting, or during storage under harsh conditions. A worst-case scenario would be eutectic formation due to variations in powder mixture homogeneity since eutectic and therapeutic mass PCT/PRP ratios are close (65:35 and 60:40, respectively) and eutectic temperature is low (~56 °C). Uniform particle size, round shape, compaction improvement and faster release of the analgesics were important additional benefits of co-spray drying. Experimental design was first applied for each drug to optimize the polymer concentration on the yield of spray drying and melting point separation (Δmp) of heated binary mixtures of co-spray dried PCT/neat PRP, and vice versa, with the two drugs always included at their therapeutic 60:40 ratio. Optimal combinations with largest Δmp and production yield were: co-spray dried PCT (15% HPC) with neat PRP and co-spray dried PRP (10% HPMC) with neat PCT. Compression studies of these combinations showed tableting improvement due to the polymers, as reflected in greater work of compaction and solid fraction, greater fracture toughness and tablet strength, easier tablet detachment from the punch surface and ejectability. Faster release of both drugs was obtained from the tablet of co-spray dried PCT (15% HPC) with neat PRP. A one-month stability test (75% RH/40 °C) showed moisture-induced alteration tablet strength.

COMPATIBILITY STUDY BETWEEN PRAVASTATIN AND EZETIMIBE, AND PHARMACEUTICAL EXCIPIENTS USED IN FIXED-DOSE COMBINATION TABLET

Objective: The purpose of this study was to qualitatively predict drug-excipient binding interactions for stable drug formulation of a pravastatin and ezetimibe fixed-dose combination (FDC) tablet. Methods: Drug impurity-excipient interactions under accelerated conditions (40°C/75% relative humidity) for 4 weeks were confirmed by high-performance liquid chromatography, X-ray diffraction (XRD), differential scanning calorimetry (DSC) and thermogravimetric (TG) analysis. Results: Pravastatin impurity was affected by four excipients under accelerated conditions for 4 weeks. Ezetimibe was affected by two excipients. Any other results were within the acceptance criteria. XRD analysis for physical stability revealed characteristic peaks of pravastatin and ezetimibe at a diffraction angle of 2θ (pravastatin: 4.1–24.4°, and ezetimibe: 13.62–29.59°) without a change in the crystalline form after 4 weeks. DSC and TG analysis showed evidence of stability in Alu-Alu foil. Conclusion: Thus, the tested excipients were confirmed to be compatible with pravastatin and ezetimibe and can be used in FDC bi-layer tablets.

Development and Characterization of a Combination Tablet Dosage Form Containing Sofosbuvir and Ribavirin Using Design of Experiments (DoE) Approach

Worldwide more than 180 million people get infected by chronic Hepatitis C Virus (HCV) and around 700,000 people pass away every year due to HCV related problems. Sofosbuvir and Ribavirin are prescribed as combined medication for the management of HCV infection globally. Therefore, optimization of a pharmaceutical dosage form containing Sofosbuvir and Ribavirin can open a new hope in the treatment of HCV infection. This study was conducted by using the Design of Experiments (DoE) approach. It is a systematic process aiming to determine the correlation between formulation factors affecting the approach and the output of the approach. During the development of formulations, two factors were considered, which are Croscarmellose Sodium (CCS) and Povidone K30 (PK30) at different concentrations ranging from 0.19% to 2.31% of the total tablet weight in 9 different formulations. Their effect on disintegration time (DT) was evaluated through statistical method and it was found between 3±0.003 and 6.5±0.015 minutes. The use of these two different disintegrants exhibited a significant effect on DT. The contour plot showed predicted ranges of concentrations of CCS and PK30 for desired DT. Fourier Transform Infrared Spectroscopy (FTIR) data, Thermogravimetric Analysis (TGA) and X-ray Diffractometry (XRD) spectrums confirmed that there was no interaction between Sofosbuvir and Ribavirin or with any other excipients used in this experiment. Dhaka Univ. J. Pharm. Sci. 20(1): 121-133, 2021 (June)

Field study to investigate the effectiveness and safety of a novel orally administered combination drug product containing milbemycin oxime and lotilaner (Credelio® Plus) against natural flea and tick infestations on dogs presented as veterinary patients in Europe

Background A pivotal randomised, blinded, positive-controlled, multicentre, European field study was conducted to evaluate the effectiveness and safety of a novel combination tablet of lotilaner and milbemycin oxime (Credelio® Plus) administered orally to client-owned dogs naturally infested with fleas and/or ticks. Methods In this field study, households with flea- or tick-infested dog(s) were enrolled on Day 0 into the study to provide data for either the tick or flea infestation cohorts. Households were randomised in a 2:1 ratio to receive either the combination investigational product (IP, Credelio Plus® tablets) or the control product (CP: Nexgard Spectra® tablets). Dogs were administered IP (flea cohort n = 135; tick cohort: n = 147) or CP (flea cohort: n = 67; tick cohort: n = 74) once every 4 weeks for a total of three times at a dose rate of 20.0–41.5 mg/kg bodyweight lotilaner and 0.75–1.53 mg/kg bodyweight milbemycin oxime (IP) or as recommended (CP). Percentage reduction was calculated by comparing individual dog flea and tick counts at each assessed post-treatment time point to their respective baseline (pre-treatment) infestation. Resolution of the clinical signs of flea allergy dermatitis (FAD) was assessed in flea-allergic dogs on the days that flea counts were performed. Results Flea effectiveness of Credelio Plus® after 3 consecutive monthly treatments was 100% against Ctenocephalides felis, C. canis and Pulex irritans. Tick effectiveness of Credelio Plus® over the same time frame was 99.3% for Ixodes ricinus and 100% against Rhipicephalus sanguineus (s.l.). Flea effectiveness of the CP after three consecutive monthly treatments was 100% against C. felis, C. canis and P. irritans. Tick effectiveness of the CP over the same time frame was 99.8% for I. ricinus and 100% against R. sanguineus. Credelio Plus® was well tolerated based on the safety assessments in all treated dogs in this field study. Within both treatment groups there was a reduction in total FAD scores from baseline. Conclusions This pivotal European field study demonstrated the excellent effectiveness and safety of a combination of lotilaner and milbemycin oxime (Credelio Plus®) administered orally to dogs naturally infested with fleas and/or ticks. Graphic Abstract

Effectiveness of Credelio® Plus, a novel chewable tablet containing milbemycin oxime and lotilaner for the treatment of larval and immature adult stages of Toxocara canis in experimentally infected dogs

Background The ascarid, Toxocara canis, is a common and important zoonotic intestinal nematode parasite that infects dogs globally. An effective treatment that kills any pre-patent stages of immature T. canis could additionally reduce or eliminate the development of patent infections that can result in clinical disease in infected dogs and would further reduce environmental contamination of eggs. Two randomized, blinded, GCP-compliant, pivotal laboratory dose confirmation studies were conducted to assess the effectiveness and safety of a new novel combination of lotilaner and milbemycin oxime tablets (Credelio Plus) administered orally to dogs that were experimentally infected with immature (L4 or immature adult [L5]) stages of T. canis. Methods The commercial tablet formulation of Credelio Plus® was administered in a time frame relative to inoculation with infective eggs. This allowed for effectiveness to be assessed against each specific immature stage of T. canis. In each study, dogs were randomized and allocated to one of four treatment groups. Each treatment group contained ten dogs that had been experimentally inoculated on Day 0 with infective T. canis eggs and then were dosed once on Day 14 or Day 24 using either placebo tablets or Credelio Plus tablets (IP) to provide minimum dosages of 0.75 mg/kg of milbemycin oxime and 20 mg/kg of lotilaner. All dogs were necropsied 5 or 6 days after their respective treatment. At necropsy, all nematodes recovered from the gastrointestinal tract were counted by species and stage. Results In both dose confirmation studies using geometric mean worm counts, effectiveness of Credelio Plus was ≥ 98.6% and ≥ 96.8% against L4 larval stage T. canis and immature adult [L5] T. canis in both studies, respectively. Conclusions These studies demonstrated that the Credelio Plus combination tablet administered orally to dogs was highly efficacious against experimental infections with L4 and immature adult [L5] stages of T. canis.

Effectiveness of a novel orally administered combination drug product containing milbemycin oxime and lotilaner (Credelio® Plus) for the treatment of larval and immature adult stages of Ancylostoma caninum in experimentally infected dogs

Background The hookworm, Ancylostoma caninum, is a common and important zoonotic intestinal nematode parasite that infects dogs globally. Both the immature and adult stages of A. caninum ingest large volumes of blood during the feeding process and can cause severe anemia and death in young dogs, even before patent infections can be diagnosed using routine faecal examination methods. Thus, effective treatment of any pre-patent stages of immature hookworms can reduce or eliminate the risk of clinical disease in infected dogs and additionally reduce environmental contamination of eggs and infective larvae. Two randomized, blinded, GCP-compliant, pivotal laboratory dose confirmation studies were conducted to evaluate the effectiveness and safety of a new novel combination of lotilaner and milbemycin oxime tablets (Credelio Plus®) administered orally to dogs experimentally infected with immature (L4 and immature adult [L5]) stages of A. caninum. Methods Treatments using the intended global commercial tablet formulation of Credelio Plus were administered in a time frame relative to inoculation with infective larvae so that effectiveness could be assessed against each specific immature stage of A. caninum. In each study, dogs were randomized to one of six (study 1) or four (study 2) treatment groups. Each treatment group contained 8 (study 1) or 10 (study 2) dogs that had been experimentally inoculated with infective A. caninum larvae on day 0 and were dosed once on day 7 or day 11. Enrolled subjects were administered placebo tablets, Credelio Plus tablets, or lotilaner mono tablets to provide minimum dosages of 0.75 mg/kg of milbemycin oxime and 20 mg/kg of lotilaner. All dogs were necropsied 5 days after their respective treatment. All nematodes recovered from the gastrointestinal tract at necropsy were counted by species and stage. Results For both dose confirmation studies and based on geometric mean worm counts, efficacy of Credelio Plus was ≥ 97.3% against L4 larval stage of A. caninum and ≥ 98.7% against immature adult (L5) A. caninum. Conclusions These studies demonstrated that the orally administered Credelio Plus combination tablet was highly efficacious in treating immature (L4 and immature adult [L5]) stages of A. caninum in experimentally infected dogs.