Clinical Assessment of Potential Drug Interactions of Faldaprevir, a Hepatitis C Virus Protease Inhibitor, With Darunavir/Ritonavir, Efavirenz, and Tenofovir

Faldaprevir is a potent hepatitis C virus NS3/4A protease inhibitor. The findings from 3 phase 1 studies reported here suggest that faldaprevir can be safely coadministered with commonly used antiretroviral

Pharmacokinetics of indacaterol acetate and mometasone furoate delivered alone or in a free or fixed dose combination in healthy volunteers

Purpose: QMF149 is a fixed-dose combination of the long-acting β2 agonist, indacaterol acetate and the corticosteroid, mometasone furoate that is currently under development for treatment of patients with asthma and chronic obstructive pulmonary disease. We describe here a study designed to assess any pharmacokinetic and/or biopharmaceutical interaction between indacaterol and mometasone furoate when administered via the Breezhaler® device, either alone or in a free or fixed combination (QMF149) in healthy adult volunteers. Methods: In this randomized, open-label, four-way crossover study, volunteers were randomised to receive indacaterol 150 µg, mometasone furoate 320 µg, alone and as free combination of the individual components, or QMF149 (indacaterol 150 μg /mometasone furoate 320 μg) once daily for 14 days in each period, followed by a 7-day washout between periods. Pharmacokinetic parameters were characterised on Day 14 up to 168 h post-dose. Results: Indacaterol AUC0-24h,ss and Cmax,ss after administration of QMF149 were 13% [ratio: 1.13; 90%CI: 1.09, 1.17] and 18% [ratio: 1.18; 90%CI: 1.12, 1.25] higher, respectively, than indacaterol monotherapy. Mometasone furoate AUC0-24h,ss and Cmax,ss after administration of QMF149 were 14% [ratio: 1.14; 90%CI: 1.09, 1.20] and 19% [ratio: 1.19; 90%CI: 1.13, 1.26], , higher, respectively than mometasone furoate monotherapy. The majority of the 90% confidence intervals of the between-treatment ratios for AUC0-24h,ss and Cmax,ss were within the 0.8 to 0.125 interval and therefore fulfilled bioequivalence criteria. The results of this study showed that there are no clinically meaningful changes in exposure between the treatment with the individual components and combination treatments. Multiple inhaled doses of indacaterol and mometasone furoate, when administered alone, in free combination or as QMF149 were well tolerated. Conclusions: The QMF149 fixed dose combination treatment showed comparable systemic exposure to the free combination and monotherapy treatments in terms of AUC0-24h,ss and Cmax,ss for both indacaterol and mometasone furoate, indicating a lack of clinically relevant PK or biopharmaceutical interaction. These data support further development of QMF149 without dose adjustment

Nanoparticle-based oral formulation can surprise you with inferior in vivo absorption in humans

Particle size reduction leads to an increase in the drug dissolution rate, which in turn can lead to a substantial increase in the bioavailability of a poorly soluble compound. To improve bioavailability, a practically insoluble investigational drug, ODM-106, was nanomilled and capsule formulations with three different drug amounts were prepared for the first-in-man study. Fast in vitro dissolution was achieved from all the capsules containing different amounts of drug nanoparticles but in the clinical study, surprisingly, low bioavailability was observed from the highest capsule strength (100 mg) in comparison to a lower strength (10 mg). In order to study further the discrepant in vitro-in vivo correlation (IVIVC), a discriminative dissolution method was developed. It was noticed that the degree of supersaturation increased significantly as the stabilizers’ concentration within the dried nanoformulations was increased. Hypromellose provided a physical barrier between nanoparticles to prevent aggregation during drying. SLS on the other hand improved wettability and provided supersaturation. The drug load, nanoparticle/polymer/surfactant/filler ratios and selected drying step were discovered to be critical to the nanoformulations’ performance. Aggregation of nanoparticles, in the absence of optimal stabilizer concentration, compromised dissolution due to decreased surface area. In conclusion, the early development of a discriminative dissolution method and cautious selection of the nanoparticle/polymer ratio before manufacturing clinical batches is recommended.Peer reviewe

A Phase 1 study of the long‐acting anti‐IL‐5 monoclonal antibody GSK3511294 in patients with asthma

AIMS: GSK3511294 is a humanized anti‐interleukin (IL)‐5 monoclonal antibody (mAb) engineered for extended half‐life and improved IL‐5 affinity versus other anti‐IL‐5 mAbs. This study examined its safety, tolerability, pharmacokinetics (PK) and effect on blood eosinophil counts. METHODS: This was a double‐blind, parallel‐group, single‐ascending‐dose, multicenter, Phase 1 study (205 722;NCT03287310) in patients with asthma and a blood eosinophil count ≥200 cells μL(−1). Patients were randomized 3:1 within dose cohorts to receive a single subcutaneous dose of GSK3511294 (2, 10, 30, 100 or 300 mg) or placebo and followed for up to 40 weeks to assess safety (primary endpoint), ratio to baseline in blood eosinophil count, plasma PK parameters and frequency/titers of binding antidrug antibodies (all secondary). RESULTS: Forty‐eight patients received the study drug and completed the study. Adverse events (AEs) occurred in 92% of placebo‐treated and 81% of GSK3511294‐treated patients. There were no AEs leading to study withdrawal or serious AEs; hypersensitivity (one event in one patient) and injection‐site reaction (three events in two patients) occurred infrequently. Marked reductions (>48%) in blood eosinophil count were seen from 24 hours post‐dose with all GSK3511294 doses but not placebo; suppression was maintained for longer with increasing dose (82% and 83% adjusted reductions vs placebo with 100 and 300 mg, respectively, at week 26). PK were linear and dose proportional over the dose range; terminal half‐life was 38‐53 days. CONCLUSIONS: GSK3511294 was well tolerated, with linear and dose proportional PK, extended half‐life and blood eosinophil count reduction, supporting less frequent dosing versus other anti‐IL‐5 mAbs

Efficacy of apolipoprotein B synthesis inhibition in subjects with mild-to-moderate hyperlipidaemia

Mipomersen, an apolipoprotein (apo) B synthesis inhibitor, has been shown to produce potent reductions in apoB and LDL-cholesterol levels in animal models as well as healthy human volunteers. A randomized, double-blind, placebo-controlled, dose-escalation study was designed to evaluate the efficacy and safety of mipomersen monotherapy with or without dose loading in subjects with mild-to-moderate hyperlipidaemia. Fifty subjects with LDL-cholesterol levels between 119 and 266 mg/dL were enrolled into five cohorts at a 4:1 randomization ratio of active to placebo. Two 13-week dose regimens were evaluated at doses ranging from 50 to 400 mg/week. Mipomersen produced dose-dependent reductions in all apoB containing lipoproteins. In the 200 and 300 mg/week dose cohorts, mean reductions from baseline in LDL cholesterol were -45 ± 10% (P= 0.000) and -61 ± 8% (P= 0.000), corresponding to a -46 ± 11% (P= 0.000) and -61 ± 7% (P= 0.000) decrease in apoB levels. Triglyceride levels were also lowered with median reductions up to 53% (P= 0.021). The most common adverse events were injection site reactions. Seven of 40 subjects (18%) showed consecutive transaminase elevations >3× upper limit of normal. Five of these subjects received 400 mg/week, four of whom had apoB levels below the limit of detection. As a consequence, the 400 mg/week cohort was discontinued. Mipomersen administered as monotherapy in subjects with mild-to-moderate hyperlipidaemia produced potent reductions in all apoB-containing lipoproteins. Higher doses were associated with hepatic transaminase increase

Omalizumab Protects against Allergen-Induced Bronchoconstriction in Allergic (Immunoglobulin E-Mediated) Asthma

<p>Background: Omalizumab has been shown to suppress responses to inhaled allergens in allergic asthma patients with pretreatment immunoglobulin E (IgE)</p>