Drugs

Plocque, Alexia; Mitri, Christie; Lefèvre, Charlène; Tabary, Olivier; Touqui, Lhousseine; Philippart, Francois

doi: 10.1007/s40265-022-01803-2pmid: 36508116

Severe manifestations of COVID-19 consist of acute respiratory distress syndrome due to an initially local reaction leading to a systemic inflammatory response that results in hypoxia. Many therapeutic approaches have been attempted to reduce the clinical consequences of an excessive immune response to viral infection. To date, systemic corticosteroid therapy is still the most effective intervention. More recently, new hope has emerged with the use of interleukin (IL)-6 receptor inhibitors (tocilizumab and sarilumab). However, the great heterogeneity of the methodology and results of published studies obfuscate the true value of this treatment, leading to a confusing synthesis in recent meta-analyses, and the persistence of doubts in terms of patient groups and the appropriate time to treat. Moreover, their effects on the anti-infectious or pro-healing response are still poorly studied. This review aims to clarify the potential role of IL-6 receptor inhibitors in the treatment of severe forms of COVID-19.

Williams, C. D.; Al-Jammali, Z.; Herink, M. C.

doi: 10.1007/s40265-022-01810-3pmid: 36529848

Use of the gabapentinoids for pain continues to increase. In 2018, the US Food and Drug Administration (FDA) strengthened the warnings for both gabapentin and pregabalin to emphasize the central nervous system side effects and the risk of respiratory depression, especially when combined with other centrally acting drugs. We reviewed the published comparative effectiveness literature for gabapentinoids for pain as well as all trials (published and unpublished) used by the FDA for the approval of the five pain indications for these agents (one for gabapentin, four for pregabalin). Among the findings of interest are the fact that the FDA rejected the application for gabapentin for diabetic peripheral neuropathy based on the risk versus benefit profile of that drug in the clinical trials that were submitted by the manufacturer. Additionally, both the comparative effectiveness trials as well as the studies used by the FDA tend to be short in duration and show only modest pain benefits for the gabapentinoids. The placebo response in these trials was frequently one-third to one-half as great as the pain benefit demonstrated by the gabapentinoid. Based on the available clinical trial evidence, we feel prescribers should be cautious when using gabapentinoids for pain, particularly when using these agents for a prolonged period or when combined with other, centrally acting agents.

Khosroyani, Homma M.; Klug, Lillian R.; Heinrich, Michael C.

doi: 10.1007/s40265-022-01820-1pmid: 36607590

Prior to the early 2000s, patients with advanced gastrointestinal stromal tumors (GIST) had very poor prognoses owing to a lack of effective therapies. The development of tyrosine kinase inhibitors at the turn of the century significantly improved the overall survival for patients with GIST. The resounding success of imatinib in the first clinical trial of a tyrosine kinase inhibitor to treat GIST led to its approval for first-line therapy for advanced GIST; this study was open to all comers and not restricted to any GIST subtype(s). The trials that led to the approvals of second-, third-, and fourth-line therapy for advanced GIST were also open to all patients with advanced/metastatic GIST. Only in retrospect do we realize the role that the molecular subtypes played in the results observed in these studies. In this review, we discuss the studies that led to the US Food and Drug Administration approval of imatinib (first line), sunitinib (second line), regorafenib (third line), and ripretinib (fourth line) for advanced KIT-mutant GIST. In addition, we review how information about GIST molecular subtypes has been used to accelerate the approval of other targeted therapies for non-KIT mutant GIST, leading to the approval of five additional drugs indicated for the treatment of specific GIST molecular subtypes. We also discuss how our understanding of the molecular subtypes will play a role in the next generation of therapeutic approaches for treating advanced GIST.

Chen, Lu; Krekels, Elke H. J.; Heijnen, Anne R.; Knibbe, Catherijne A. J.; Brüggemann, Roger J.

doi: 10.1007/s40265-022-01819-8pmid: 36607589

BackgroundPosaconazole is widely used for the prophylaxis and treatment of invasive fungal diseases. Because of the limited and variable absorption of the initially available oral suspension, a delayed-release tablet and intravenous formulation were developed.ObjectiveThis study aimed to characterize the pharmacokinetics, including the absolute oral bioavailability, of all posaconazole formulations in healthy volunteers.MethodsData from 182 healthy volunteers with 3898 densely sampled posaconazole concentrations were pooled from eight phase I clinical studies on the three formulations of various single and multiple dosage regimens between 50 and 400 mg. Analysis and simulations were performed using NONMEM 7.5.0. In the covariate analysis, the influence of food (fed vs fasted), nonlinearity, and for the delayed-release tablet, comedication (antacid, ranitidine, esomeprazole, and metoclopramide) were tested.ResultsA two-compartment model with respectively, four and eight absorption transit compartments, best described the profiles of the oral suspension and delayed-release tablet. For the suspension, both a food effect and a dose-dependent nonlinear bioavailability were quantified, resulting in lower bioavailability when fasted or at a higher dose. The typical bioavailability of the suspension at 100 mg and 400 mg was derived to be respectively, 17.1% and 10.1% under fasted conditions and 59.1% and 49.2% under fed conditions. The absolute bioavailability of the delayed-release tablet was 58.8% (95% confidence interval 33.2–80.4) under fasted conditions and approached complete absorption under fed conditions for dosages up to 300 mg. Food intake reduced the absorption rate constant of the suspension by 52.2% (confidence interval 45.2–59.2). The impact of comedication on the absorption of the delayed-release tablet was not statistically significant. Model-based simulations indicate that under fed conditions, the licensed dosages of the three formulations yield a steady-state trough concentration ≥ 0.7 mg/L in over 90% of healthy volunteers. About 35% of healthy volunteers who receive the licensed 300-mg delayed-release tablet under fasted conditions do not achieve this target, while for the suspension this percentage varies between 55 and 85%, depending on the dose.ConclusionsFor both oral posaconazole formulations, we quantified bioavailability and absorption rate, including food effects, in healthy volunteers. The pharmacokinetic superiority of the delayed-release tablet was demonstrated under both fed and fasted conditions, compared with the oral suspension. The impact of food on the bioavailability of the delayed-release tablet was larger than anticipated, suggesting that administering the delayed-release tablet with food enhances absorption.

Keam, Susan J.

doi: 10.1007/s40265-022-01821-0pmid: 36509938

Ozoralizumab (Nanozora®), a trivalent anti-tumour necrosis factor alpha (TNFα) NANOBODYⓇ compound, has been developed by Taisho Pharmaceutical Co. Ltd (under license from Ablynx, an affiliate of Sanofi) for the treatment of rheumatoid arthritis (RA). In September 2022, ozoralizumab was approved in Japan for the treatment of RA that is inadequately managed by current available treatments. This article summarizes the milestones in the development of ozoralizumab leading to this first approval.

Keam, Susan J.

doi: 10.1007/s40265-022-01827-8pmid: 36571670

Tremelimumab (tremelimumab-actl; IMJUDO®), a cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) blocking antibody, is being developed by AstraZeneca, under license from Pfizer, for the treatment of a range of malignant tumours. Tremelimumab was approved in the USA in October 2022 in combination with durvalumab for the treatment of adult patients with unresectable hepatocellular carcinoma (uHCC). In addition, tremelimumab in combination with durvalumab and platinum-based chemotherapy was approved in the USA in November 2022 for the treatment of adult patients with metastatic non-small cell lung cancer (mNSCLC) with no sensitizing epidermal growth factor receptor mutation or anaplastic lymphoma kinase genomic tumour aberrations. In December 2022, tremelimumab in combination with durvalumab received a Positive Opinion from the EU Committee for Medicinal Products for Human Use for the first line treatment of adults with advanced or unresectable HCC. Tremelimumab in combination with durvalumab is under regulatory review for these indications in Japan and in other countries worldwide. This article summarizes the milestones in the development of tremelimumab leading to this first approval.

Blair, Hannah A.

doi: 10.1007/s40265-022-01825-wpmid: 36508117