Expert opinion on drug metabolism & toxicology
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Expert Opin Drug Metab Toxicol · Apr 2017
ReviewPharmacokinetic drug evaluation of ceftobiprole for the treatment of MRSA.
Methicillin-resistant Staphylococcus aureus (MRSA), while decreasing in overall incidence, is still a prominent concern world-wide. New agents coming to market in the last 10 years allow practitioners to optimize treatment for MRSA infections. Ceftobiprole is a cephalosporin agent with MRSA activity, currently approved in selected countries for the treatment of community-acquired pneumonia and hospital-acquired pneumonia. ⋯ Concern for appropriate dosing in critically ill patients remains due to its ineffectiveness for the treatment of ventilator-associated pneumonia (VAP). While ceftobiprole has activity against gram-negative organisms, the allowance for use of an additional agent for gram-negative infections in clinical trials limits recommendations for monotherapy for empirical treatment of HAP. Ceftobiprole's place in therapy will lie in its activity against gram positive organisms, such as Streptococcus spp. and Staphylococcus spp.
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Expert Opin Drug Metab Toxicol · Dec 2016
ReviewPharmacokinetic drug evaluation of selexipag for the treatment of pulmonary arterial hypertension.
Management of pulmonary arterial hypertension (PAH) remains challenging even in the contemporary era. Intravenous prostacyclin therapy, while associated with decreased mortality, has practical limitations and requires significant lifestyle modifications. The recently approved long-acting oral IP prostacyclin receptor agonist for treatment of PAH, selexipag, is a non-prostanoid agent that vasodilates, impacts remodeling (anti-proliferative), reduces endothelial cell dysfunction, inhibits platelet aggregation (anti-thrombotic), and increases right heart inotropy. ⋯ We further discuss the methodology and results of phase II and III trials, which led to approval of selexipag for PAH management. Expert opinion: As compared to previously developed oral prostacyclins, selexipag has limited adverse effects despite similar or better efficacy. Its final place in the treatment paradigm is not yet clear but it does represent a significant advance in the area of oral PAH therapy.
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Expert Opin Drug Metab Toxicol · Nov 2016
Pharmacokinetic and pharmacodynamic evaluation of ibrutinib for the treatment of chronic lymphocytic leukemia: rationale for lower doses.
Ibrutinib, a first-in-class covalent inhibitor of Bruton's tyrosine kinase (BTK), is approved in many countries for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) and for previously untreated disease with a 17p deletion and, most recently, as a frontline therapy for CLL. In controlled trials in CLL, ibrutinib produced high response rates and improved survival in both the frontline and relapsed settings. While ibrutinib controls CLL with impressive efficacy, it only infrequently induces complete remissions, particularly of relapsed CLL, and does not eradicate minimal residual disease. ⋯ Major clinical trials of ibrutinib in CLL are summarized, and its safety profile explored. Expert opinion: Ibrutinib represents a transformative advance in CLL management and has validated BTK as a therapeutic target in this disease, but has some limitations, leading to the emergence of other BTK inhibitors and mechanism-based combination strategies. Given complete BTK occupancy at lower doses of ibrutinib and declining levels of BTK on ibrutinib therapy, lower doses of ibrutinib in CLL are being explored.
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Expert Opin Drug Metab Toxicol · Oct 2016
ReviewPharmacotherapy during pediatric extracorporeal membrane oxygenation: a review.
Pediatric critical illness and associated alterations in organ function can change drug pharmacokinetics (PK). Extracorporeal membrane oxygenation (ECMO), a life-saving therapy for severe cardiac and/or respiratory failure, causes additional PK alterations that affect drug disposition. ⋯ Clinicians caring for pediatric patients treated with ECMO must have an understanding of PK alterations that could lead to either therapeutic failures or increased drug toxicity during this life-saving therapy. Limited data currently exist for optimal drug dosing in pediatric populations who are treated with ECMO. While there are clear challenges to conducting and analyzing data associated with clinical pharmacokinetic-pharmacodynamic studies of children on ECMO, we present techniques to address these challenges. Improved understanding of the physiology and drug disposition during ECMO combined with PK-PD modeling will allow for more adaptable and individualized dosing schemes.
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Expert Opin Drug Metab Toxicol · Oct 2016
ReviewEvaluation of the pharmacokinetics and metabolism of pembrolizumab in the treatment of melanoma.
Advanced melanoma is a devastating disease that has propelled research in therapeutics beyond chemotherapy and radiotherapy. Being highly immunogenic, melanoma is a model tumor for immunotherapy and has highlighted the therapeutic potential of the immune checkpoint inhibitors. ⋯ Pembrolizumab was the first PD-1 inhibitor to be approved by the U.S. Food and Drug Administration (FDA). Remarkably, this accelerated approval for the treatment of advanced, heavily pretreated melanoma was based on response rates alone from a phase I trial. As anticipated, pembrolizumab confirmed a survival advantage in phase II and III trials and has led the way for the study of other drugs that share its mechanism of action. Defining disease and patient characteristics associated with a response remains amongst the most pressing priorities.