Expert opinion on drug metabolism & toxicology
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Expert Opin Drug Metab Toxicol · Feb 2019
ReviewNovel β-lactam-β-lactamase inhibitor combinations: expectations for the treatment of carbapenem-resistant Gram-negative pathogens.
The burden of antimicrobial resistance among Gram-negative bacteria is increasing and growing into a major threat of public health. Treatment options for carbapenem-resistant Enterobacteriaceae are limited and resistance rates to existing compounds are mounting. The pipeline includes only a small number of novel anti-infective agents in development or in the market with promising results against multidrug-resistant (MDR) Gram-negative. ⋯ Expert opinion: Ceftazidime-avibactam and meropenem-vaborbactam are promising therapeutic options as both are active against Enterobacteriaceae producing ESBL, AmpC, and KPC, whereas only avibactam inhibits certain class D β-lactamases, mainly OXA-48. New drugs active against Gram-negative MDR isolates including imipenem/cilastatin with relebactam and avibactam combined with aztreonam or ceftaroline are in different stages of development. However, the disadvantage to be seriously considered by the clinician is that β-lactam/β-lactamase inhibitors are ineffective against metallo-β-lactamases (with the exception of aztreonam-avibactam) as well as Acinetobacter baumannii.
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Expert Opin Drug Metab Toxicol · Dec 2018
ReviewSafety and performance of current abuse-deterrent formulations.
Prescription opioid abuse is now an epidemic that has forced the government and industries to take initiatives. These include developing abuse-deterrent formulations (ADFs), issuing regulatory guidances and allocating massive budgets to ensure the safety and effectiveness of these medications. Areas covered: This review covers the regulatory guidance on evaluation and labeling of the branded and generic ADFs. ⋯ Expert opinion: Despite the development of a dozen products with abuse-deterrent features, most of these technologies rely on the same deterrent agent, making it easier for abusers to focus their manipulation efforts and share their experience to defeat the technology. Further advancement in the field requires developing more robust, more diverse, safer, and affordable deterrent technologies for the extended- and immediate-release opioid products. Moreover, advances in the reporting of the post-market results, issuance of policies in support of the ADFs, and concurrent monitoring of the illicit opioid market are other considerations that can further help in confronting the epidemic.
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Expert Opin Drug Metab Toxicol · Jul 2018
ReviewNew paradigm for rapid achievement of appropriate therapy in special populations: coupling antibiotic dose optimization rapid microbiological methods.
Some special patient populations (e.g. critically ill, burns, hematological malignancy, post-major surgery, post-major trauma) have characteristics that lead to higher rates of failure and mortality associated with infection. Choice of effective antibiotics and optimized doses are challenging in these patients that are commonly infected by multidrug-resistant pathogens. Areas covered: A review of the importance of diagnosis and the place of newer microbiological methods (e.g. whole-genome sequencing) to ensure rapid transition from empiric to directed antibiotic therapy is provided. ⋯ Expert opinion: Product information dosing regimens do not address the pharmacokinetic alterations that can occur in special patient populations and increase the likelihood of therapeutic failure and the emergence of bacterial resistance. Altered dosing approaches, supplemented with the use of dosing software and therapeutic drug monitoring, may be needed to ensure optimal antibiotic exposure and better therapeutic outcomes in these patients with severe infection. Dose optimization needs to be coupled with advanced microbiological techniques that enable rapid microbiological identification and characterization of resistance mechanism to ensure that maximally effective directed therapy can be chosen.
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Expert Opin Drug Metab Toxicol · May 2018
ReviewPharmacokinetic drug evaluation of niraparib for the treatment of ovarian cancer.
Ovarian cancer is a disease with a propensity to recur despite dramatic responses to initial treatment, which typically consists of a combination of cytoreductive surgery and platinum-based chemotherapy. A maintenance therapy, which may prevent or delay relapse while not negatively impacting quality of life, is critical to improving outcomes. Areas covered: This review discusses the pharmacologic properties, clinical efficacy, and safety profile of niraparib, a poly(ADP-ribose) polymerase (PARP) inhibitor indicated for the maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. ⋯ Food and Drug Administration (FDA) for the maintenance treatment of recurrent ovarian cancer, regardless of a patient's germline or somatic mutational status. This approval has had a sweeping impact on treatment strategies, moving the indication for a PARP inhibitor earlier in the treatment course and greatly expanding the population of patients who may benefit from this class of drugs. Active clinical trials suggest that new indications and novel treatment combinations are eagerly sought.
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Expert Opin Drug Metab Toxicol · Apr 2018
ReviewLenvatinib in the management of metastatic renal cell carcinoma: a promising combination therapy?
To date, results of combination therapy studies have shown no meaningful clinical benefit over monotherapy and an unacceptably high degree of toxicity in the treatment of metastatic renal cell carcinoma (RCC), with the exception of a combination of immune-checkpoint inhibitors and the association of lenvatinib with everolimus. Lenvatinib is a potent multi-targeted tyrosine kinase inhibitor that targets VEGFR pathways. Everolimus inhibits primarily mTORC1 complex, a downstream effecter of the intracellular PI3K/AKT/mTOR pathway. ⋯ Expert opinion: Lenvatinib plus everolimus showed promising results in a phase II trial, leading to FDA approval of this combination. Their synergic action on inhibiting the VEGF/VEGFR, FGF (a compensatory mechanism to VEGFR inhibition) and mTOR pathway could be a potential mechanism to overcome treatment resistance. Given that the activity of lenvatinib as an immune-regulator in tumor microenvironment has been demonstrated in cell lines, novel combinations, in particular with immune-checkpoint inhibitors, are under development.