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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The FDA approved trastuzumab emtansine in 2013 for HER2+ve metastatic breast cancer in patients who have been treated previously with trastuzumab and a taxane (i.e., paclitaxel or docetaxel), and who have already been treated for metastatic breast cancer or have developed tumor recurrence within six months of adjuvant therapy. At the request of the FDA, in the US this agent was approved with the generic name of “ado-trastuzumab emtansine”, rather than the original USAN (United States Adopted Name) name of “trastuzumab emtansine” issued in 2009 to help prevent dispensing errors. During preclinical development and clinical trials, it also became known as trastuzumab-DM1 or T-DM1 (DM1 = mertansine) or trastuzumab-MCC-DM1 (MCC-DM1 = emtansine).
Regulators and Regulations
Published in Mickey C. Smith, E.M. (Mick) Kolassa, Walter Steven Pray, Government, Big Pharma, and the People, 2020
Mickey C. Smith, E.M. (Mick) Kolassa, Walter Steven Pray
Generic names are produced by the U.S. Adopted Names Council (USAN), a non-governmental Agency, with representatives from American Medical Association, American Pharmaceutical Association, the FDA, and the U.S. Pharmacopeia (USP). The latter is also non-governmental and more than 200 years old. The USP is also the name of a compendium of Drugs which, along with a companion compendium, the National Formulary, contains a “description, method of preparation and dosage for virtually all drugs”. Both are accepted worldwide. At one time, some States required every Pharmacy to maintain a current copy of both the USP and NF. No more.
Sacituzumab govitecan, a novel, third-generation, antibody-drug conjugate (ADC) for cancer therapy
Published in Expert Opinion on Biological Therapy, 2020
David M. Goldenberg, Robert M. Sharkey
Experimentation showed that in-vitro stability in serum determined the conjugate of choice, with a linker designated CL2 having an intermediate stability of 1–2 days [76]. This linker was then modified further to remove phenylalanine at the cathepsin B cleavage site (CL2A derivative), which did not affect the rate of SN-38 release [74,78]. By using a less-stable linker, it was anticipated that SN-38 would become accessible to tumor cells in the immediate environment, and not only the cells directly targeted by SG (‘bystander effect’) [74,77]. This conjugate of CL2A-SN-38 coupled to a humanized anti-TROP-2 antibody was designated IMMU-132, but later named sacituzumab govitecan by the United States Adopted Names Council (USAN), and then had the suffix hziy added by FDA.
A systematic review of European regional and national guidelines: a focus on the recommended use of nabiximols in the management of spasticity in multiple sclerosis
Published in Expert Review of Neurotherapeutics, 2022
Francisco Javier Carod-Artal, Peyman Adjamian, Carlos Vila Silván, Makarand Bagul, Claudio Gasperini
As well as non-pharmacological treatments, for example, physiotherapy [5,6], a range of classic pharmacological anti-spasticity treatments can be prescribed to manage MSS [7]. Well-established options include baclofen, benzodiazepines (e.g. diazepam), tizanidine, and dantrolene, all of which are available for over 30 years [7]. Some alternative treatments, for example, tizanidine, not available in all countries and gabapentin (which is not specifically approved for the management of MSS and is mainly indicated for the treatment of neuropathic pain), are also becoming established in clinical practice [7]. However, these treatments are not effective or are intolerable in a proportion of individuals, as reviewed by Beard et al. (2003) [7]. Those who are non-responsive to, or who cannot tolerate these treatments can become eligible for the cannabinoid-based medicine, Sativex® oromucosal spray (GW/Jazz Pharmaceuticals). This option is currently licensed in some, predominantly European countries and despite not being approved in the USA, its United States Adopted Name (USAN), ‘nabiximols,’ has become a widely recognized generic term for Sativex oromucosal spray. Approximately 50–70% [8–10] of individuals with inadequate response to previously prescribed anti-spasticity treatments have been shown to respond to this medicine. Another option for resistant spasticity, which has been shown to be effective, is the intrathecal baclofen subcutaneous pump, requiring a surgical implant of the pump and a catheter [11,12]. Complexity of implant and maintenance, risk of complications including toxicity and withdrawal [13] limit the use of this option and this is typically reserved for the treatment of severe spasticity.
Today’s drug discovery and the shadow of the rule of 5
Published in Expert Opinion on Drug Discovery, 2023
The seminal contribution of Lipinski, Lombardo, Dominy, and Feeny describing ‘Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings’ [1] and the identical reprint in a commemorative issue of the same journal in 2001 [2] together present one of the most cited and influential papers in Medicinal Chemistry. This remarkable piece of scholarship presented a reasoned and well-substantiated case for restraint in the selection, design, and prioritization of experimental molecules in the era of drug discovery dominated by high-throughput screening (HTS). Experience of the authors in handling many compounds with suboptimal pharmacological properties, often characterized by poor solubility and/or poor permeability, prompted a comparative physical characterization of contemporary molecules at Pfizer with representative compounds that progressed in clinical trials, identified by their US Adopted Names (USAN). The simplicity of the message was designed to influence the profound pattern recognition skills of medicinal chemists. A discussion and critical assessment of methodology used was followed by many inciteful and prescient comments on the progression of molecules and their likelihood of positive future progression. To many, this became a framework to work within and a tool used by management to assess teams and construct identikit product profiles to define expectations in the HTS-fueled discovery pipelines [3]. Furthermore, the guidelines became synonymous to the term ‘drug like,’ suggesting that compounds within the prescribed limits could become drugs based on these properties [4], despite noted caveats and the methodology employed in the publications [5].