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Introduction
Published in Shein-Chung Chow, Innovative Statistics in Regulatory Science, 2019
Regarding model-informed drug development (MIDD), as indicated by PDUFA VI, MIDD can be classified into six categories: (i) PK/PD; (ii) PK, population PK (POPPK); and physiologically based PK (PBPK) modeling; (iii) disease models including clinical trial model; (iv) system biology: quantitative system pharmacology (QSP) and congenital insensitivity to pain with anhidrosis (CIPA); (v) quantitative structure activity relationship (QSAR) and quantitative structure property relationship (QSPR); and (vi) clinical trial simulation (see Figure 1.5). Statistically speaking, MIDD is to study response-exposure relationship, which can be performed in the following steps: (i) model building, (ii) model validation, and (iii) model generalizability. Model building may involve the identification of risk factors (predictors), test for collinearity, and goodness-of-fit. For model validation, a typical approach is to randomly split the data into two sets: one for model building and one for model validation. At this stage of model validation, it is considered internal validation. For external validation, it is usually referred to as model generalizability, i.e., the predictive model can be generalized from one patient population to another or from one medical center to another.
Preclinical target validation for non-addictive therapeutics development for pain
Published in Expert Opinion on Therapeutic Targets, 2022
Richard Hargreaves, Karen Akinsanya, Seena K. Ajit, Neel T. Dhruv, Jamie Driscoll, Peter Farina, Narender Gavva, Marie Gill, Andrea Houghton, Smriti Iyengar, Carrie Jones, Annemieke Kavelaars, Ajamete Kaykas, Walter J. Koroshetz, Pascal Laeng, Jennifer M. Laird, Donald C. Lo, Johan Luthman, Gordon Munro, Michael L. Oshinsky, G. Sitta Sittampalam, Sarah A. Woller, Amir P. Tamiz
Numerous retrospective analyses indicate that targets supported by human genetics are more likely to succeed in the clinic than targets without such evidence [17]. Although most of the examples are from non-pain indications there are a few clear examples for pain targets through human genetic studies. Studies of families with either pain insensitivity or hypersensitivity revealed genes that have significant contribution to sensation of pain [18]. A large Swedish family with pain free joint destruction found to carry a mutation in the nerve growth factor beta (NGFB) gene causing insensitivity to deep pain without anhidrosis (hereditary sensory and autonomic neuropathy, type V; HSAN V) [19]. Biallelic loss of function in NGF has been found to be the underpinning cause of congenital insensitivity to pain and anhidrosis (CIPA) of consanguineous families. Furthermore, carriers of biallelic loss of function mutations in the NGF receptor TRKA have also been found to have CIPA [20]. Similarly, carriers of loss-of-function mutations within the sodium channel gene SCN9A have been found to have no pain sensation whereas gain-of-function mutations underlie Erythromelalgia [21].
Neurotrophic Keratopathy in Pediatric Patients
Published in Seminars in Ophthalmology, 2021
Separate from this classification system but also a congenital cause of neurotrophic keratopathy is Congenital Insensitivity to Pain with Anhidrosis (CIPA). This disorder is characterized by an abnormal or absent response to painful stimuli, anhidrosis, and intellectual disability. It occurs as a result of a mutation in the neurotrophic tyrosine kinase receptor type 1 gene which encodes the receptor for nerve growth factor, a protein required for nervous system organization and function, specifically sympathetic and sensory neurons. In a recent case series from Jordan, Masri et al. chronicled seven patients with CIPA, four of whom developed corneal ulcers that were attributed to decreased innervation of corneal tissue.11
A Child Presenting with Recurrent Corneal Ulcers: Hereditary Sensory and Autonomic Neuropathy IV (HSAN IV)
Published in Neuro-Ophthalmology, 2019
Beena Suresh, Vaishnavi Reddy, Ingo Kurth, Sujatha Jagadeesh
Hereditary sensory and autonomic neuropathy type IV (HSAN IV), also called as congenital insensitivity to pain with anhidrosis (CIPA) or Nishida syndrome, is an autosomal recessive disorder characterized by recurrent episodic fevers, anhidrosis, absence of reaction to noxious stimuli, self-mutilating behaviour and mental retardation. HSAN IV is due to the absence of afferent neurons, which are activated by tissue-damaging stimuli. Nerve growth factor (NGF) supports the survival of nociceptive sensory and autonomic sympathetic neurons as well as cholinergic neurons of the basal forebrain. Defects in NGF signal transduction at its receptor leads to failure of neuronal survival. 2–4