MedGen

Vitamin D-dependent rickets-3 (VDDR3) is characterized by early-onset rickets, reduced serum levels of the vitamin D metabolites 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and deficient responsiveness to the parent molecule as well as activated forms of vitamin D (Roizen et al., 2018). For discussion of genetic heterogeneity of vitamin D-dependent rickets, see 264700. [from OMIM]

Ondansetron and tropisetron are highly specific and selective members of the 5-HT3 receptor antagonists and are used for the prevention of chemotherapy-induced, radiation-induced and postoperative nausea and vomiting. While tropisetron is extensively metabolized by CYP2D6 to inactive metabolites, ondansetron is metabolized by multiple cytochrome P450 enzymes including CYP3A4, CYP1A2 and CYP2D6, though there is substantial data to support a major role of CYP2D6 in ondansetron metabolism. For both drugs, there is evidence linking the CYP2D6 genotype with phenotypic variability in drug efficacy. CYP2D6 ultrarapid metabolizers may have increased metabolism of the drugs, resulting in decreased drug efficacy. There are suitable alternatives to ondansetron and tropisetron that are not affected by CYP2D6 metabolism. Therapeutic guidelines for ondansetron and tropisetron based on CYP2D6 genotype have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and are available on the PharmGKB website. [from PharmGKB]

Esomeprazole (brand name Nexium) is a proton pump inhibitor (PPI) used to treat gastroesophageal reflux disease (GERD) and to reduce the risk of gastric ulcers associated with nonsteroidal anti-inflammatory drug NSAID use. Esomeprazole is also used in the treatment of hypersecretory conditions, such as Zollinger-Ellison syndrome, and in combination with antibiotics to eradicate Helicobacter pylori (H. pylori) infection. Esomeprazole reduces the acidity (raises the pH) in the stomach by inhibiting the secretion of gastric acid. The level of esomeprazole an individual is exposed to is influenced by several factors, such as the dose used and how quickly the drug is metabolized and inactivated. Esomeprazole is primarily metabolized by the CYP2C19 enzyme. Individuals with increased CYP2C19 enzyme activity (“CYP2C19 ultrarapid metabolizers”) may have an insufficient response to standard doses of esomeprazole, because the drug is inactivated at a faster rate. In contrast, individuals who have reduced or absent CYP2C19 enzyme activity (i.e., CYP2C19 intermediate and poor metabolizers) have a greater exposure to esomeprazole. The 2018 FDA-approved drug label for esomeprazole states that 3% of Caucasians, and 15–20% of Asians are CYP2C19 poor metabolizers, and that poor metabolizers have approximately twice the level of exposure to esomeprazole, compared with CYP2C19 normal metabolizers. However, the drug label does not include dosing recommendations for CYP2C19 poor metabolizers. Esomeprazole recommendations have been published by the Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP), which indicates that no change in dosing is recommended for CYP2C19 poor, intermediate, or ultrarapid metabolizers. The DPWG states that although genetic variation in CYP2C19 influences the plasma concentration of esomeprazole, there is insufficient evidence to support an effect on treatment outcomes or side effects. [from Medical Genetics Summaries]

Clozapine is one of the most effective antipsychotics available in the treatment of schizophrenia and the only antipsychotic found to be effective in treatment-resistant schizophrenia (TRS). Clozapine is also used to reduce the risk of recurrent suicidal behavior in individuals with schizophrenia or schizoaffective disorder. Compared with typical antipsychotics, clozapine is far less likely to cause movement disorders, known as extrapyramidal side effects, which include dystonia, akathisia, parkinsonism, and tardive dyskinesia. However, there are significant risks associated with clozapine therapy that limits its use to only the most severely ill individuals who have not responded adequately to standard drug therapy. Most notably, because of the risk of clozapine-induced agranulocytosis, clozapine treatment requires monitoring of white blood cell counts (WBC) and absolute neutrophil counts (ANC), and in the US, the FDA requires that individuals receiving clozapine be enrolled in a computer-based registry. There is also a propensity for clozapine use to induce metabolic effects, resulting in substantial weight gain. Clozapine is metabolized in the liver by the cytochrome P450 (CYP450) superfamily of enzymes. The CYP1A2 enzyme is the main CYP enzyme involved in clozapine metabolism, and CYP1A2 activity is a potential determinant of clozapine dose requirements. Other CYP enzymes involved in clozapine metabolism include CYP2D6, CYP3A4, and CYP2C19. The FDA-approved drug label states that a subset of the population (2–10%) have reduced activity of CYP2D6 (“poor metabolizers”[PMs]) and these individuals may develop higher than expected plasma concentrations of clozapine with typical standard doses. Therefore, the FDA states that a dose reduction may be necessary in individuals who are CYP2D6 PMs. However, the Dutch Pharmacogenetics Working Group (DPWG) does not recommend dose alterations based on CYP2D6 genotype, though the gene-drug interaction is acknowledged. The DPWG further states that there is not a gene-drug interaction between CYP1A2 and clozapine due to the limited effect of known genetic variants on CYP1A2 function. Consequently, neither the FDA nor the DPWG recommend dose alterations based on CYP1A2 genotype. Additionally, clozapine clearance is affected by gender, tobacco use, and ethnicity, with further contributions from pharmacologic interactions. Females have lower CYP1A2 enzyme activity than males. Non-smokers have lower CYP1A2 activity than smokers and Asians and Amerindians have lower activity than Caucasians. Clozapine clearance can also be affected by co-medications that induce or inhibit CYP1A2 and the presence of inflammation or obesity. [from Medical Genetics Summaries]