Drug interactions

Drugs for allergy are often taken in combination with other drugs, either to treat allergy or other conditions. In common with many pharmaceuticals, most such drugs are subject to metabolism by P450 enzymes and to transmembrane transport. This gives rise to considerable potential for drug-drug interactions, to which must be added consideration of drug-diet interactions. The potential for metabolism-based drug interactions is increasingly being taken into account during drug development, using a variety of in silico and in vitro approaches. Prediction of transporter-based interactions is not as advanced. The clinical importance of a drug interaction will depend upon a number of factors, and it is important to address concerns quantitatively, taking into account the therapeutic index of the compound

Pharmacokinetics in special populations

Pharmacokinetics are typically dependent on a variety of physiological variables (e.g., age, ethnicity, or pregnancy) or pathological conditions (e.g., renal and hepatic insufficiency, cardiac dysfunction, obesity, etc.). The influence of some of these conditions has not always been thoroughly assessed in the clinical studies of antiallergic drugs. However, the knowledge of the physiological grounds of the pharmacokinetics can provide some insight for predicting the potential alterations and guiding the initial prescription strategies. It is important to recognize that both pharmacokinetic and pharmacodynamic differences between populations should be considered. The available information on drugs used for the therapy of allergic diseases is reviewed in this chapter

The EU Response to the Presence of Nitrosamine Impurities in Medicines

The unexpected detection of nitrosamine impurities in human medicines has recently seen global regulators act to understand the risks of these contaminations to patients and to limit their presence. Over 300 nitrosamines are known, many of which are highly potent mutagenic carcinogens. Regulators first became aware of the presence of nitrosamines in EU medicines in 2018, with reports of detection of N-nitroso-dimethylamine (NDMA) in valsartan from one manufacturer. A subsequent EU review of all valsartan medicines was triggered by the European Medicines Agency (EMA) and was later extended to other angiotensin receptor blockers/sartans. A separate review was also started for ranitidine medicines. This was followed by an EU-wide examination of the risk of presence of nitrosamines in all human medicines. This article reflects on the investigation of the EU regulatory network into the presence of nitrosamines and the scientific knowledge informing recommendations for developers on how to limit nitrosamines in medicines

Prioritisation of data-poor pharmaceuticals for empirical testing and environmental risk assessment

There are more than 3,500 active pharmaceutical ingredients (APIs) on the global market for human and veterinary use. Residues of these APIs eventually reach the aquatic environment. Although an environmental risk assessment (ERA) for marketing authorization applications of medicinal products is mandatory in the European Union since 2006, an ERA is lacking for most medicines approved prior to 2006 (legacy APIs). Since it is unfeasible to perform extensive ERA tests for all these legacy APIs, there is a need for prioritization of testing based on the limited data available. Prioritized APIs can then be further investigated to estimate their environmental risk in more detail. In this study, we prioritized more than 1,000 APIs used in Europe based on their predicted risk for aquatic freshwater ecosystems. We determined their risk by combining an exposure estimate (Measured or Predicted Environmental Concentration; MEC or PEC, respectively) with a Predicted No Effect Concentration (PNEC). We developed several procedures to combine the limited empirical data available with in silico data, resulting in multiple API rankings varying in data needs and level of conservativeness. In comparing empirical with in silico data, our analysis confirmed that the PEC estimated with the default parameters used by the European Medicines Agency often – but not always – represents a worst-case scenario. Comparing the ecotoxicological data for the three main taxonomic groups, we found that fish represents the most sensitive species group for most of the APIs in our list. We furthermore show that the use of in silico tools can result in a substantial underestimation of the ecotoxicity of APIs. After combining the different exposure and effect estimates into four risk rankings, the top-ranking APIs were further screened for availability of ecotoxicity data in data repositories. This ultimately resulted in the prioritization of 15 APIs for further ecotoxicological testing and/or exposure assessment

Drug metabolism and pharmacokinetics

In this article, aspects of absorption, distribution, metabolism, and excretion have been described bearing in mind the pathogenesis of allergic diseases and their possible therapeutic opportunities. The importance of the routes of administration of the different therapeutic groups has been emphasized. The classical aspects of drug metabolism and disposition related to oral administration have been reviewed, but special emphasis has been given to intranasal, cutaneous, transdermal, and ocular administration as well as to the absorption and the subsequent bioavailability of drugs. Drug-metabolizing enzymes and transporters present in extrahepatic tissues, such as nasal mucosa and the respiratory tract, have been particularly discussed. As marketed antiallergic drugs include both racemates and enantiomers, aspects of stereoselective absorption, distribution, metabolism, and excretion have been discussed. Finally, a new and promising methodology, microdosing, has been presented, although it has not yet been applied to drugs used in the treatment of allergic diseases

Commentary on the draft revised guideline on the environmental risk assessment of medicinal products for human use

Abstract Applicants for marketing authorisation for human medicinal products in the European Union must submit an environmental risk assessment which is assessed by assessors from the national competent authorities. The EMA guideline on the environmental risk assessment of medicinal products for human use came into effect on 1 December 2006. After 12 years’ experience with the guideline, the EMA has released for public consultation a draft revision of the guideline. The revision proposes significant substantive and structural changes to the guideline. The major changes proposed in the revision are outlined together with the rationale for the changes and the expected impact on stakeholders

EMA commentary on the ICH guideline for testing for carcinogenicity of pharmaceuticals

The global regulatory requirements for the assessment of the carcinogenic potential of pharmaceuticals provided for the conduct of long-term carcinogenicity studies in two rodent species, usually the rat and the mouse. Given the their extensive use of animals as well as the costs of these studies, it is in keeping with the mission of International Council on Harmonization of Technical Requirements of Pharmaceuticals for Human Use (ICH) to examine whether this practice requiring long-term carcinogenicity studies in two species could be reduced without compromising human safety