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Kenneth L Hastings

Publications and source records attributed to Kenneth L Hastings.

9 recordsLinked to original sources
PubMed2006

Drug-induced phospholipidosis: issues and future directions.

Numerous drugs containing a cationic amphiphilic structure are capable of inducing phospholipidosis in cells under conditions of in vivo administration or ex vivo incubation. The principal characteristics of this condition include the reversible accumulation of polar phospholipids in association with the development of unicentric or multicentric lamellated bodies within cells. There is an abundance of data providing an understanding of potential mechanisms for the induction of phospholipidosis; however, the process is likely to be complex and may differ from one drug to another. The functional consequences of the presence of this condition on cellular or tissue function are not well understood. The general consensus is that the condition is an adaptive response rather than a toxicological manifestation; however, additional studies to examine this question are needed. Until this issue is resolved, concerns about phospholipidosis will continue to exist at regulatory agencies. Procedures for the screening of potential phospholipogenic candidate compounds are available. In contrast, a clear need exists for the identification of valid biomarkers to assess the development of phospholipidosis in preclinical and clinical studies.

Animals↗
PubMed2005

Developmental toxicology evaluations--issues with including neurotoxicology and immunotoxicology assessments in reproductive toxicology studies.

Developmental and reproductive toxicology (DART) has routinely been a part of safety assessment. Attention is now focused on the effects of chemicals on the developing nervous and immune systems. This focus on developmental neurotoxicology (DNT) and developmental immunotoxicology (DIT) is based on the premise that children differ from adults in some aspects of their biology and, thus, may also differ in their responses to chemicals. This session's objective was to discuss issues common to DNT and DIT as they relate to DART protocols, including high dose selection and maternal toxicity, adequacy of pup exposure during lactation, use of a different dosing paradigm for DART versus DNT or DIT studies, and whether DIT and DNT endpoints can be incorporated into a single DART study for hazard identification purposes. Consensus was achieved on all topics except the adequacy for risk assessment purposes of the use of a limited number of endpoints for DIT and DNT, with the DNT endpoints being the primary focus of disagreement. Panelists indicated that a combination study design for hazard identification was feasible, though flexibility to meet the scientific needs of the project was emphasized. The adequacy of existing triggers for additional developmental studies was also questioned. Panelists iterated the importance of understanding pup exposure during the various life stages and the use of toxicokinetic data in designing these studies. The group agreed to consider the HESI ACSA Life Stages Task Force recommendations as a next step to address some of the issues and challenges raised during this session.

Abnormalities, Drug-Induced↗
PubMed2005

Clinical relevance of preclinical testing for allergic side effects.

Immune-mediated hypersensitivity reactions include exaggerated humoral or cell mediated responses to specific antigens and may culminate in adverse, potentially life threatening effects. The immune status of the host and presence of infections or other disorders can alter the kind and extent of immune mediated side effects in individuals. Such variability in the immune status may influence the type of idiosyncratic reaction(s) that patients manifest. The issues typically encountered from a drug development standpoint include the potential for contact hypersensitivity, respiratory sensitivity, systemic hypersensitivity, photoallergy, and pseudoallergy. There are no accepted in vitro or in vivo models available to measure and predict all types of hypersensitivity reactions in humans. There is a need for the development of preclinical models to predict all types of hypersensitivity reactions in humans. The FDA immunotoxicology guidance document recommends doing preclinical testing in animal models for topical and inhalational drugs before initiation of multiple dose studies in humans. Any signs of potential immune related drug hypersensitivity should be further evaluated in an attempt to further understand the potential for hypersensitivity reactions in humans. In summary, existing preclinical models have limited capability for prediction of drug allergy in humans except for topical and inhalational drugs. Additional tools are needed to evaluate drugs in early development and improve performance of existing assays.

Animals↗
PubMed2004

A proposed testing framework for developmental immunotoxicology (DIT).

A group of thirty immunotoxicology experts from the U.S. and E.U. representing government, industry, and academia met in May 2003, in Washington, D.C., to reach consensus regarding the most appropriate methods to assess developmental immunotoxicology (DIT) for hazard identification, including under what conditions such testing might be required. The following points represent the major conclusions from this roundtable discussion: (1) the rat is the preferred model; (2) any DIT protocol should be based on immune assays already validated; (3) DIT methods should be incorporated into standard developmental and reproductive toxicity protocols to the extent possible rather than a "stand-alone" protocol; (4) the approach to address DIT potential should be similar for chemicals and drugs, but the experimental design should be flexible and should reflect the specific questions to be answered; (5) it is possible to utilize a study design that assesses all critical windows in one protocol, with the results leading to further study of specific effects, as warranted; (6) animals should be exposed throughout the treatment protocol; (7) the triggers for DIT may include structure-activity-relationships, results from other toxicity studies, the intended use of a drug/chemical and/or its anticipated exposure of neonates and/or juveniles.

Animals↗
PubMed2003

Detection of systemic hypersensitivity to drugs using standard guinea pig assays.

The most commonly used assays designed to detect either skin or systemic immune-based hypersensitivity reactions are those using guinea pigs (GP). We obtained data from various FDA records to evaluate the correlation between GP assay results and reported post-marketing systemic hypersensitivity reactions. We examined the new drug application (NDA) reviews of approved drugs for the results of GP assays. Post-marketing human data were extracted from the FDA adverse event reporting system (AERS). Drug usage data were obtained from a commercial database maintained by IMS Health Inc. We found 83 (21%) of 396 drugs approved between 1978 and 1998 had reported GP test results. Among these 83 drugs, 14 (17%) were found to have positive results in at least one GP assay. Simple reporting index (RI) values for systemic hypersensitivity reactions were calculated from AERS data and usage to produce the index of adverse event reports per million shipping units of drug. A variety of definitions of positive human response were examined. A statistically significant association was seen for rash between post-marketing and clinical trials adverse event reports. No statistically significant associations between human data and GP test results were observed. These data suggest that standard GP assays have limited ability to predict human systemic hypersensitivity potential for pharmaceuticals.

Adverse Drug Reaction Reporting Systems↗
PubMed2002

Implications of the new FDA/CDER immunotoxicology guidance for drugs.

Although it has long been recognized that drugs, like other xenobiotics, could have adverse effects on immune function, historically, the assessment of the immunotoxic potential of pharmaceuticals has been undertaken in a haphazard fashion. Typically, studies have been conducted either after adverse effects were observed in clinical trials or if obvious signs of immunotoxicity were seen in nonclinical studies. This situation is changing with the promulgation of new guidances and guidelines by various regulatory agencies, especially in those countries involved in the ICH process. It is anticipated that studies conducted to comply with these regulatory requirements will result in a much better understanding of the immunotoxic potential of pharmaceuticals. In addition, new methods are likely to be developed for detecting drug-induced adverse immune effects. In particular, better methods need to be developed for the prospective identification of drugs which have the potential to induce allergic reactions. In this review, the essential points of the new FDA/CDER guidance document will be discussed, especially with respect to promotion of research into issues such as drug allergy.

Adjuvants, Immunologic↗