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Lawrence J Lesko

Publications and source records attributed to Lawrence J Lesko.

14 recordsLinked to original sources
PubMed2004

Translation of pharmacogenomics and pharmacogenetics: a regulatory perspective.

Pharmacogenomics and pharmacogenetics provide methodologies that can lead to DNA-based tests to improve drug selection, identify optimal dosing, maximize drug efficacy or minimize the risk of toxicity. Rapid advances in basic research have identified many opportunities for the development of 'personalized' treatments for individuals and/or subsets of patients defined by genetic and/or genomic tests. However, the integration of these tests into routine clinical practice remains a major multidisciplinary challenge, and even for well-established biomarkers there has been little progress. Here, we consider this challenge from a regulatory perspective, highlighting recent initiatives from the FDA that aim to facilitate the integration of pharmacogenetics and pharmacogenomics into drug development and clinical practice.

Drug Approval↗
PubMed2004

Drug-drug, drug-dietary supplement, and drug-citrus fruit and other food interactions: what have we learned?

Serious drug-drug interactions have contributed to recent U.S. market withdrawals and also recent nonapprovals of a few new molecular entities. Many of these interactions involved the inhibition or induction of metabolizing enzymes and efflux transporters, resulting in altered systemic exposure and adverse drug reactions or loss of efficacy. In addition to drug-drug interactions, drug-dietary supplement and drug-citrus fruit interactions, among others, could also cause adverse drug reactions or loss of efficacy and are important issues to consider in the evaluation of new drug candidates. This commentary reviews (1). the current understanding of the mechanistic basis of these interactions, (2). issues to consider in the interpretation of study results, and (3). recent labeling examples to illustrate the translation of study results to information useful for patients and health care providers.

Beverages↗
PubMed2003

Pharmacogenetics and pharmacogenomics in drug development and regulatory decision making: report of the first FDA-PWG-PhRMA-DruSafe Workshop.

The use of pharmacogenetics and pharmacogenomics in the drug development process, and in the assessment of such data submitted to regulatory agencies by industry, has generated significant enthusiasm as well as important reservations within the scientific and medical communities. This situation has arisen because of the increasing number of exploratory and confirmatory investigations into variations in RNA expression patterns and DNA sequences being conducted in the preclinical and clinical phases of drug development, and the uncertainty surrounding the acceptance of these data by regulatory agencies. This report summarizes the outcome of a workshop cosponsored by the Food and Drug Administration (FDA), the Pharmacogenetics Working Group (PWG), the Pharmaceutical Research and Manufacturers of America (PhRMA), and the PhRMA Preclinical Safety Committee (DruSafe). The specific aim of the workshop was to identify key issues associated with the application of pharmacogenetics and pharmacogenomics, including the feasibility of a regulatory "safe harbor" for exploratory genome-based data, and to provide a forum for industry-regulatory agency dialogue on these important issues.

Clinical Trials as Topic↗
PubMed2002

Variability in cimetidine absorption and plasma double peaks following oral administration in the fasted state in humans: correlation with antral gastric motility.

The role of gastrointestinal motility and pH in determining cimetidine bioavailability as well as double peaks in plasma profiles following oral administration, in the quiescent or active phase of antral motility, to humans in the fasted state was examined. Plasma cimetidine-time curves did not show the presence of double peaks in any subject following intravenous administration. The incidence of double peaks was 73% following oral administration and was independent of antral migrating motility complex phase. Further, it was found that oral administration of cimetidine in the quiescent phase resulted in significantly higher bioavailability and in other pharmacokinetic parameters compared to that obtained following administration in the active phase. Excellent linearity in plots of motility peaks vs. plasma peaks with slopes close to unity were evident for both quiescent (r(2)=0.93) and active phase (r(2)=0.97) administration. A total of 14 peaks out of 22 (10 subjects, 64%) and 20 out of 27 peaks (11 subjects, 74%), were accounted for in quiescent and active phase oral administration, respectively. The proximal occurrence of plasma peaks to antral motility peaks typical of phase III contractions strongly implies that motility patterns may be responsible for secondary maxima following oral cimetidine administration in the fasted state.

Administration, Oral↗
PubMed2002

Biopharmaceutics classification system: the scientific basis for biowaiver extensions.

The current BSC guidance issued by the FDA allows for biowaivers based on conservative criteria. Possible new criteria and class boundaries are proposed for additional biowaivers based on the underlying physiology of the gastrointestinal tract. The proposed changes in new class boundaries for solubility and permeability are as follows: 1. Narrow the required solubility pH range from 1.0-7.5 to 1.0-6.8. 2. Reduce the high permeability requirement from 90% to 85%. The following new criterion and potential biowaiver extension require more research: 1. Define a new intermediate permeability class boundary. 2. Allow biowaivers for highly soluble and intermediately permeable drugs in IR solid oral dosage forms with no less than 85% dissolved in 15 min in all physiologically relevant dissolution media, provided these IR products contain only known excipients that do not affect the oral drug absorption. The following areas require more extensive research: 1. Increase the dose volume for solubility classification to 500 mL. 2. Include bile salt in the solubility measurement. 3. Use the intrinsic dissolution method for solubility classification. 4. Define an intermediate solubility class for BCS Class II drugs. 5. Include surfactants in in vitro dissolution testing.

Biopharmaceutics↗
PubMed2002

Medical applications of microarray technologies: a regulatory science perspective.

The potential medical applications of microarrays have generated much excitement, and some skepticism, within the biomedical community. Some researchers have suggested that within the decade microarrays will be routinely used in the selection, assessment, and quality control of the best drugs for pharmaceutical development, as well as for disease diagnosis and for monitoring desired and adverse outcomes of therapeutic interventions. Realizing this potential will be a challenge for the whole scientific community, as breakthroughs that show great promise at the bench often fail to meet the requirements of clinicians and regulatory scientists. The development of a cooperative framework among regulators, product sponsors, and technology experts will be essential for realizing the revolutionary promise that microarrays hold for drug development, regulatory science, medical practice and public health.

Forecasting↗
PubMed2002

Effect of St John's wort on the pharmacokinetics of fexofenadine.

BACKGROUND: St John's wort is a popular over-the-counter dietary supplement and herbal remedy that has been implicated in drug interactions with several substrates of P-glycoprotein. The effect of St John's wort on P-glycoprotein activity in vivo was examined with use of fexofenadine as selective probe drug. METHODS: A 3-period, open-label, fixed-schedule study design was used. Fexofenadine, 60 mg, was administered orally before administration of St John's wort, with a single dose of St John's wort (900 mg), and after 2 weeks of treatment with St John's wort (300 mg 3 times a day) to determine P-glycoprotein activity. RESULTS: A single dose of St John's wort significantly (P <.05) increased the maximum plasma concentration of fexofenadine by 45% and significantly (P <.05) decreased the oral clearance by 20%, with no change in half-life or renal clearance. Long-term administration of St John's wort did not cause a significant change in fexofenadine disposition relative to the untreated phase. Compared with the single-dose treatment phase, long-term St John's wort caused a significant 35% decrease (P <.05) in maximum plasma concentration and a significant 47% increase (P <.05) in fexofenadine oral clearance. CONCLUSIONS: A single dose of St John's wort resulted in a significant inhibition of intestinal P-glycoprotein. Long-term treatment with St John's wort reversed the changes in fexofenadine disposition observed with single-dose administration.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Scientific perspectives on drug transporters and their role in drug interactions.

Recently, increased interest in drug transporters and research in this area has revealed that drug transporters play an important role in modulating drug absorption, distribution, and elimination. Acting alone or in concert with drug metabolizing enzymes they can affect the pharmacokinetics and pharmacodynamics of a drug. This commentary will focus on the potential role that drug transporters may play in drug-drug interactions and what information may be needed during drug development and new drug application (NDA) submissions to address potential drug interactions mediated by transporters.

Drug Interactions↗