Using Multiple Drug Exposure Levels to Optimize Power in Pharmacogenetic Trials

2003 ◽  
Vol 43 (8) ◽  
pp. 816-824 ◽  
Author(s):  
Richard Judson
Keyword(s):  
Drug Exposure ◽  
Multiple Drug ◽  
Exposure Levels

Fetal Drug Syndromes

1980 ◽  
Vol 2 (3) ◽  
pp. 89-93
Author(s):  
REBA MICHELS HILL ◽  
DAVID W. SMITH
Keyword(s):  
Physical Disability ◽  
Drug Exposure ◽  
Multiple Drug ◽  
Diabetic Patients ◽  
Women Of Childbearing Age ◽  
Childbearing Age ◽  
Vitamin K3 ◽  
Single Drug ◽  
Epileptic Patients ◽  
Frozen Plasma

1. The antiepileptic drug syndrome does occur, but 80% to 90% of the babies born to mothers on antiepileptic drugs are normal. 2. The minor malformations are not physically handicapping to the child. 3. The majority of major anomalies are medically or surgically correctable. Some, such as the VSD, correct spontaneously. 4. Exposure of the fetus to phenobarbital alone may result in a similar yndrome, so the term "hydantion syndrome" is a misnomer. 5. Infants with lQ >120 may be born to mothers on phenytoin or phenobarbital. 6. There appears to be an increased number of malformations and lowering of IQ from multiple drug exposure rather than single drug exposure. 7. The physical appearance of the child may be reasonable and not grotesque. 8. Infants exposed to alcohol, phenobarbital, or phenytoin have been reported to have malignancy, but the incidence must be compared to the general population to see whether it is significant. 9. Vitamin K3 must be given immediately after birth and a clotting profile checked to see whether additional vitamin K3 is needed, or whether frozen plasma is indicated, because hemorrhage may result in a 33% mortality. 10. Multiple deficiency states occur in patients on chronic drug therapy, and these deficiency states may contribute to the neurologic and physical disability. Vitamin supplements for pregnant epileptic patients may be indicated. 11. Seizures do not increase in the epileptic patients who are given supplementary folic acid as believed by neurologists. 12. A comparison was made between the morbidity in the infant of the epileptic and that of the infant of the diabetic. Since 1950, there have been no recommendations to abort diabetic patients. Their infants have morbidity similar to that of infants of epileptics. Physicians learned what contributed to the morbidity and treated it. 13. Physicians should not administer trimethadione or paramethadione to women of childbearing-age since by the time a pregnancy is diagnosed fetal injury may have already occurred.

scholarly journals Implementation and evaluation of adverse drug reaction monitoring system in a tertiary care teaching hospital in Mumbai, India

2013 ◽  
Vol 6 (1) ◽  
pp. 41-46 ◽  
Author(s):  
Dindayal Patidar ◽  
Mithun S. Rajput ◽  
Nilesh P. Nirmal ◽  
Wenny Savitri
Keyword(s):  
Drug Therapy ◽  
Adverse Drug Reactions ◽  
Drug Exposure ◽  
Improve Patient Safety ◽  
Tertiary Care ◽  
Good Method ◽  
Morbidity And Mortality ◽  
Multiple Drug ◽  
Drug Reactions ◽  
Multiple Drug Therapy

Abstract Adverse drug reactions (ADR) are a significant cause of morbidity and mortality, often identified only post-marketingly. Improvement in current ADR reporting, including utility of underused or innovative methods, is crucial to improve patient safety and public health. Hospital-based monitoring is one of the methods used to collect data about drug prescriptions and adverse events. The aims of this study were to identify the most frequent ADRs recognized by the attending physicians, study their nature, and to target these ADRs in order to take future preventive measures. A prospective study was conducted over a 7-month period in an internal medicine department using stimulated spontaneous reporting for identifying ADRs. Out of the 254 admissions, 32 ADRs in 37 patients (14.56%) were validated from the total of 36 suspected ADRs in 41 patients. Female predominance was noted over males in case of ADRs. Fifty percent of total ADRs occurred due to multiple drug therapy. Dermatological ADRs were found to be the most frequent (68.75%), followed by respiratory, central nervous system and gastrointestinal ADRs. The drugs most frequently involved were antibiotics, antitubercular agents, antigout agents, and NSAIDs. The most commonly reported reactions were itching and rashes. Out of the 32 reported ADRs, 50% of the reactions were probable, 46.87% of the reactions were possible and 3.12% of the reactions were definite. The severity assessment done by using the Hartwig and Seigel scale indicated that the majority of ADRs were ‘Mild’ followed by ‘Moderate’ and ‘Severe’ reactions, respectively. Out of all, 75% of ADRs were recovered. The most potent management of ADRs was found to be drug withdrawal. Our study indicated that hospital based monitoring was a good method to detect links between drug exposure and adverse drug reactions. Adequate training regarding pharmacology and optimization of drug therapy might be helpful to reduce ADR morbidity and mortality.

Toxicokinetics and Hydrolysis of Artelinate and Artesunate in Malaria-Infected Rats

2005 ◽  
Vol 24 (4) ◽  
pp. 241-250 ◽  
Author(s):  
Qigui Li ◽  
Lisa H. Xie ◽  
Yuanzheng Si ◽  
Elaine Wong ◽  
Ravi Upadhyay ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Enterohepatic Circulation ◽  
Metabolizing Enzymes ◽  
Antimalarial Agents ◽  
Elimination Half ◽  
Conversion Rates ◽  
Daily Dose ◽  
Exposure Levels ◽  
Distribution Studies ◽  
Hydrolysis Of

Comparative toxicokinetic (TK) and hydrolysis studies of intravenously administered two new antimalarial agents, artelinate (AL) and artesunate (AS), were performed in malaria-infected rats using three daily equimolar doses (96 μmoles/kg). The TK evaluation was related to select one drug for severe malaria treatment in U.S. Army. Drug concentration of AS with daily dose of 36.7 mg/kg was one-third less on day 3 than on day 1, which resembled its active metabolite, dihydroartemisinin (DHA), suggesting an autoinduction of hepatic drug-metabolizing enzymes for AS. The results were similar to other artemisinin drugs, but not for AL. TK parameters of AL were very comparable from day 1 to day 3 at same AS molecular dose at 40.6 mg/kg. AS is the prodrug of DHA with the DHA/AS ratio of 5.26 compared to the ratio of 0.01 for DHA/AL. Other TK parameters revealed that the total AUC1–3 days (84.4 μg · h ml−1) of AL was fivefold higher than that of AS (15.7 mu;g h ml−1 of AS plus DHA). The elimination half-life of AL (7.1 h) was much longer than that of AS (0.36 h) or DHA (0.72 h). The remarkable alteration of the TK shape of AL may be caused by poor conversion rates to DHA and an enterohepatic circulation, which is confirmed by the present TK and tissue distribution studies. Compared to AS, higher drug exposure levels and longer exposure time of AL in the rat blood may be the cause of its increased toxicity.

scholarly journals Pharmacoepidemiology of Drug Exposure in Intubated and Non-Intubated Preterm Infants With Severe Bronchopulmonary Dysplasia

2021 ◽  
Vol 12 ◽  
Author(s):  
T. Lewis ◽  
W. Truog ◽  
L. Nelin ◽  
N. Napolitano ◽  
R. L. McKinney ◽  
...  
Keyword(s):  
Preterm Infants ◽  
Bronchopulmonary Dysplasia ◽  
Drug Exposure ◽  
Respiratory Support ◽  
Rank Test ◽  
Multiple Drug ◽  
Continuous Variables ◽  
Short Acting ◽  
Non Invasive ◽  
Drug Classes

Background: Infants with severe bronchopulmonary dysplasia (BPD) are commonly treated with off-label drugs due to lack of approved therapies. To prioritize drugs for rigorous efficacy and safety testing, it is important to describe exposure patterns in this population.Objective: Our objective was to compare rates of drug exposure between preterm infants with severe bronchopulmonary dysplasia based on respiratory support status at or beyond 36 weeks post-menstrual age.Methods: A cross-sectional cohort study was performed on October 29, 2019. Preterm infants with severe BPD were eligible and details of respiratory support and drug therapy were recorded. Wilcoxon paired signed rank test was used to compare continuous variables between the invasive and non-invasive groups. Fisher’s exact test was used to compare binary variables by respiratory support status.Results: 187 infants were eligible for the study at 16 sites. Diuretics were the drug class that most subjects were receiving on the day of study comprising 54% of the entire cohort, followed by inhaled steroids (47%) and short-acting bronchodilators (42%). Infants who were invasively ventilated (verses on non-invasive support) were significantly more likely to be receiving diuretics (p 0.013), short-acting bronchodilators (p < 0.01), long-acting bronchodilators (p < 0.01), systemic steroids (p < 0.01), systemic pulmonary hypertension drugs (p < 0.01), and inhaled nitric oxide (p < 0.01).Conclusion: Infant with severe BPD, especially those who remain on invasive ventilation at 36 weeks, are routinely exposed to multiple drug classes despite insufficient pharmacokinetic, safety, and efficacy evaluations. This study helps prioritize sub-populations, drugs and drug classes for future study.

Multiple drug exposure as a risk factor for the seriousness of adverse drug reactions

2011 ◽  
Vol 19 (3) ◽  
pp. 395-399 ◽  
Author(s):  
ANA FILIPA MACEDO ◽  
CARLOS ALVES ◽  
NUNO CRAVEIRO ◽  
FRANCISCO BATEL MARQUES
Keyword(s):  
Risk Factor ◽  
Adverse Drug Reactions ◽  
Drug Exposure ◽  
Multiple Drug ◽  
Drug Reactions

Therapeutic Drug Monitoring: Role for a Pharmacist in Multidisciplinary Antiretroviral Management

2005 ◽  
Vol 18 (4) ◽  
pp. 310-321
Author(s):  
Judianne C. Slish ◽  
Linda M. Catanzaro ◽  
Olanrewaju Okusanya ◽  
Lisa M. Demeter ◽  
Mary Albrecht ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Drug Exposure ◽  
Treatment Guidelines ◽  
Management Strategies ◽  
Additional Patient ◽  
Fixed Dose ◽  
Therapeutic Drug ◽  
Multiple Drug ◽  
Clinical Tool

The current treatment guidelines for HIV pharmacotherapy recommend combinations of antiretrovirals (ARVs) to achieve optimal suppression of HIV replication. However, the initiation and long-term management of ARV therapy in a patient is often complicated by variable medication adherence, complex medication use with multiple drug interactions, the occurrence of drug toxicity, and drug therapy for comorbid conditions that require additional patient education and laboratory monitoring. For these reasons, the inclusion of a well-trained pharmacist in multidisciplinary health system management strategies has been increasing. Furthermore, the use of fixed-dose ARVs is accompanied by considerable interpatient variation in pharmacokinetics yielding a range of drug exposures from any given ARV dose. One approach to overcoming this variable drug exposure is to use plasma concentration monitoring (eg, therapeutic drug monitoring [TDM]) as a clinical tool to adjust doses to achieve targeted concentration ranges, often in conjunction with HIV resistance tests. While data in support of TDM are emerging, the development of programs that include an HIV pharmaceutical care specialist and an adherence program with an integrated clinical pharmacology resource that can provide reliable TDM assays has been reported and provides the rationale for including pharmacists in the implementation of ARV TDM programs.

The prevalence of prenatal alcohol exposure in neonates suspected of multiple drug exposure.

2003 ◽  
Vol 73 (2) ◽  
pp. P9-P9
Author(s):  
D. Chan ◽  
B. Bar-Oz ◽  
B. Pellerin ◽  
C. Paciorek ◽  
T. Karaskov ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Prenatal Alcohol Exposure ◽  
Alcohol Exposure ◽  
Multiple Drug ◽  
Prenatal Alcohol

Emerging Research Paradigm for Infant Drug Exposure Through Breast Milk

2019 ◽  
Vol 25 (5) ◽  
pp. 528-533 ◽  
Author(s):  
Shinya Ito
Keyword(s):  
Risk Assessment ◽  
Breast Milk ◽  
Data Acquisition ◽  
Drug Exposure ◽  
Physiologically Based Pharmacokinetics ◽  
First Line ◽  
Lactating Women ◽  
Infant Exposure ◽  
Development Processes ◽  
Exposure Levels

Background: Information on drug secretion into milk is insufficient due to the exclusion of lactating women from clinical trials and drug development processes. As a result, non-adherence to the necessary drug therapy and discontinuation of breastfeeding occur, even if the predicted level of infant exposure is low. In contrast, inadvertent infant exposure to drugs in breast milk continues to happen due to lack of rational risk assessment, resulting in serious toxicity cases including death. This problem is multifactorial, but one of the key elements is the lack of pharmacokinetic information on drug secretion into milk and resultant infant exposure levels, the first line of evidence for risk assessment. Methods: Basic PK principles in drug excretion into milk were explained. The literature was scanned to identify approaches for PK data acquisition in this challenging field. Results: This review describes the feasibility to develop such approaches, and the knowledge gaps that still exist. A combination of population pharmacokinetics approach (to estimate averages and variations of drug concentration profiles in milk) and physiologically-based pharmacokinetics modeling of infants (to predict the population profiles of infant drug exposure levels) appears useful. Conclusions: In order to facilitate participant enrollment and PK data acquisition in a timely manner, networks of investigators become crucial.

scholarly journals Non-VKA Oral Anticoagulants: Accurate Measurement of Plasma Drug Concentrations

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Jonathan Douxfils ◽  
Helen Mani ◽  
Valentine Minet ◽  
Bérangère Devalet ◽  
Bernard Chatelain ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Oral Anticoagulants ◽  
Invasive Procedure ◽  
Bleeding Risk ◽  
Daily Practice ◽  
Drug Approval ◽  
Multiple Drug ◽  
Individual Level ◽  
Chronic Renal Impairment ◽  
Drug Concentrations

Non-VKA oral anticoagulants (NOACs) have now widely reached the lucrative market of anticoagulation. While the marketing authorization holders claimed that no routine monitoring is required and that these compounds can be given at fixed doses, several evidences arisen from the literature tend to demonstrate the opposite. New data suggests that an assessment of the response at the individual level could improve the benefit-risk ratio of at least dabigatran. Information regarding the association of rivaroxaban and apixaban exposure and the bleeding risk is available in the drug approval package on the FDA website. These reviews suggest that accumulation of these compounds increases the risk of experiencing a bleeding complication. Therefore, in certain patient populations such as patients with acute or chronic renal impairment or with multiple drug interactions, measurement of drug exposure may be useful to ensure an optimal treatment response. More specific circumstances such as patients experiencing a haemorrhagic or thromboembolic event during the treatment duration, patients who require urgent surgery or an invasive procedure, or patient with a suspected overdose could benefit from such a measurement. This paper aims at providing guidance on how to best estimate the intensity of anticoagulation using laboratory assays in daily practice.

scholarly journals Network integration and modelling of dynamic drug responses at multi-omics levels

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Nathalie Selevsek ◽  
Florian Caiment ◽  
Ramona Nudischer ◽  
Hans Gmuender ◽  
Irina Agarkova ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Molecular Medicine ◽  
Time Resolved ◽  
Anthracycline Cardiotoxicity ◽  
Drug Responses ◽  
Associated Proteins ◽  
Exposure Levels ◽  
Remodeling Of Extracellular Matrix

Abstract Uncovering cellular responses from heterogeneous genomic data is crucial for molecular medicine in particular for drug safety. This can be realized by integrating the molecular activities in networks of interacting proteins. As proof-of-concept we challenge network modeling with time-resolved proteome, transcriptome and methylome measurements in iPSC-derived human 3D cardiac microtissues to elucidate adverse mechanisms of anthracycline cardiotoxicity measured with four different drugs (doxorubicin, epirubicin, idarubicin and daunorubicin). Dynamic molecular analysis at in vivo drug exposure levels reveal a network of 175 disease-associated proteins and identify common modules of anthracycline cardiotoxicity in vitro, related to mitochondrial and sarcomere function as well as remodeling of extracellular matrix. These in vitro-identified modules are transferable and are evaluated with biopsies of cardiomyopathy patients. This to our knowledge most comprehensive study on anthracycline cardiotoxicity demonstrates a reproducible workflow for molecular medicine and serves as a template for detecting adverse drug responses from complex omics data.

Sign in / Sign up

Export Citation Format

Share Document