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Clinical Pharmacokinetics Aug 2015Tramadol hydrochloride is used worldwide as an analgesic drug with a unique dual function. The metabolic enzymes cytochrome P450 (CYP) 3A4, CYP2B6, and CYP2D6 and the... (Review)
Review
BACKGROUND AND OBJECTIVE
Tramadol hydrochloride is used worldwide as an analgesic drug with a unique dual function. The metabolic enzymes cytochrome P450 (CYP) 3A4, CYP2B6, and CYP2D6 and the various transporters [adenosine triphosphate-binding cassette B1/multidrug resistance 1/P-glycoprotein, organic cation transporter 1, serotonin transporter (SERT), norepinephrine transporter (NET)] and receptor genes (opioid receptor μ 1 gene) give possible genetic differences that might affect the pharmacokinetics and/or pharmacodynamics of tramadol. Therefore, the aim of this review is to present a systematic walkthrough of all possible genetic factors involved in the pharmacology of tramadol.
METHOD
A systematic literature search was conducted in PubMed and EMBASE involving all metabolic enzymes, drug transporters and receptors, as well as SERT and NET that are involved in the pharmacokinetics and pharmacodynamics of tramadol. An additional search on population pharmacokinetics with genetic factors as covariates was performed separately.
RESULTS
A total of 56 studies (45 cohort and case-control studies, three case reports, six in vitro studies, and two animal studies) were included.
CONCLUSION
In this systematic review, the current knowledge on all possible genetic factors that might influence the metabolism or clinical efficacy of tramadol has been collected and summarized. Only the effect of CYP2D6 polymorphisms on the metabolism of tramadol and the consequent effect on pain relief has been thoroughly studied and sufficiently established as clinically relevant.
Topics: Analgesics, Opioid; Animals; Biological Availability; Case-Control Studies; Clinical Studies as Topic; Cohort Studies; Cytochrome P-450 CYP2D6; Humans; Pain; Pharmacogenetics; Tramadol
PubMed: 25910878
DOI: 10.1007/s40262-015-0268-0 -
Antimicrobial Agents and Chemotherapy Dec 2016Chagas disease is a neglected parasitic illness affecting approximately 8 million people, predominantly in Latin America. Benznidazole is the drug of choice for... (Meta-Analysis)
Meta-Analysis
Chagas disease is a neglected parasitic illness affecting approximately 8 million people, predominantly in Latin America. Benznidazole is the drug of choice for treatment, although its availability has been limited. A paucity of knowledge of the pharmacokinetic properties of this drug has contributed to its limited availability in several jurisdictions. The objective of this study was to conduct a systematic literature review and a Bayesian meta-analysis of pharmacokinetic studies to improve estimates of the basic pharmacokinetic properties of benznidazole. A systematic search of the Embase, Medline, LILACS, and SciELO (Scientific Electronic Library Online) databases was conducted. Eligible studies reported patient-level data from single-100-mg-dose pharmacokinetic evaluations of benznidazole in adults or otherwise provided data relevant to the estimation of pharmacokinetic parameters which could be derived from such studies. A Bayesian hierarchical model was used for analysis. Secondary data (i.e., data from studies that did not include patient-level, single-100-mg-dose data) were used for the generation of empirical priors for the Bayesian analysis. The systematic search identified nine studies for inclusion. Nine pharmacokinetic parameters were estimated, including the area under the concentration-time curve (AUC), the maximum concentration of drug in plasma (C), the time to C, the elimination rate constant (k), the absorption rate constant (K), the absorption and elimination half-lives, the apparent oral clearance, and the apparent oral volume of distribution. The results showed consistency across studies. AUC and C were 51.31 mg · h/liter (95% credible interval [CrI], 45.01, 60.28 mg · h/liter) and 2.19 mg/liter (95% CrI, 2.06, 2.33 mg/liter), respectively. K and k were 1.16 h (95% CrI, 0.59, 1.76 h) and 0.052 h (95% CrI, 0.045, 0.059 h), respectively, with the corresponding absorption and elimination half-lives being 0.60 h (95% CrI, 0.38, 1.11 h) and 13.27 h (95% CrI, 11.79, 15.42 h), respectively. The oral clearance and volume of distribution were 2.04 liters/h (95% CrI, 1.77, 2.32 liters/h) and 39.19 liters (95% CrI, 36.58, 42.17 liters), respectively. A Bayesian meta-analysis was used to improve the estimates of the standard pharmacokinetic parameters of benznidazole. These data can inform clinicians and policy makers as access to this drug increases.
Topics: Area Under Curve; Chagas Disease; Humans; Nitroimidazoles; Trypanocidal Agents
PubMed: 27550362
DOI: 10.1128/AAC.01567-16 -
Current Reviews in Clinical and... 2022The use of levetiracetam (LEV) has been increasing, given its favorable pharmacokinetic profile. Numerous population pharmacokinetic studies for LEV have been conducted....
BACKGROUND
The use of levetiracetam (LEV) has been increasing, given its favorable pharmacokinetic profile. Numerous population pharmacokinetic studies for LEV have been conducted. However, there are some discrepancies regarding factors affecting its pharmacokinetic variability. Therefore, this systematic review aimed to summarize significant predictors for LEV pharmacokinetics as well as the need for dosage adjustments.
METHODS
We performed a systematic search for population pharmacokinetic studies of LEV conducted using a nonlinear-mixed effect approach from PubMed, Scopus, CINAHL Complete, and Science Direct databases from their inception to March 2020. Information on study design, model methodologies, significant covariate-parameter relationships, and model evaluation was extracted. The quality of the reported studies was also assessed.
RESULTS
A total of 16 studies were included in this review. Only two studies were conducted with a two-compartment model, while the rest were performed with a one-compartment structure. Bodyweight and creatinine clearance were the two most frequently identified covariates on LEV clearance (CL). Additionally, postmenstrual age (PMA) or postnatal age (PNA) were significant predictors for CL in neonates. Only three studies externally validated the models. Two studies conducted pharmacodynamic models for LEV with relatively small sample size.
CONCLUSION
Significant predictors for LEV pharmacokinetics are highlighted in this review. For future research, a population pharmacokinetic-pharmacodynamic model using a larger sample size should be conducted. From a clinical perspective, the published models should be externally evaluated before clinical implementation.
Topics: Anticonvulsants; Body Weight; Humans; Infant, Newborn; Kinetics; Levetiracetam; Research Design
PubMed: 33622228
DOI: 10.2174/1574884716666210223110658 -
Lipids in Health and Disease Jan 2024Obstructive sleep apnea (OSA) has a bidirectional association with metabolic syndrome, and insulin resistance (IR). The triglyceride-glucose (TyG) index could be a... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Obstructive sleep apnea (OSA) has a bidirectional association with metabolic syndrome, and insulin resistance (IR). The triglyceride-glucose (TyG) index could be a simply calculated marker of IR in OSA. However, its clinical application appears still limited. Hence, this systematic review and meta-analysis aimed to respond to this question by analyzing all the existing studies showing an association between OSA and the TyG index.
METHODS
Four online databases, including PubMed, Scopus, the Web of Science, and Embase were searched for studies evaluating the TyG index in OSA. After screening and data extraction, a random-effect meta-analysis was performed to compare the TyG index in OSA patients vs. healthy controls by calculating standardized mean difference (SMD) and 95% confidence interval (CI) and pooling the area under the curves (AUCs) for diagnosis of OSA based on this index.
RESULTS
Ten studies involving 16,726 individuals were included in the current systematic review. Meta-analysis indicated that there was a significantly higher TyG index in patients with OSA, compared with the healthy controls (SMD 0.856, 95% CI 0.579 to 1.132, P < 0.001). Also, TyG had a diagnostic ability for OSA representing a pooled AUC of 0.681 (95% CI 0.627 to 0.735). However, based on the two studies' findings, no difference between different severities of OSA was observed. Finally, our data showed that the TyG index is a good potential predictor of adverse outcomes in these patients.
CONCLUSION
Our study revealed that the TyG index is an easy-to-measure marker of IR for assessing OSA, both in diagnosis and prognosis. Our study supports its implementation in routine practice to help clinicians in decision-making and patient stratification.
Topics: Humans; Area Under Curve; Databases, Factual; Glucose; Insulin Resistance; Sleep Apnea, Obstructive; Triglycerides
PubMed: 38185682
DOI: 10.1186/s12944-024-02005-3 -
Frontiers in Endocrinology 2023The performance in evaluating thyroid nodules on ultrasound varies across different risk stratification systems, leading to inconsistency and uncertainty regarding... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The performance in evaluating thyroid nodules on ultrasound varies across different risk stratification systems, leading to inconsistency and uncertainty regarding diagnostic sensitivity, specificity, and accuracy.
OBJECTIVE
Comparing diagnostic performance of detecting thyroid cancer among distinct ultrasound risk stratification systems proposed in the last five years.
EVIDENCE ACQUISITION
Systematic search was conducted on PubMed, EMBASE, and Web of Science databases to find relevant research up to December 8, 2022, whose study contents contained elucidation of diagnostic performance of any one of the above ultrasound risk stratification systems (European Thyroid Imaging Reporting and Data System[Eu-TIRADS]; American College of Radiology TIRADS [ACR TIRADS]; Chinese version of TIRADS [C-TIRADS]; Computer-aided diagnosis system based on deep learning [S-Detect]). Based on golden diagnostic standard in histopathology and cytology, single meta-analysis was performed to obtain the optimal cut-off value for each system, and then network meta-analysis was conducted on the best risk stratification category in each system.
EVIDENCE SYNTHESIS
This network meta-analysis included 88 studies with a total of 59,304 nodules. The most accurate risk category thresholds were TR5 for Eu-TIRADS, TR5 for ACR TIRADS, TR4b and above for C-TIRADS, and possible malignancy for S-Detect. At the best thresholds, sensitivity of these systems ranged from 68% to 82% and specificity ranged from 71% to 81%. It identified the highest sensitivity for C-TIRADS TR4b and the highest specificity for ACR TIRADS TR5. However, sensitivity for ACR TIRADS TR5 was the lowest. The diagnostic odds ratio (DOR) and area under curve (AUC) were ranked first in C-TIRADS.
CONCLUSION
Among four ultrasound risk stratification options, this systemic review preliminarily proved that C-TIRADS possessed favorable diagnostic performance for thyroid nodules.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero, CRD42022382818.
Topics: Humans; Thyroid Nodule; Network Meta-Analysis; Thyroid Neoplasms; Area Under Curve
PubMed: 37720531
DOI: 10.3389/fendo.2023.1227339 -
Reproductive Toxicology (Elmsford, N.Y.) Jan 2012It is clear that cocaine and cocaine metabolites are present in the placenta and may harm the fetus. The results of the experimental manipulation of cocaine exposure are... (Review)
Review
It is clear that cocaine and cocaine metabolites are present in the placenta and may harm the fetus. The results of the experimental manipulation of cocaine exposure are not reported in the literature in a consistent manner. We conducted a systematic review of selected articles that demonstrated the analytical detection of cocaine and its metabolites in the placenta and that were published from January 1, 1956-June 30, 2011 using Medline, Toxline and Scopus databases. The collected data confirm that the placenta does not act as a barrier to fetal exposure, that cocaine quickly crosses the placenta and that one of the essential roles of the placenta is to metabolize cocaine during pregnancy. Our systematic review summarized the results showing that cocaine, benzoylecgonine and norcocaine are stored in the myometrium and the placental membrane and maintain continuous drug delivery to the amniotic fluid (and to the fetus) probably via diffusion.
Topics: Amniotic Fluid; Animals; Biological Assay; Biotransformation; Central Nervous System Stimulants; Cocaine; Cocaine-Related Disorders; Diffusion; Female; Fetal Blood; Humans; Maternal-Fetal Exchange; Myometrium; Placenta; Placental Circulation; Pregnancy; Pregnancy Complications
PubMed: 22094170
DOI: 10.1016/j.reprotox.2011.10.012 -
A systematic review and empirical analysis of the relation between dose and duration of drug action.Journal of Clinical Pharmacology Jan 2010There is a log-linear relation between the dose and duration of action of drugs with single-compartment pharmacokinetics and direct, reversible mechanisms of action.... (Review)
Review
There is a log-linear relation between the dose and duration of action of drugs with single-compartment pharmacokinetics and direct, reversible mechanisms of action. However, it has been suggested that this relation does not extend to drugs whose metabolites are active or slowly eliminated, drugs with saturable kinetics, and drugs with hit-and-run effects. The purpose of this study is to test this hypothesis and to quantify the relationship by way of a systematic review coupled to an empirical analysis. All issues of 4 clinical pharmacology journals from 1980 to 2005 are hand-searched for articles that present pharmacodynamic response versus time curves for 4 or more different doses. Data on duration of action, dose, and area under the plasma concentration versus time curve from zero to infinity (AUC) are abstracted and analyzed by panel data regression modeling, with within-study fixed effects. Duration of drug action is defined as the time during which a pharmacodynamic effect (or response) exceeds a nominal threshold. The generalized models of all observations from 33 publications, with duration of action as the dependent variable and the logarithm of the dose (or AUC) as the explanatory variable, yield significant log-linear relationships. The regressions for individual studies are correctly specified in 27 cases; there are insufficient data for analysis in 10 studies, and a log-linear specification is deemed inappropriate in 6. Analysis of published dose-ranging studies shows that the duration of action of a drug is directly proportional to the logarithm of dose across a wide range of different drugs, extending a result that was previously documented for very few compounds.
Topics: Area Under Curve; Dose-Response Relationship, Drug; Humans; Models, Statistical; Prescription Drugs; Time Factors
PubMed: 19797537
DOI: 10.1177/0091270008329555 -
Journal of Clinical Epidemiology Jun 2019The objective of this study was to compare performance of logistic regression (LR) with machine learning (ML) for clinical prediction modeling in the literature. (Comparative Study)
Comparative Study Meta-Analysis
OBJECTIVES
The objective of this study was to compare performance of logistic regression (LR) with machine learning (ML) for clinical prediction modeling in the literature.
STUDY DESIGN AND SETTING
We conducted a Medline literature search (1/2016 to 8/2017) and extracted comparisons between LR and ML models for binary outcomes.
RESULTS
We included 71 of 927 studies. The median sample size was 1,250 (range 72-3,994,872), with 19 predictors considered (range 5-563) and eight events per predictor (range 0.3-6,697). The most common ML methods were classification trees, random forests, artificial neural networks, and support vector machines. In 48 (68%) studies, we observed potential bias in the validation procedures. Sixty-four (90%) studies used the area under the receiver operating characteristic curve (AUC) to assess discrimination. Calibration was not addressed in 56 (79%) studies. We identified 282 comparisons between an LR and ML model (AUC range, 0.52-0.99). For 145 comparisons at low risk of bias, the difference in logit(AUC) between LR and ML was 0.00 (95% confidence interval, -0.18 to 0.18). For 137 comparisons at high risk of bias, logit(AUC) was 0.34 (0.20-0.47) higher for ML.
CONCLUSION
We found no evidence of superior performance of ML over LR. Improvements in methodology and reporting are needed for studies that compare modeling algorithms.
Topics: Algorithms; Area Under Curve; Humans; Logistic Models; Models, Theoretical; Outcome Assessment, Health Care; Predictive Value of Tests; Sensitivity and Specificity; Supervised Machine Learning
PubMed: 30763612
DOI: 10.1016/j.jclinepi.2019.02.004 -
Clinical Pharmacokinetics Dec 2022Venous thromboembolism (VTE) is a leading cause of morbidity and mortality globally. The direct oral anticoagulants, including rivaroxaban, are relatively novel...
INTRODUCTION
Venous thromboembolism (VTE) is a leading cause of morbidity and mortality globally. The direct oral anticoagulants, including rivaroxaban, are relatively novel therapeutic options in the treatment and prevention of VTE. There is a conflicting and inconclusive evidence surrounding the pharmacokinetics (PK) of rivaroxaban in patients with VTE who are obese.
OBJECTIVES
We conducted a systematic review to provide an overview, and to synthesize the available evidence in the current literature pertaining to rivaroxaban PK in obese subjects who are healthy or diseased.
METHODS
The PubMed, Embase, ScienceDirect, Rayyan, and Cochrane Library databases were systematically searched from 1 May 2021 through 28 February 2022. Studies investigating rivaroxaban PK in adult obese subjects were included in the review. Pertinent data, including anthropometric parameters, rivaroxaban dosage regimen, PK parameters, PK model, and outcome measures were extracted. Reference values of rivaroxaban PK parameters in the general population were used for comparison purposes. The review protocol was registered in the PROSPERO database (CRD42020177770).
RESULTS
In the 11 studies included in this systematic review, over 7140 healthy or diseased subjects received rivaroxaban therapy, with varying clinical indications in the diseased population. The reported PK parameters of rivaroxaban in obese subjects compared with reference values in the general population were variable. The reported values of the volume of distribution (V) among obese subjects (73.4-82.8 L) fell within the range of values reported/calculated for the general population (59.4-104 L), assuming complete bioavailability. However, some of the reported values of clearance (CL) in obese subjects (7.86-16.8 L.h) do not fall within the range of values reported/calculated for the general population (5.57-11.3 L.h). The reported maximum plasma concentrations in obese subjects versus the general population following a 10 mg dose were 149 vs. 143-180 µg.L, and following a 20 mg dose were 214-305 vs. 299-360 µg.L, respectively. The area under the plasma concentration versus time curves (AUC) over different intervals in obese subjects versus the general population following a 10 mg dose were 1155 (AUC from time zero to infinity [AUC]) vs. 1029 (AUC) µg.h.L; and 1204-2800 (AUC from time zero to 24 h [AUC]) vs. 3200 (AUC) µg.h.L, respectively, following a 20 mg dose. The reported values of half-life and time to reach the maximum plasma concentration in obese subjects versus the general population were not consistent across studies.
CONCLUSION
Variable changes and inconsistencies in different rivaroxaban PK parameters were reported in obese subjects. Further well-designed studies are warranted to better characterize the PK and clinical outcomes of rivaroxaban in subjects with obesity.
Topics: Adult; Humans; Rivaroxaban; Venous Thromboembolism; Half-Life; Obesity; Biological Availability; Anticoagulants
PubMed: 36201149
DOI: 10.1007/s40262-022-01160-z -
Clinical Pharmacokinetics Oct 2021Mycophenolic acid (MPA) is among the most commonly prescribed medications for immunosuppression following organ transplantation. Highly variable MPA exposure and drug... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Mycophenolic acid (MPA) is among the most commonly prescribed medications for immunosuppression following organ transplantation. Highly variable MPA exposure and drug response are observed among individuals receiving the same dosage of the drug. Identification of candidate genes whose polymorphisms could be used to predict MPA exposure and clinical outcome is of clinical value.
OBJECTIVES
This study aimed to determine the impact of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of MPA in humans by means of a systematic review and meta-analysis.
METHODS
A systematic search was conducted on PubMed, EMBASE, Web of Sciences, Scopus, and the Cochrane Library databases. A meta-analysis was conducted to determine any associations between genetic polymorphisms and pharmacokinetic or pharmacodynamic parameters of MPA. Pooled-effect estimates were calculated by means of the random-effects model.
RESULTS
A total of 37 studies involving 3844 individuals were included in the meta-analysis. Heterozygous carriers of the UGT1A9 -275T>A polymorphism were observed to have a significantly lower MPA exposure than wild-type individuals. Four single nucleotide polymorphisms (SNPs), namely UGT1A9 -2152C>T, UGT1A8 518C>G, UGT2B7 211G>T, and SLCO1B1 521T>C, were also significantly associated with altered MPA pharmacokinetics. However, none of the investigated SNPs, including SNPs in the IMPDH gene, were found to be associated with the clinical efficacy of MPA. The only SNP that was associated with adverse outcomes was SLCO1B3 344T>G.
CONCLUSIONS
The present systematic review and meta-analysis identified six SNPs that were significantly associated with pharmacokinetic variability or adverse effects of MPA. Our findings represent the basis for future research and clinical implications with regard to the role of pharmacogenetics in MPA pharmacokinetics and drug response.
Topics: Area Under Curve; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver-Specific Organic Anion Transporter 1; Mycophenolic Acid; Pharmacogenetics; Polymorphism, Single Nucleotide
PubMed: 34105062
DOI: 10.1007/s40262-021-01037-7