Clin Pharmacokinet
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Observational Study
Midazolam pharmacokinetics in morbidly obese patients following semi-simultaneous oral and intravenous administration: a comparison with healthy volunteers.
While in vitro and animal studies have shown reduced cytochrome P450 (CYP) 3A activity due to obesity, clinical studies in (morbidly) obese patients are scarce. As CYP3A activity may influence both clearance and oral bioavailability in a distinct manner, in this study the pharmacokinetics of the CYP3A substrate midazolam were evaluated after semi-simultaneous oral and intravenous administration in morbidly obese patients, and compared with healthy volunteers. ⋯ In morbidly obese patients, systemic clearance of midazolam is unchanged, while oral bioavailability is increased. Given the large increase in volumes of distribution, dose adaptations for intravenous midazolam should be considered. Further research should elucidate the exact physiological changes at intestinal and hepatic level contributing to these findings.
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Review Meta Analysis
Impact of cytochrome P450 2C19 polymorphisms on citalopram/escitalopram exposure: a systematic review and meta-analysis.
Citalopram and escitalopram, selective serotonin reuptake inhibitors, are primarily metabolized by cytochrome P450 (CYP) 2C19, which is a highly polymorphic enzyme known to cause inter-individual differences in pharmacokinetics. However, the impact of CYP2C19 polymorphisms on citalopram or escitalopram exposure has yet to be fully clarified, especially with regard to the quantitative impact of the CYP2C19*17 allele. ⋯ This is the first meta-analysis based on a systematic review of accumulated information that addresses the relationship between CYP2C19 genotypes and the exposure to citalopram or escitalopram. All functional CYP2C19 genotype groups demonstrated significant effects on (es)citalopram exposure. The findings based on our pooled analysis are likely to help in understanding the inter-individual variability in the exposure to citalopram and escitalopram in psychiatric patients and to facilitate dose selection, particularly for the homozygous carriers of CYP2C19*2 or *3 (loss of function) and CYP2C19*17 (gain of function) alleles. The results could improve individualization of citalopram or escitalopram therapy and could also be used for physiologically based pharmacokinetic modeling as well as pharmacokinetic/pharmacodynamic modeling.
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The objective of the current review was to provide an updated and comprehensive summary on pharmacokinetic data describing the distribution of antimicrobials into interstitial fluid (ISF) by comparing drug concentration versus time profiles between ISF and blood/plasma in healthy individuals and/or diseased populations. An extensive literature search identified 55 studies detailing 87 individual comparisons. For each antibiotic (antibacterial) (or antibiotic class), we comment on dosing implications based on tissue ISF distribution characteristics and determine the suitability of conducting clinical pharmacokinetic monitoring (CPM) using a previously published scoring algorithm. ⋯ Data also suggest that piperacillin can be categorized as a 'likely suitable' agent for CPM in ISF. Regression analyses of data from the published studies, including protein binding, molecular weight, and predicted partition coefficient (using XlogP3) as dependent variables, indicated that protein binding was the only significant predictor for the extent of drug distribution as determined by ratios of the area under the concentration-time curve between muscle ISF/total plasma (R (2) = 0.65, p < 0.001) and adipose ISF/total plasma (R (2) = 0.48, p < 0.004). Although recurrent limitations (i.e., small sample size, lack of statistical comparisons, lack of steady-state conditions, high individual variability) were identified in many studies, these data are still valuable and allowed us to generate general dosing guidelines and assess the suitability of using ISF for CPM.
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Duloxetine, a selective serotonin (5-hydroxytryptamine) and norepinephrine reuptake inhibitor, has been approved since 2004 for the treatment of adults with major depressive disorder (MDD). It is currently not approved for use in pediatric patients (aged <18 years) with MDD. The clinical development program for duloxetine in the pediatric MDD population, which consisted of three clinical studies, provided extensive data on the safety, tolerability, and pharmacokinetics of duloxetine across a wide dose range in pediatric patients of differing ages, sex, body weights, and sexual maturation. ⋯ Duloxetine pharmacokinetics was similar in children and adolescents with MDD. The statistically significant effects of dose, BSA, and race on duloxetine pharmacokinetics in pediatric patients did not appear to be clinically meaningful. At a given dose, the typical steady-state duloxetine concentrations in the pediatric population were lower than in adults, and the distribution of steady-state duloxetine concentrations in pediatric patients were typically in the lower range of concentrations in adults.
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Levofloxacin is a commonly prescribed antimicrobial where recommendations exist to reduce doses for renal impairment but not to increase doses for augmented renal function. Morbidly obese patients are increasing in prevalence, and represent a population that can have augmented renal function requiring higher-than-standard doses. ⋯ The proposed approach serves as a relevant alternative to the current fixed-dosing paradigm of levofloxacin in the morbidly obese.