scholarly journals Population pharmacokinetic models of first choice beta-lactam antibiotics for severe infections treatment: What antibiotic regimen to prescribe in children?

2020 ◽  
Vol 23 ◽  
pp. 470-485
Author(s):  
Amélie Marsot
Keyword(s):  
Pediatric Population ◽  
Individual Characteristics ◽  
Essential Medicines ◽  
World Health ◽  
Population Pharmacokinetic ◽  
Inclusion Criteria ◽  
Drug Dosing ◽  
First Choice ◽  
Dosing Regimens ◽  
Severe Infections

Background: To perform a review describing the pharmacokinetic (PK) parameters and covariates of interest of the eight first choice β-lactams (BL) antibiotics for treatment of severe infections in pediatric population. Pediatric sepsis and septic shock reportedly affect 30% of children admitted to pediatric intensive care units, with a 25% mortality rate. Eight BL are included as first choice antibiotic for severe infections in pediatric population in the World Health Organization model list of essential medicines for children. Methods: The PubMed/Medline databases was searched and included studies if they described a population PK model of piperacillin, amoxicillin, ampicillin, cefotaxime, ceftriaxone, cloxacillin, imipenem or meropenem in neonates or children. We compared the PK parameters for each drug. We analysed the used covariates to estimate PK parameters. We compared the pharmacokinetics/pharmacodynamics (PK/PD) targets and the drug dosing recommendations. Results: Thirty-four studies met inclusion criteria with seven studies for piperacillin, five for amoxicillin, three for ampicillin, three for cefotaxime, two for ceftriaxone, two for imipenem and twelve for meropenem. None met inclusion criteria for cloxacillin. Ages ranged from 0-19.1 years with 12 studies including preterm. Body weight, age and renal function were the three major covariates in neonates and children. Different PK/PD targets were observed (between 40% to 100% of the dosing regimen interval of time over which the unbound (or free) drug concentration remains above the minimal inhibitory concentration (MIC) (fT>MIC) or four times the MIC (fT>4xMIC)). Several drug-dosing regimens were fond recommended according to the age and pathogens MIC using intermittent, timed or continuous infusions. Conclusions: Consensus is lacking on the optimal dosing regimens for these eight first choice antibiotics. A more personalized approach to antibiotic drugs dosing with individual characteristics of patient and pathogen susceptibility is required. According PK/PD targets and used dosing regimens, prospective clinical studies are required to investigate clinical cure, patient survival and emergence of antimicrobial resistance.

scholarly journals Towards Rational Dosing Algorithms for Vancomycin in Neonates and Infants Based on Population Pharmacokinetic Modeling

2015 ◽  
Vol 60 (2) ◽  
pp. 1013-1021 ◽  
Author(s):  
Esther J. H. Janssen ◽  
Pyry A. J. Välitalo ◽  
Karel Allegaert ◽  
Roosmarijn F. W. de Cock ◽  
Sinno H. P. Simons ◽  
...  
Keyword(s):  
Pediatric Population ◽  
External Validation ◽  
Population Pharmacokinetic ◽  
Target Area ◽  
Pharmacokinetic Models ◽  
Time Curve ◽  
Population Pharmacokinetic Modeling ◽  
Model Based ◽  
Dosing Algorithm ◽  
Dosing Regimens

ABSTRACTBecause of the recent awareness that vancomycin doses should aim to meet a target area under the concentration-time curve (AUC) instead of trough concentrations, more aggressive dosing regimens are warranted also in the pediatric population. In this study, both neonatal and pediatric pharmacokinetic models for vancomycin were externally evaluated and subsequently used to derive model-based dosing algorithms for neonates, infants, and children. For the external validation, predictions from previously published pharmacokinetic models were compared to new data. Simulations were performed in order to evaluate current dosing regimens and to propose a model-based dosing algorithm. The AUC/MIC over 24 h (AUC24/MIC) was evaluated for all investigated dosing schedules (target of >400), without any concentration exceeding 40 mg/liter. Both the neonatal and pediatric models of vancomycin performed well in the external data sets, resulting in concentrations that were predicted correctly and without bias. For neonates, a dosing algorithm based on body weight at birth and postnatal age is proposed, with daily doses divided over three to four doses. For infants aged <1 year, doses between 32 and 60 mg/kg/day over four doses are proposed, while above 1 year of age, 60 mg/kg/day seems appropriate. As the time to reach steady-state concentrations varies from 155 h in preterm infants to 36 h in children aged >1 year, an initial loading dose is proposed. Based on the externally validated neonatal and pediatric vancomycin models, novel dosing algorithms are proposed for neonates and children aged <1 year. For children aged 1 year and older, the currently advised maintenance dose of 60 mg/kg/day seems appropriate.

scholarly journals Integrated Population Pharmacokinetic Analysis of Voriconazole in Children, Adolescents, and Adults

2012 ◽  
Vol 56 (6) ◽  
pp. 3032-3042 ◽  
Author(s):  
Lena E. Friberg ◽  
Patanjali Ravva ◽  
Mats O. Karlsson ◽  
Ping Liu
Keyword(s):  
Pediatric Population ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Loading Dose ◽  
Time Curve ◽  
Individual Parameter ◽  
Dosing Regimens

ABSTRACTTo further optimize the voriconazole dosing in the pediatric population, a population pharmacokinetic analysis was conducted on pooled data from 112 immunocompromised children (2 to <12 years), 26 immunocompromised adolescents (12 to <17 years), and 35 healthy adults. Different maintenance doses (i.e., 3, 4, 6, 7, and 8 mg/kg of body weight intravenously [i.v.] every 12 h [q12h]; 4 mg/kg, 6 mg/kg, and 200 mg orally q12h) were evaluated in these children. The adult dosing regimens (6 mg/kg i.v. q12h on day 1, followed by 4 mg/kg i.v. q12h, and 300 mg orally q12h) were evaluated in the adolescents. A two-compartment model with first-order absorption and mixed linear and nonlinear (Michaelis-Menten) elimination adequately described the voriconazole data. Larger interindividual variability was observed in pediatric subjects than in adults. Deterministic simulations based on individual parameter estimates from the final model revealed the following. The predicted total exposure (area under the concentration-time curve from 0 to 12 h [AUC0-12]) in children following a 9-mg/kg i.v. loading dose was comparable to that in adults following a 6-mg/kg i.v. loading dose. The predicted AUC0-12s in children following 4 and 8 mg/kg i.v. q12h were comparable to those in adults following 3 and 4 mg/kg i.v. q12h, respectively. The predicted AUC0-12in children following 9 mg/kg (maximum, 350 mg) orally q12h was comparable to that in adults following 200 mg orally q12h. To achieve voriconazole exposures comparable to those of adults, dosing in 12- to 14-year-old adolescents depends on their weight: they should be dosed like children if their weight is <50 kg and dosed like adults if their weight is ≥50 kg. Other adolescents should be dosed like adults.

scholarly journals Population Pharmacokinetics and Dosage Optimization of Linezolid in Critically Ill Pediatric Patients

2021 ◽  
Vol 65 (5) ◽  
Author(s):  
Mei Yang ◽  
Libo Zhao ◽  
Xiaohui Wang ◽  
Chen Sun ◽  
Hengmiao Gao ◽  
...  
Keyword(s):  
Body Weight ◽  
Critically Ill ◽  
Pediatric Patients ◽  
Pediatric Population ◽  
Treatment Success ◽  
Critically Ill Children ◽  
Population Pharmacokinetic ◽  
Optimal Dosage ◽  
Dosing Regimen ◽  
Dosing Regimens

ABSTRACT Linezolid is an oxazolidinone antibiotic exhibiting efficacy against multidrug-resistant (MDR) Gram-positive-related infections. However, its population pharmacokinetic (PopPK) profile in critically ill Chinese children has not been characterized. Optimal dosing regimens should be established according to the population pharmacokinetic (PopPK)/pharmacodynamic (PD) properties of linezolid in the specific population. This work aims to describe the pharmacokinetic (PK) properties of linezolid, assess the factors affecting interpatient variability, and establish an optimized regimen for children in pediatric intensive care units (PICU). A single-center, prospective, open-labeled PK study was performed. Ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was applied to measure the plasma levels during linezolid treatment. PopPK analysis was conducted using Phoenix NLME software. A total of 63 critically ill pediatric patients were included. The data showed good fit for a two-compartment model with linear elimination. Body weight and aspartate aminotransferase (AST) were the most significant covariates explaining variabilities in linezolid PK for the pediatric population. The therapeutic target was defined as the ratio of the area under the drug plasma concentration-time curve over 24 h to a MIC (AUC/MIC) of >80. Different dosing regimens were evaluated using Monte Carlo simulation to determine the optimal dosage strategy for linezolid. Although the probability of target attainment (PTA) was high (>96%) for 10 mg/kg body weight every 8 h at a MIC of ≤1 mg/liter, it was lower than 70% at a MIC of >1 mg/liter. Thus, the dosing regimen required adjustment. When the dosing regimen was adjusted to 15 mg/kg every 6 h, the PTA increased from 63.6% to 94.6% at a MIC of 2 mg/liter, thereby indicating a higher degree of treatment success. Children with AST of >40 U/liter had a significantly higher AUC than those with AST of ≤40 U/liter (205.45 versus 159.96). Therefore, dosage adjustment was required according to the AST levels. The PopPK characteristics of linezolid in critically ill children were evaluated, and an optimal dosage regimen was constructed based on developmental PopPK/PD model and simulation. (This study has been registered in the Chinese Clinical Trial Registry under no. ChiCTR1900021386).

scholarly journals Gliclazide: Biopharmaceutics Characteristics to Discuss the Biowaiver of Immediate and Extended Release Tablets

2020 ◽  
Vol 10 (20) ◽  
pp. 7131
Author(s):  
Bruna de Carvalho Mapa ◽  
Lorena Ulhôa Araújo ◽  
Neila Márcia Silva-Barcellos ◽  
Tamires Guedes Caldeira ◽  
Jacqueline Souza
Keyword(s):  
Extended Release ◽  
Immediate Release ◽  
Pharmacokinetic Profile ◽  
Dosage Forms ◽  
New Drugs ◽  
Essential Medicines ◽  
World Health ◽  
Drug Candidate ◽  
Dissolution Profile ◽  
First Choice

The lists of essential medicines of the World Health Organization (WHO) and Brazil include gliclazide as an alternative to the oral antidiabetic drug of first choice, metformin, in the treatment of type 2 diabetes mellitus because of its pharmacokinetic profile and few side effects. Thus, it is also considered by WHO and the International Pharmaceutical Federation (FIP) as a drug candidate to biowaiver, which is the evaluation of how favorable the biopharmaceutics characteristics are in order to obtain waiver from the relative bioavailability/bioequivalence (RB/BE) studies to register new medicines. This paper presents a review about the solubility, permeability and dissolution of gliclazide. A critical analysis of the information allowed to identify gliclazide as a Biopharmaceutics Classification System (BCS) Class II drug. Therefore, new drugs in immediate release dosage forms will not be eligible for biowaiver. Regarding the extended release dosage forms, besides the limited solubility, no information on the comparative dissolution profile was found, which would be necessary to analyze a possible biowaiver for a smaller dosage. It can be concluded that the registration of new medicines containing gliclazide must undergo RB/BE studies, since there is not enough evidence to recommend the replacement and waiver of such studies for immediate and extended release formulations.

Chemistry of Iodinated Contrast Media (ICM): A Minireview

2020 ◽  
Vol 17 ◽  
Author(s):  
Maithili Pramod Joshi ◽  
Ameya Chaudhari ◽  
Prashant S. Kharkar ◽  
Shreerang V. Joshi
Keyword(s):  
Adverse Effects ◽  
Contrast Media ◽  
Aqueous Solubility ◽  
Synthetic Methods ◽  
Essential Medicines ◽  
World Health ◽  
Iodinated Contrast Media ◽  
Environmental Aspects ◽  
Iodinated Contrast ◽  
Health Organization

: Historically, the use of Iodinated Contrast Media (ICM) for diagnostic purposes, particularly radiography and computed tomography (CT), is well-known. Many of the ICM are included in the World Health Organization (WHO)’s List of Essential Medicines. Depending on the chemotype and the presence of ionizable functional group(s), the ICM are categorized in the ionic/nonionic monomers/dimers. The lipophilicity, aqueous solubility, viscosity and osmolality are major characteristics dictating their use for one procedure versus the other. Over last several decades, substantial advancement occurred in the design and development of novel ICM, solely to reduce their propensity to cause adverse effects. Given the nature of their acute usage, some of the agents with appreciable toxicity are still used. Understanding their chemistry aspects is crucial to appreciate, acknowledge and justify the usage of these extremely important torch-bearers of diagnostic agent’s class. The present review article presents an in-depth overview of the synthetic methods, therapeutic indications, potential adverse effects along with the commercial and environmental aspects of ICM. The safety and tolerability of these agents is a field that has gained significant importance, which is given due importance in the discussion.

scholarly journals Mapping the inequality of the global distribution of seasonal influenza vaccine

2021 ◽  
pp. 0308518X2199835
Author(s):  
Yen Ching Yau ◽  
Michael T Gastner
Keyword(s):  
Influenza Vaccine ◽  
Respiratory Diseases ◽  
Seasonal Influenza ◽  
Developed Countries ◽  
Essential Medicines ◽  
World Health ◽  
Equitable Access ◽  
Seasonal Influenza Vaccine ◽  
Choropleth Map ◽  
Vaccine Distribution

With an estimated annual worldwide death toll of between 290 000 and 650 000, seasonal influenza remains one of the deadliest respiratory diseases. Influenza vaccines provide moderate to high protection and have been on the World Health Organization’s Model List of Essential Medicines since 1979. Approximately 490 million doses of influenza vaccine are produced per year, but an investigation of geographic allocation reveals enormous disparities. Here, we present two maps that visualise the inequality of the distribution across 195 countries: a conventional choropleth map and a cartogram. In combination, these two maps highlight the widespread lack of coverage in Africa and many parts of Asia. As COVID-19 vaccines are now being distributed in developed countries, data for seasonal influenza vaccine distribution emphasises the need for policymakers to ensure equitable access to COVID-19 vaccines.

scholarly journals Treatment of COVID-19 with Chloroquine: Implication for Malaria Chemotherapy Using ACTs in Disease Endemic Countries

2020 ◽  
Author(s):  
Neils Ben Quashie ◽  
Nancy Odurowah Duah-Quashie
Keyword(s):  
Intermittent Preventive Treatment ◽  
Preventive Treatment ◽  
World Health ◽  
Cross Resistance ◽  
Drug Resistant ◽  
Combination Therapies ◽  
Parasite Resistance ◽  
Demand And Supply ◽  
First Choice ◽  
Health Organization

Abstract Based on reports of parasite resistance and on World Health Organization recommendation, chloroquine was replaced with the artemisinin-based combination therapies (ACTs) as the first choice of drugs for the treatment of uncomplicated malaria. Disuse of chloroquine led to restoration of drug-sensitive parasite to some extent in certain countries. Ever since chloroquine and hydroxychloroquine were touted as potential treatment for coronavirus disease 2019 (COVID-19), there has been a dramatic surge in demand for the drugs. Even in areas where chloroquine is proscribed, there has been an unexpected increase in demand and supply of the drug. This situation is quite worrying as the indiscriminate use of chloroquine may produce drug-resistant parasites which may impact negatively on the efficacy of amodiaquine due to cross-resistance. Amodiaquine is a partner drug in one of the ACTs and in some of the drugs used for intermittent preventive treatment. We herein discuss the consequences of the escalated use of chloroquine in the management of COVID-19 on chemotherapy or chemoprevention of malaria and offer an advice. We speculate that parasite strains resistant to chloroquine will escalate due to the increased and indiscriminate use of the drug and consequently lead to cross-resistance with amodiaquine which is present in some drug schemes aforementioned. Under the circumstance, the anticipated hope of reverting to the use of the ‘resurrected chloroquine’ to manage malaria in future is likely to diminish. The use of chloroquine and its derivatives for the management of COVID-19 should be controlled.

scholarly journals ‘Choking the national demos’: research partnerships and the material constitution of global health

2021 ◽  
Vol 17 (1) ◽  
pp. 122-127
Author(s):  
John Harrington
Keyword(s):  
Human Rights ◽  
Global Health ◽  
Access To Medicines ◽  
Functional Health ◽  
Essential Medicines ◽  
World Health ◽  
Moral Principle ◽  
International Human Rights Law ◽  
Health Law ◽  
The World

By foregrounding a widened view of the rule of law in transnational legal processes, the works under discussion in this symposium can support innovative critical perspectives on global health law –a field that has gained wide attention due to the spread of COVID-19 around the world (Lander, 2020; Bhatt, 2020). Legal and socio-legal scholars in the decade and a half before the pandemic worked on locating global health law and articulating its underlying principles. Lawrence Gostin's 2014 monograph offers a synoptic view centred on international institutions (e.g. the World Health Organization, World Trade Organization, UN Human Rights Council) and problems (e.g. infectious-disease response, tobacco control), along with an elaboration of its normative basis in universal moral principle and international human rights law (Gostin, 2014). Struggles over access to essential medicines and intellectual property in the early 2000s are, for example, represented in terms of the right to health constraining international trade law. Andreas Fischer-Lescano and Guenther Teubner's 2004 reading is oriented more by social theory than by doctrinal or ethical frames (Fischer-Lescano and Teubner, 2004, pp. 1006, 1008). A functional health regime has ‘differentiated out’, they observe, and operates as a discrete communication system across borders, albeit one that is threatened by the preponderant economic system. On this model, the battle for access to medicines amounts to ensuring, via human rights guarantees, that the rationality of the health system is not replaced by that of its economic rival in legal and policy communications (Fischer-Lescano and Teubner, 2004, pp. 1030, 1046).

P6147Access to essential cardiovascular medicines in Kerala, the state with the highest cardiovascular disease burden in India

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
G Satheesh ◽  
S Puthean ◽  
M Ansil ◽  
M K Unnikrishnan ◽  
A Sharma ◽  
...  
Keyword(s):  
Public Sector ◽  
Private Sector ◽  
Premature Mortality ◽  
Generic Medicine ◽  
Essential Medicines ◽  
World Health ◽  
Healthcare Needs ◽  
Consumer Prices ◽  
Majority Population ◽  
Government Worker

Abstract Introduction The 2030 Agenda for Sustainable Development has prioritized the reduction of premature mortality due to NCDs – including cardiovascular diseases (CVD) - by a third. To achieve this goal, countries must achieve 80% availability of affordable essential medicines. Essential medicines as identified by the World Health Organization are those that meet the priority healthcare needs of majority population. Globally, India has the second highest CVD burden with over 1.7 million deaths annually, with the highest CVD morbidity and mortality rate in Kerala. Purpose To evaluate the availability, prices and affordability of essential CVD medicines in Kerala state to facilitate implementation of informed public health policy. Methods Using WHO/HAI methodology, we obtained data on availability and prices for 25 essential CVD medicines in a representative sample of 7 public-sector hospitals (survey anchors) and 37 private retail pharmacies located near the survey anchors in four districts. Additionally, we obtained the data from 10 government-subsidized discount pharmacies. We report availability as percentage of surveyed facilities where a given medicine was found. Median prices ratios (MPRs) were calculated by comparing consumer prices to the MSH International Reference Prices (IRPs). Medicines were considered affordable if the monthly supply costs less than one-day's wage of the lowest paid government worker. Results In the public-sector facilities (hospital and discount pharmacies combined), the mean (SD) availability of the surveyed CVD medicines was 52% (35.3%) for generic and 35.3% (20.7%) for originator brand (OB) version. 28% of surveyed medicines (including amlodipine, clopidogrel, losartan, metformin) were available in over 80% pharmacies. 12% (captopril, streptokinase and glyceryl trinitrate) were not available in any of the facilities. In the private sector, mean (SD) availability of generic and OB versions was 64.4% (37.2%) and 43.7% (34.6%), respectively. MPR was 1.28 [range: 0.02 (insulin NPH) – 16.7 (simvastatin)] for both lowest-priced generics (LPG) and most-sold generics (MSG). The lowest paid government worker in Kerala would spend 0.06 - 3.48 days' wages for the monthly supply of essential CVD medicines in the private sector. In government-subsidized discount pharmacies, mean availability was 49.3%. The generic medicine prices were 74% lower than in the private sector. Conclusions Availability of essential CVD medications in both public and private sector pharmacies fall short of the 80% target. In the private-sector, many essential CVD medications seem unaffordable especially considering the polypharmacy among CVD patients. Introducing policies to improve medicine availability in government-subsidized discount pharmacies is crucial in tackling Kerala's ever-increasing CVD burden.

scholarly journals Pregnancy-Related Effects on Nelfinavir-M8 Pharmacokinetics: a Population Study with 133 Women

2006 ◽  
Vol 50 (6) ◽  
pp. 2079-2086 ◽  
Author(s):  
Déborah Hirt ◽  
Jean-Marc Treluyer ◽  
Vincent Jullien ◽  
Ghislaine Firtion ◽  
Hélène Chappuy ◽  
...  
Keyword(s):  
Population Study ◽  
Time Course ◽  
Plasma Concentrations ◽  
Elimination Rate ◽  
Concomitant Administration ◽  
Individual Characteristics ◽  
Individual Treatment ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Linear Absorption

ABSTRACT A relationship between nelfinavir antiretroviral efficacy and plasma concentrations has been previously established. As physiological changes associated with pregnancy have a large impact on the pharmacokinetics of many drugs, a nelfinavir population study with women was developed, and the large intersubject variability was analyzed in order to optimize individual treatment schedules for this drug during pregnancy. A population pharmacokinetic model was developed in order to describe the concentration time course of nelfinavir and its metabolite M8 in pregnant and nonpregnant women. Individual characteristics, such as age, body weight, and weeks of gestation or delivery, which may influence nelfinavir-M8 pharmacokinetics were investigated. Data from therapeutic drug monitoring in 133 women treated with nelfinavir were retrospectively analyzed with NONMEM. Nelfinavir pharmacokinetics was described by a one-compartment model with linear absorption and elimination and M8 produced from the nelfinavir central compartment. Mean pharmacokinetic estimates and the corresponding intersubject percent variabilities for a nonpregnant woman were the following: absorption rate, 0.83 h−1; absorption lag time, 0.85 h; apparent nelfinavir elimination clearance (CL10/F), 35.5 liters/h (50%); apparent volume of distribution (V/F), 596 liters (118%); apparent formation clearance to M8 (CL1M/F), 0.65 liters/h (69%); and M8 elimination rate constant (k M0), 3.3 h−1 (59%). During pregnancy, we observed significant increases in nelfinavir (44.4 liters/h) and M8 (5 h−1) elimination but unchanged nelfinavir transformation clearance to M8, suggesting an induction of CYP3A4 but no effect on CYP2C19. Apparent nelfinavir clearance and volume showed a twofold increase on the day of delivery, suggesting a decrease in bioavailability on this day. The M8 elimination rate was increased by concomitant administration of nonnucleoside reverse transcriptase inhibitors. A trough nelfinavir plasma concentration above 1 mg/liter was previously shown to improve the antiretroviral response. The Bayesian individual pharmacokinetic estimates suggested that the dosage should not be changed in pregnant women but may be doubled on the day of delivery.

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