scholarly journals Pharmacokinetics of Isoniazid in Low-Birth-Weight and Premature Infants

2014 ◽  
Vol 58 (4) ◽  
pp. 2229-2234 ◽  
Author(s):  
A. Bekker ◽  
H. S. Schaaf ◽  
H. I. Seifart ◽  
H. R. Draper ◽  
C. J. Werely ◽  
...  

ABSTRACTIsoniazid (INH) is recommended for use as posttuberculosis exposure preventive therapy in children. However, no pharmacokinetic data are available for INH treatment in low-birth-weight (LBW) infants, who undergo substantial developmental and physiological changes. Our objectives in this study were to determine the pharmacokinetic parameters of INH at a dose of 10 mg/kg of body weight/day and to define its pharmacokinetics relative to the arylamineN-acetyltransferase-2 (NAT2) genotype. An intensive prospective pharmacokinetic sampling study was conducted at Tygerberg Children's Hospital, South Africa, in which we measured INH blood plasma concentrations at 2, 3, 4 and 5 h postdose. Twenty LBW infants (14 male, 16 exposed to HIV) were studied. The median birth weight was 1,575 g (interquartile range, 1,190 to 2,035 g) and the median gestational age was 35 weeks (interquartile range, 34 to 38 weeks). TheNAT2acetylation statuses of the infants were homozygous slow (SS) (5 infants), heterozygous intermediate (FS) (11 infants), and homozygous fast (FF) (4 infants). Using a noncompartmental analysis approach, the median maximum drug concentration in blood serum (Cmax) was 5.63 μg/ml, the time after drug administration to reachCmaxTmax) was 2 h, the area under the concentration-time curve from 2 to 5 h (AUC2–5) was 13.56 μg · h/ml, the half-life (t1/2) was 4.69 h, and the elimination constant rate (kel) was 0.15 h−1. The alanine aminotransferase levels were normal, apart from 2 isolated values at two and three times above the normal levels. Only the three-times-elevated value was repeated at 6 months and normalized. All LBW infants achieved target INH blood plasma concentrations comparable to the adult values. Reduced elimination was observed in smaller and younger infants and in slow acetylators, cautioning against higher doses. The safety data, although limited, were reassuring. More data, however, are required for newborn infants.

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
Adebanjo Adegbola ◽  
Rana Abutaima ◽  
Adeniyi Olagunju ◽  
Omotade Ijarotimi ◽  
Marco Siccardi ◽  
...  

ABSTRACT Artemether-lumefantrine is often coadministered with efavirenz-based antiretroviral therapy for malaria treatment in HIV-infected women during pregnancy. Previous studies showed changes in lumefantrine pharmacokinetics due to interaction with efavirenz in nonpregnant adults. The influence of pregnancy on this interaction has not been reported. This pharmacokinetic study involved 35 pregnant and 34 nonpregnant HIV-malaria-coinfected women receiving efavirenz-based antiretroviral therapy and was conducted in four health facilities in Nigeria. Participants received a 3-day standard regimen of artemether-lumefantrine for malaria treatment, and intensive pharmacokinetic sampling was conducted from 0.5 to 96 h after the last dose. Plasma efavirenz, lumefantrine, and desbutyl-lumefantrine were quantified using validated assays, and pharmacokinetic parameters were derived using noncompartmental analysis. The median middose plasma concentrations of efavirenz were significantly lower in pregnant women (n = 32) than in nonpregnant women (n = 32) at 1,820 ng/ml (interquartile range, 1,300 to 2,610 ng/ml) versus 2,760 ng/ml (interquartile range, 2,020 to 5,640 ng/ml), respectively (P = 0.006). The lumefantrine area under the concentration-time curve from 0 to 96 h was significantly higher in pregnant women (n = 27) at 155,832 ng · h/ml (interquartile range, 102,400 to 214,011 ng · h/ml) than nonpregnant women at 90,594 ng · h/ml (interquartile range, 58,869 to 149,775 ng · h/ml) (P = 0.03). A similar trend was observed for the lumefantrine concentration at 12 h after the last dose of lumefantrine, which was 2,870 ng/ml (interquartile range, 2,180 to 4,880 ng/ml) versus 2,080 ng/ml (interquartile range, 1,190 to 2,970 ng/ml) in pregnant and nonpregnant women, respectively (P = 0.02). The lumefantrine-to-desbutyl-lumefantrine ratio also tended to be lower in pregnant women than in nonpregnant women (P = 0.076). Overall, pregnancy tempered the extent of efavirenz-lumefantrine interactions, resulting in increased lumefantrine exposure. However, any consideration of dosage adjustment for artemether-lumefantrine to enhance exposure in this population needs to be based on data from a prospective study with safety and efficacy endpoints.


2018 ◽  
Vol 38 (6) ◽  
pp. 463-466 ◽  
Author(s):  
Laure Peyro Saint Paul ◽  
Maxence Ficheux ◽  
Danièle Debruyne ◽  
Magalie Loilier ◽  
Nicolas Bouvier ◽  
...  

The DaptoDP (NCT 2012-005699-33) study aimed to evaluate the pharmacokinetic parameters of daptomycin (DAP) in peritoneal dialysis-related peritonitis (PDRP) patients following intraperitoneal (IP) administration. The authors have already reported the findings on the 200-mg dosing and present here the follow-up results of the 300-mg dosing. The primary endpoint was a dialysate concentration of DAP above the effective concentration in situ during 6 hours of dwell time i.e., 16 mg/L. Secondary endpoints were to avoid the toxic threshold of 120 mg/L DAP and to be above 16 mg/L DAP for 2 hours in plasma. Pharmacokinetic parameters were evaluated on days 1 and 5. Safety data were evaluated on days 1 to 14 based on clinical and biological parameters. Daptomycin was administered in Nutrineal during 6 hours of dwell time for 14 days plus the usual antibiotic therapy in a separate dwell. Because the 200-mg dosing objectives were not reached, a higher DAP dose of 300 mg was tested in the next 3 patients. Effective dialysate and plasma concentrations were achieved at the 300-mg DAP dose with the plasma concentration well below the toxic threshold, even at steady state, during which the accumulation factor never exceeded 3. The optimal DAP dose of 300 mg daily by the IP route, as determined by the pharmacokinetic data, needs to be clinically confirmed prior to routine use. The peritoneal bioavailability of DAP supports using the IP route as an alternative to the intravenous route for peritonitis and systemic infections.


2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Lauren Dyer ◽  
Rachel Hardeman ◽  
Dovile Vilda ◽  
Katherine Theall ◽  
Maeve Wallace

Abstract Background A growing body of evidence is beginning to highlight how mass incarceration shapes inequalities in population health. Non-Hispanic blacks are disproportionately affected by incarceration and criminal law enforcement, an enduring legacy of a racially-biased criminal justice system with broad health implications for black families and communities. Louisiana has consistently maintained one of the highest rates of black incarceration in the nation. Concurrently, large racial disparities in population health persist. Methods We conducted a cross-sectional analysis of all births among non-Hispanic black women in Louisiana in 2014 to identify associations between parish-level (county equivalent) prevalence of jail incarceration within the black population and adverse birth outcomes (N = 23,954). We fit a log-Poisson model with generalized estimating equations to approximate the relative risk of preterm birth and low birth weight associated with an interquartile range increase in incarceration, controlling for confounders. In sensitivity analyses, we additionally adjusted for the parish-level index crime prevalence and analyzed regression models wherein white incarceration was used to predict the risk of adverse birth outcomes in order to quantify the degree to which mass incarceration may harm health above and beyond living in a high crime area. Results There was a significant 3% higher risk of preterm birth among black women associated with an interquartile range increase in the parish-level incarceration prevalence of black individuals, independent of other factors. Adjusting for the prevalence of index crimes did not substantively change the results of the models. Conclusion Due to the positive significant associations between the prevalence of black individuals incarcerated in Louisiana jails and estimated risk of preterm birth, mass incarceration may be an underlying cause of the persistent inequities in reproductive health outcomes experienced by black women in Louisiana. Not only are there economic and social impacts stemming from mass incarceration, but there may also be implications for population health and health inequities, including the persistence of racial disparities in preterm birth and low birth weight.


2017 ◽  
Vol 2017 ◽  
pp. 1-7
Author(s):  
Christopher Vinnard ◽  
Isabel Manley ◽  
Brittney Scott ◽  
Mariana Bernui ◽  
Joella Adams ◽  
...  

Background. Rifampin malabsorption is frequently observed in tuberculosis patients coinfected with human immunodeficiency virus (HIV) but cannot be predicted by patient factors such as CD4+ T cell count or HIV viral load. Methods. We sought to describe the relationship between HIV-associated immune activation, measures of gut absorptive capacity and permeability, and rifampin pharmacokinetic parameters in a pilot study of 6 HIV-infected, tuberculosis-uninfected patients who were naïve to antiretroviral therapy. Results. The median rifampin area under the concentration-versus-time curve during the 8-hour observation period was 42.8 mg·hr/L (range: 21.2 to 57.6), with a median peak concentration of 10.1 mg/L (range: 5.3 to 12.5). We observed delayed rifampin absorption, with a time to maximum concentration greater than 2 hours, in 2 of 6 participants. There was a trend towards increased plasma concentrations of sCD14, a marker of monocyte activation in response to bacterial translocation, among participants with delayed rifampin absorption compared to participants with rapid absorption (p=0.06). Conclusions. Delayed rifampin absorption may be associated with elevated markers of bacterial translocation among HIV-infected individuals naïve to antiretroviral therapy. This trial is registered with NCT01845298.


PEDIATRICS ◽  
1990 ◽  
Vol 86 (6) ◽  
pp. 916-921 ◽  
Author(s):  
Staffan K. T. Polberger ◽  
Göran A. Fex ◽  
Irene E. Axelsson ◽  
Niels C. R. Räihä

Concentrations of 11 plasma proteins were measured in 28 healthy, growing, very low birth weight, appropriate-for-gestational-age infants fed varying levels of human milk protein intake (range 1.7 to 3.9 g/kg per day). Significant positive correlations were found between ween mean protein intake and concentrations of 7 of the plasma proteins studied (transthyretin, retinol-binding protein, and transferrin: P < .001; vitamin D-binding protein and apolipoprotein B: P < .01; albumin and apolipoprotein A I: P < .05). A weak negative correlation with mean protein intake was seen for the plasma level of orosomucoid, whereas no significant correlations were found for the plasma concentrations of fibronectin and α1-antichymotrypsin. Protein intake, not energy intake, constituted the main contribution to the changes in the concentrations of transthyretin, retinol-binding protein, and transferrin. The levels of plasma transthyretin and transferrin were also strongly correlated with weight and length growth of the infants during the study as well as with other indicators of protein nutritional status such as preprandial concentrations of plasma amino acids and serum and urine urea. These data indicate that of the 11 plasma proteins studied, transthyretin, transferrin, and retinol-binding protein are the most suitable to evaluate protein nutritional status in very low birth weight infants.


PEDIATRICS ◽  
1977 ◽  
Vol 59 (3) ◽  
pp. 407-422 ◽  
Author(s):  
David K. Rassin ◽  
Gerald E. Gaull ◽  
Kirsti Heinonen ◽  
Niels C. R. Räihäa

The optimal quantity and quality of protein for low-birth-weight infants is undefined. In this study, 106 well, appropriate-for-gestational-age, low-birth-weight infants weighing 2,100 gm or less were divided into three gestational age groups and assigned randomly within each age group to one of five feeding regimens: pooled human milk; formula 1 (protein content, 1.5 gm/100 ml, 60 parts bovine whey proteins to 40 parts bovine caseins); formula 2 (3.0 gm/100 ml, 60:40); formula 3 (1.5 gm/100 ml, 18:82); and formula 4 (3.0 gm/100 ml, 18:82). The concentrations of the free amino acids in the plasma and urine of these infants were determined. The plasma concentrations of free amino acids were generally far greater in the infants fed the 3.0-gm/100 ml protein diets than they were in the infants fed pooled human milk. The plasma concentrations of free amino acids of the infants fed the 1.5-gm/100 ml protein diets were intermediate. In general, the concentrations of the free amino acids in the plasma of the infants fed the 3.0-gm/100 ml caseinpredominant formula (F4) were furthest from those fed pooled human milk. Glutamate showed the highest plasma amino acid concentrations in infants fed both the high- and low-protein casein-predominant formulas. This was true despite the fact that the intake of glutamate on the high-protein, whey-predominant formula was twice that on the low-protein, casein-predominant formula. The differences between groups in the essential amino acids in plasma were generally greater than those of the nonessential amino acids. The concentrations of amino acids in the urine tended to parallel those of the plasma.


2015 ◽  
Vol 10 (9) ◽  
pp. 1934578X1501000 ◽  
Author(s):  
Rosario Russo ◽  
Angelo Mancinelli ◽  
Michele Ciccone ◽  
Fabio Terruzzi ◽  
Claudio Pisano ◽  
...  

Diosmin is a naturally occurring flavonoid present in citrus fruits and other plants belonging to the Rutaceae family. It is used for the treatment of chronic venous insufficiency (CVI) for its pheblotonic and vaso-active properties, safety and tolerability as well. The aim of the current in vivo study was to investigate the pharmacokinetic profile of a branded micronized diosmin (μSMIN Plus™) compared with plain micronized diosmin in male Sprague-Dawley rats. After oral administration by gastric gavage, blood samples were collected via jugular vein catheters at regular time intervals from baseline up to 24 hours. Plasma concentrations were assessed by LC/MS. For each animal, the following pharmacokinetic parameters were calculated using a non-compartmental analysis: maximum plasma drug concentration (Cmax), time to reach Cmax (Tmax), area under the plasma concentration-time curve (AUC0-last), elimination half-life (t1/2), and relative oral bioavailability (%F). The results of the current study clearly showed an improvement in the pharmacokinetic parameters in animals treated with μSMIN Plus™ compared with animals treated with micronized diosmin. In particular, μSMIN Plus™ showed a 4-fold increased bioavailability compared with micronized diosmin. In conclusion, the results from the current study provided a preliminary pharmacokinetic profile for μSMIN Plus™, which may represent a new tool for CVI management.


2015 ◽  
Vol 59 (12) ◽  
pp. 7232-7239 ◽  
Author(s):  
Eric Wenzler ◽  
Mark H. Gotfried ◽  
Jeffrey S. Loutit ◽  
Stephanie Durso ◽  
David C. Griffith ◽  
...  

ABSTRACTThe steady-state concentrations of meropenem and the β-lactamase inhibitor RPX7009 in plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations were obtained in 25 healthy, nonsmoking adult subjects. Subjects received a fixed combination of meropenem (2 g) and RPX7009 (2 g) administered every 8 h, as a 3-h intravenous infusion, for a total of three doses. A bronchoscopy and bronchoalveolar lavage were performed once in each subject at 1.5, 3.25, 4, 6, or 8 h after the start of the last infusion. Meropenem and RPX7009 achieved a similar time course and magnitude of concentrations in plasma and ELF. The mean pharmacokinetic parameters ± the standard deviations of meropenem and RPX7009 determined from serial plasma concentrations were as follows:Cmax= 58.2 ± 10.8 and 59.0 ± 8.4 μg/ml,Vss= 16.3 ± 2.6 and 17.6 ± 2.6 liters; CL = 11.1 ± 2.1 and 10.1 ± 1.9 liters/h, andt1/2= 1.03 ± 0.15 and 1.27 ± 0.21 h, respectively. The intrapulmonary penetrations of meropenem and RPX7009 were ca. 63 and 53%, respectively, based on the area under the concentration-time curve from 0 to 8 h (AUC0–8) values of ELF and total plasma concentrations. When unbound plasma concentrations were considered, ELF penetrations were 65 and 79% for meropenem and RPX7009, respectively. Meropenem concentrations in AMs were below the quantitative limit of detection, whereas median concentrations of RPX7009 in AMs ranged from 2.35 to 6.94 μg/ml. The results from the present study lend support to exploring a fixed combination of meropenem (2 g) and RPX7009 (2 g) for the treatment of lower respiratory tract infections caused by meropenem-resistant Gram-negative pathogens susceptible to the combination of meropenem-RPX7009.


2000 ◽  
Vol 44 (3) ◽  
pp. 752-755 ◽  
Author(s):  
Giorgio Gatti ◽  
Alessandra Vigano' ◽  
Natascia Sala ◽  
Stefano Vella ◽  
Matteo Bassetti ◽  
...  

ABSTRACT The indinavir dosage regimen currently used for human immunodeficiency virus (HIV)-infected children is not based on pharmacokinetic data obtained in the target patient population. The purpose of our study was to characterize indinavir pharmacokinetics and pharmacodynamics in HIV-infected children. Eleven children (age range, 9.0 to 13.6 years; weight range, 21.7 to 56.0 kg) receiving indinavir (500 mg/m2 every 8 h) in combination with lamivudine and stavudine were studied. The correlation of indinavir pharmacokinetic parameters and demographic parameters was evaluated. Also, the pharmacodynamic relationship between parameters of indinavir exposure and parameters of renal toxicity and immunologic recovery was studied. The area under the indinavir concentration-time curve (AUC) and patient body surface area (BSA) showed a significant negative correlation (r = 0.73; P = 0.012). Patients with smaller BSA had excessive indinavir AUC compared to adults. On the other hand, the median minimum drug concentration in plasma (C min) was lower than that reported for adults. The maximum indinavir concentration in serum was higher in patients with renal toxicity (5 out of 11 children), but the difference was not statistically significant (15.3 ± 8.2 versus 9.8 ± 4.4 mg/liter; P = 0.19). There was a trend toward higher immunologic efficacy in patients with greater indinavir exposure: the time-averaged AUC of the percentage of CD4+ lymphocytes over the baseline value for patients with indinavir C min > 95% inhibitory concentration (IC95) was higher than in patients withC min < IC95(P = 0.068). Our study suggests that a dose reduction may be appropriate for children with small BSA and that a 6-h dosage regimen may be indicated for a substantial percentage of patients. Due to the low number of patients enrolled in this study, our results should be confirmed by a larger study.


2003 ◽  
Vol 90 (2) ◽  
pp. 353-361 ◽  
Author(s):  
Delana A. Adelekan ◽  
Christine A. Northrop-Clewes ◽  
Joshua A. Owa ◽  
Adesola O. Oyedeji ◽  
Adedayo A. Owoeye ◽  
...  

Using the World Health Organization criterion, the prevalence of sub-clinical vitamin A deficiency can be assessed using plasma retinol concentrations <0·7 μmol/l. However, plasma retinol can be depressed by infection; thus, the use of this criterion alone may overestimate deficiency. In the present study, we investigated the usefulness of the acute-phase proteins (APP) α1-antichymotrypsin (ACT) and α1-acid glycoprotein (AGP), plasma carotenoids and anthropometric and gestational indices to interpret plasma retinol in the blood of 192 apparently healthy Nigerian neonates collected randomly during days 1–20 postpartum. The mean weight (2·64 kg) and length (0·458 m) of the neonates and plasma concentrations (geometric mean, μmol/l) of retinol (0·54), α-carotene (0·072), ß-carotene (0·076) and lutein (0·080) were low. The prevalence of vitamin A deficiency was 72 %, indicating a severe public health problem. Babies who were of low birth weight (P<0·003) or premature and low birth weight (P<0·023) had significantly lower retinol concentrations than full-term normal weight babies. Thirty-two neonates had abnormal ACT and forty-four abnormal AGP concentrations. Positive correlations between retinol and ACT (r0·186,P=0·05) and AGP (r0·31,P=0·0001) during days 1–5 may be due to the increasing plasma retinol from maternal milk and a coincidental increasing capacity to synthesise APP. Subsequently, negative correlations between retinol and ACT (r−0·28,P=0·02) and AGP (r−0·29,P=0·018) from day 6 onwards reflected the continuing increase in plasma retinol, but no further increase in the APP. Overall, weight, ACT, lutein and age explained 30 % of the variance in retinol, but lutein was the most significant (r20·18,P<0·0001). Hence, the distribution of plasma retinol concentrations in this group of neonates was more strongly linked with nutrition (via the surrogate marker lutein) than infection.


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