scholarly journals Bedaquiline exposure in pregnancy and breastfeeding in women with rifampicin-resistant tuberculosis

2021 ◽  
Author(s):  
Richard Court ◽  
Kamunkhwala Gausi ◽  
Buyisile Mkhize ◽  
Lubbe Wiesner ◽  
Catriona Waitt ◽  
...  
Keyword(s):  
Human Milk ◽  
Pregnant Women ◽  
Post Partum ◽  
Plasma Concentrations ◽  
Maternal Plasma ◽  
Population Pharmacokinetic ◽  
Breastfed Infants ◽  
Liquid Chromatography Tandem Mass ◽  
Low Exposure ◽  
The One

Aim We aimed to explore the effect of pregnancy on bedaquiline pharmacokinetics and describe bedaquiline exposure in the human milk of mothers treated for rifampicin-resistant TB, where there is no human data available. Methods We performed a longitudinal pharmacokinetic study in pregnant women treated for rifampicin-resistant TB to explore the effect of pregnancy on bedaquiline exposure. Pharmacokinetic sampling was performed at four time-points over six hours in the third trimester, and again at approximately six weeks postpartum. We obtained serial human milk samples from breastfeeding mothers, and a single plasma sample taken from breastfed and non-breastfed infants to assess bedaquiline exposure. We used liquid chromatography-tandem mass spectrometry to perform the human milk and plasma bedaquiline assays, and population pharmacokinetic modelling to interpret the bedaquiline concentrations. Results We recruited 13 women, six of whom completed the ante- and post-partum PK sampling. All participants were HIV-positive on antiretroviral therapy. We observed lower ante- and post-partum bedaquiline exposures than reported in non-pregnant controls. Bedaquiline concentrations in human milk were higher than maternal plasma (milk to maternal plasma ratio: 24:1). A single random plasma bedaquiline and M2 concentration was available in four infants (median age: 6.5 weeks): concentrations in the one breastfed infant were similar to maternal plasma concentrations; concentrations in the three non-breastfed infants were detectable but lower than maternal plasma concentrations. Conclusion We report low exposure of bedaquiline in pregnant women treated for rifampicin-resistant TB. Bedaquiline significantly accumulates in human milk; breastfed infants receive mg/kg doses of bedaquiline equivalent to maternal doses.

scholarly journals Total and Free Plasma Concentrations of Progesterone, Cortisol and Oestradiol-I7ß during Pregnancy, Parturition and Early Lactation in Sows

1984 ◽  
Vol 37 (4) ◽  
pp. 267 ◽  
Author(s):  
JL Whitely ◽  
DL Willcox ◽  
JA Newton ◽  
GD Bryant-Greenwood ◽  
PE Hartmann
Keyword(s):  
Post Partum ◽  
Plasma Concentrations ◽  
Free Fraction ◽  
Maternal Plasma ◽  
Free Concentration ◽  
Free Cortisol ◽  
Dialysis Method ◽  
Three Stages ◽  
Free Plasma ◽  
Total Concentrations

The total (bound plus free) concentrations of progesterone, 20a-<iihydroprogesterone, oestradiol-17{:1 and cortisol were determined in the plasma of sows at three stages during pregnancy and more intensively from 5 days pre-partum to 5 days post-partum. The free fractions of progesterone, oestradiol-17{3 and cortisol were measured in the same samples by a rate dialysis method. Up to day 110 of gestation, the amounts of free hormone in plasma did not fluctuate independently of their total concentrations. During farrowing, the total and free concentrations of progesterone and cortisol varied independently of each other, whereas total and free oestradiol-17{3 declined simultaneously. The initiation of parturition was associated with a decrease in circulating total progesterone, and was accentuated by a decrease in the free fraction (P<O� 005) so that its active free concentration was only 20% of its day 1 pre-partum value. Total and free cortisol concentrations rose rapidly during labour so that at 12-18 h after birth of the first piglet 30% of that cortisol in maternal plasma was free hormone.

Plasma levels of atrial natriuretic peptides during pregnancy and post partum in the rat

1989 ◽  
Vol 120 (1) ◽  
pp. 113-117 ◽  
Author(s):  
C. Jansakul ◽  
R. G. King ◽  
A. L. A. Boura ◽  
S. P. Brennecke ◽  
G. M. Handberg
Keyword(s):  
Plasma Volume ◽  
Natriuretic Peptides ◽  
Post Partum ◽  
Plasma Concentrations ◽  
Maternal Plasma ◽  
Atrial Natriuretic Peptides ◽  
Female Wistar Rats ◽  
Near Term ◽  
The Relationship ◽  
Atrial Natriuretic

ABSTRACT Plasma concentrations of atrial natriuretic peptides (ANP) in female Wistar rats were measured by radioimmunoassay at oestrus, during pregnancy, during parturition and between 3 h and 4 days post partum. Concentrations of ANP in rats on days 10, 15 and 17 of pregnancy were not significantly different from those in non-pregnant animals in oestrus (32·5 ± 2·2 pmol/l; mean ± s.e.m., n = 9), but levels near term (days 20 and 21 of pregnancy) were reduced by approximately 50%. However, plasma concentrations of ANP at 6, 12 and 24 h post partum were approximately twice those of non-pregnant animals in oestrus, but returned to normal levels within 4 days after parturition. Maternal plasma volume increased significantly during pregnancy, and fell 15–20% 6–24 h post partum. These results suggest that the relationship between plasma volume and the plasma concentration of ANP is reset during pregnancy and changes rapidly post partum. The results do not necessarily, however, imply any changes in the relationship between atrial pressure and the concentration of ANP. Journal of Endocrinology (1989) 120, 113–117

scholarly journals New Colistin Population Pharmacokinetic Data in Critically Ill Patients Suggesting an Alternative Loading Dose Rationale

2014 ◽  
Vol 58 (12) ◽  
pp. 7324-7330 ◽  
Author(s):  
N. Grégoire ◽  
O. Mimoz ◽  
B. Mégarbane ◽  
E. Comets ◽  
D. Chatelier ◽  
...  
Keyword(s):  
Steady State ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Plasma Concentrations ◽  
Multidrug Resistant ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Loading Dose ◽  
Liquid Chromatography Tandem Mass

ABSTRACTColistin is an old antibiotic that has recently gained a considerable renewal of interest as the last-line defense therapy against multidrug-resistant Gram-negative bacteria. It is administered as colistin methanesulfonate (CMS), an inactive prodrug, and it was shown that due to slow CMS conversion, colistin plasma concentrations increase very slowly after treatment initiation, which constitutes the rationale for a loading dose in critically ill patients. However, faster CMS conversion was observed in healthy volunteers but using a different CMS brand, which may also have a major impact on colistin pharmacokinetics. Seventy-three critically ill patients not undergoing dialysis received multiple doses of CMS. The CMS concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and a pharmacokinetic analysis was conducted using a population approach. We confirmed that CMS renal clearance and colistin concentrations at steady state are mostly governed by creatinine clearance, but we predict a typical maximum concentration of drug in serum (Cmax) of colistin close to 2 mg/liter, occurring 3 h after an initial dose of 2 million international units (MIU) of CMS. Accordingly, the estimated colistin half-life (t1/2) was relatively short (3.1 h), with rapid attainment of steady state. Our results are only partially consistent with other recently published results. We confirm that the CMS maintenance dose should be adjusted according to renal function in critically ill patients. However, much higher than expected colistin concentrations were observed after the initial CMS dose, with rapid steady-state achievement. These discrepancies challenge the pharmacokinetic rationale for a loading dose, which may still be appropriate for rapid bacterial eradication and an improved clinical cure rate.

scholarly journals Population Pharmacokinetic and Pharmacodynamic Modeling of Amodiaquine and Desethylamodiaquine in Women with Plasmodium vivax Malaria during and after Pregnancy

2012 ◽  
Vol 56 (11) ◽  
pp. 5764-5773 ◽  
Author(s):  
Joel Tarning ◽  
Palang Chotsiri ◽  
Vincent Jullien ◽  
Marcus J. Rijken ◽  
Martin Bergstrand ◽  
...  
Keyword(s):  
Pregnant Women ◽  
Plasmodium Vivax ◽  
Plasma Concentrations ◽  
Inhibitory Effect ◽  
Biologically Active ◽  
Pharmacodynamic Modeling ◽  
Population Pharmacokinetic ◽  
Content Type ◽  
Plasmodium Vivax Malaria

ABSTRACTAmodiaquine is effective for the treatment ofPlasmodium vivaxmalaria, but there is little information on the pharmacokinetic and pharmacodynamic properties of amodiaquine in pregnant women with malaria. This study evaluated the population pharmacokinetic and pharmacodynamic properties of amodiaquine and its biologically active metabolite, desethylamodiaquine, in pregnant women withP. vivaxinfection and again after delivery. Twenty-seven pregnant women infected withP. vivaxmalaria on the Thai-Myanmar border were treated with amodiaquine monotherapy (10 mg/kg/day) once daily for 3 days. Nineteen women, with and withoutP. vivaxinfections, returned to receive the same amodiaquine dose postpartum. Nonlinear mixed-effects modeling was used to evaluate the population pharmacokinetic and pharmacodynamic properties of amodiaquine and desethylamodiaquine. Amodiaquine plasma concentrations were described accurately by lagged first-order absorption with a two-compartment disposition model followed by a three-compartment disposition of desethylamodiaquine under the assumption of completein vivoconversion. Body weight was implemented as an allometric function on all clearance and volume parameters. Amodiaquine clearance decreased linearly with age, and absorption lag time was reduced in pregnant patients. Recurrent malaria infections in pregnant women were modeled with a time-to-event model consisting of a constant-hazard function with an inhibitory effect of desethylamodiaquine. Amodiaquine treatment reduced the risk of recurrent infections from 22.2% to 7.4% at day 35. In conclusion, pregnancy did not have a clinically relevant impact on the pharmacokinetic properties of amodiaquine or desethylamodiaquine. No dose adjustments are required in pregnancy.

Changes in concentration of human atrial natriuretic peptide in normal pregnancy and toxaemia

1987 ◽  
Vol 114 (2) ◽  
pp. 325-328 ◽  
Author(s):  
Y. Otsuki ◽  
E. Okamoto ◽  
I. Iwata ◽  
E. Nishino ◽  
N. Mitsuda ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Atrial Natriuretic Peptide ◽  
Pregnant Women ◽  
Natriuretic Peptide ◽  
Plasma Concentrations ◽  
Normal Pregnancy ◽  
Maternal Plasma ◽  
Human Atrial Natriuretic Peptide ◽  
Atrial Natriuretic

ABSTRACT Changes in concentration of human atrial natriuretic peptide (hANP) in normal and toxaemic pregnancy were examined. The maternal plasma concentration of hANP increased gradually during normal pregnancy to a maximum of 20·0±2·4 pmol/l (mean ± s.e.m.) after week 36 of pregnancy. From week 20, the plasma concentrations of hANP were significantly higher than those in non-pregnant women (9·3±2·0 pmol/l). In toxaemia with hypertension, maternal plasma hANP levels were increased after week 26 of pregnancy (37·7±6·0 pmol/l) compared with those in normal gravida at the same time (17·1±1·6 pmol/l). Maternal plasma hANP levels in toxaemia only with oedema were not different from those in normal gravida. J. Endocr. (1987) 114, 325–328

scholarly journals Population Pharmacokinetics of Lumefantrine in Pregnant Women Treated with Artemether-Lumefantrine for Uncomplicated Plasmodium falciparum Malaria

2009 ◽  
Vol 53 (9) ◽  
pp. 3837-3846 ◽  
Author(s):  
Joel Tarning ◽  
Rose McGready ◽  
Niklas Lindegardh ◽  
Elizabeth A. Ashley ◽  
Mupawjay Pimanpanarak ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Pregnant Women ◽  
Population Pharmacokinetics ◽  
Plasma Concentrations ◽  
Plasmodium Falciparum Malaria ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Increased Risk ◽  
Pharmacokinetic Properties

ABSTRACT Artemether-lumefantrine has become one of the most widely used antimalarial drugs in the world. The objective of this study was to determine the population pharmacokinetic properties of lumefantrine in pregnant women with uncomplicated multidrug-resistant Plasmodium falciparum malaria on the northwestern border of Thailand. Burmese and Karen women (n = 103) with P. falciparum malaria and in the second and third trimesters of pregnancy were treated with artemether-lumefantrine (80/480 mg) twice daily for 3 days. All patients provided five capillary plasma samples for drug quantification, and the collection times were randomly distributed over 14 days. The concentration-time profiles of lumefantrine were assessed by nonlinear mixed-effects modeling. The treatment failure rate (PCR-confirmed recrudescent infections at delivery) was high; 16.5% (95% confidence interval, 9.9 to 25.1). The population pharmacokinetics of lumefantrine were described well by a two-compartment open model with first-order absorption and elimination. The final model included interindividual variability in all pharmacokinetic parameters and a linear covariate relationship between the estimated gestational age and the central volume of distribution. A high proportion of all women (40%, 41/103) had day 7 capillary plasma concentrations of <355 ng/ml (which corresponds to approximately <280 ng/ml in venous plasma), a threshold previously associated with an increased risk of therapeutic failure in nonpregnant patients in this area. Predictive modeling suggests that a twice-daily regimen given for 5 days would be preferable in later pregnancy. In conclusion, altered pharmacokinetic properties of lumefantrine contribute to the high rates of failure of artemether-lumefantrine treatment in later pregnancy. Dose optimization is urgently needed.

scholarly journals Lumefantrine and Desbutyl-Lumefantrine Population Pharmacokinetic-Pharmacodynamic Relationships in Pregnant Women with Uncomplicated Plasmodium falciparum Malaria on the Thailand-Myanmar Border

2015 ◽  
Vol 59 (10) ◽  
pp. 6375-6384 ◽  
Author(s):  
Frank Kloprogge ◽  
Rose McGready ◽  
Warunee Hanpithakpong ◽  
Daniel Blessborn ◽  
Nicholas P. J. Day ◽  
...  
Keyword(s):  
Pregnant Women ◽  
Treatment Outcomes ◽  
Falciparum Malaria ◽  
Plasma Concentrations ◽  
Plasmodium Falciparum Malaria ◽  
Population Pharmacokinetic ◽  
Time To Event ◽  
Combined Model ◽  
Therapeutic Outcomes ◽  
Cure Rates

ABSTRACTArtemether-lumefantrine is the most widely used antimalarial artemisinin-based combination treatment. Recent studies have suggested that day 7 plasma concentrations of the potent metabolite desbutyl-lumefantrine correlate better with treatment outcomes than those of lumefantrine. Low cure rates have been reported in pregnant women with uncomplicated falciparum malaria treated with artemether-lumefantrine in northwest Thailand. A simultaneous pharmacokinetic drug-metabolite model was developed based on dense venous and sparse capillary lumefantrine and desbutyl-lumefantrine plasma samples from 116 pregnant patients on the Thailand-Myanmar border. The best model was used to evaluate therapeutic outcomes with a time-to-event approach. Lumefantrine and desbutyl-lumefantrine concentrations, implemented in anEmaxmodel, both predicted treatment outcomes, but lumefantrine provided better predictive power. A combined model including both lumefantrine and desbutyl-lumefantrine did not improve the model further. Simulations suggested that cure rates in pregnant women with falciparum malaria could be increased by prolonging the treatment course. (These trials were registered at controlled-trials.com [ISRCTN 86353884].)

scholarly journals Maternal Plasma Pyridoxal 5′-Phosphate Concentration Is Inversely Associated with Plasma Cystathionine Concentration across All Trimesters in Healthy Pregnant Women

2019 ◽  
Vol 149 (8) ◽  
pp. 1354-1362
Author(s):  
Maria F Mujica-Coopman ◽  
Dayana R Farias ◽  
Ana B Franco-Sena ◽  
Juliana S Vaz ◽  
Gilberto Kac ◽  
...  
Keyword(s):  
Pregnant Women ◽  
Carbon Metabolism ◽  
Plasma Concentrations ◽  
First Trimester ◽  
Maternal Blood ◽  
Maternal Plasma ◽  
Third Trimester ◽  
Metabolite Concentrations ◽  
Mixed Regression ◽  
One Carbon Metabolism

ABSTRACTBackgroundVitamin B-6 (B-6), in the form of pyridoxal 5′phosphate (PLP), is critical for one-carbon metabolism reactions and cellular function. Plasma PLP concentration decreases throughout pregnancy, but the functional consequences of this have not been studied. Plasma cystathionine is a sensitive indicator of suboptimal B-6 status in healthy adults.ObjectivesThe aim of this study was to determine the relation between plasma PLP and cystathionine concentrations, and to assess longitudinal changes in plasma concentrations of metabolites of one-carbon metabolism, including total homocysteine (tHcy), cysteine, methionine, glycine, serine, and glutathione, over the course of pregnancy.DesignThis was a prospective cohort study of 186 healthy Brazilian pregnant women (20–40 y). Plasma PLP and metabolite concentrations were quantified in fasting maternal blood samples collected between 5–13, 20–26, and 30–36 weeks of gestation. Linear mixed regression models were used to determine the association of 1) first-trimester PLP tertiles, and 2) the variation of PLP concentration throughout pregnancy, with related metabolite concentrations across weeks of gestation.ResultsMedian (IQR) PLP concentration decreased from 36.2 (29.2–44.5) to 21.0 (15.9–26.0) to 16.8 (12.9–21.4) nmol/L in the first, second, and third trimester, respectively, whereas cystathionine concentration increased from 63.2 (49.7–78.9) to 122 (98.0–167) to 143 (114–193) nmol/L, respectively (both P < 0.001). The variation of PLP throughout pregnancy was inversely associated with cystathionine concentration across weeks of gestation, after adjusting for confounding factors; β (95% CI) = −0.387 (−0.752, −0.219), P = 0.04. This association significantly differed by trimester and was strongest in the third trimester. Plasma concentrations of glycine, serine, methionine, cysteine, and tHcy decreased, and that of glutathione increased, between the first and second trimesters (all P < 0.05).ConclusionsThe variation of PLP concentration predicted cystathionine concentration throughout pregnancy. Increases in plasma cystathionine across trimesters may reflect maternal intracellular B-6 deficiency.

Maternal plasma concentrations of perfluoroalkyl and polyfluoroalkyl substances during pregnancy and anogenital distance in male infants

2019 ◽  
Vol 34 (7) ◽  
pp. 1356-1368 ◽  
Author(s):  
Youping Tian ◽  
Hong Liang ◽  
Maohua Miao ◽  
Fen Yang ◽  
Honglei Ji ◽  
...  
Keyword(s):  
Pregnant Women ◽  
Science And Technology ◽  
Plasma Concentrations ◽  
Maternal Plasma ◽  
Male Rat ◽  
Inverse Association ◽  
Anogenital Distance ◽  
Unit Increase ◽  
Polyfluoroalkyl Substances ◽  
Perfluoroalkyl And Polyfluoroalkyl Substances

Abstract STUDY QUESTION Are maternal plasma concentrations of perfluoroalkyl and polyfluoroalkyl substances (PFASs) during pregnancy associated with anogenital distance (AGD) in male infants at birth, 6, and 12 months of age? SUMMARY ANSWER Higher maternal plasma concentrations of some PFASs were associated with shorter AGD in male infants at birth and 6 months of age. WHAT IS KNOWN ALREADY Two animal studies have found that exposure to PFASs was associated with shorter AGD in male rat fetuses and wild male minks. There is only one human study on the topic that did not identify consistent patterns between maternal serum concentrations of PFASs during pregnancy and AGD in male infants. STUDY DESIGN, SIZE, DURATION In the prospective cohort study, a total of 1292 eligible pregnant women were recruited at 12–16 weeks of gestation between April and December 2012 at the Maternal and Child Health Hospital of Minhang district in Shanghai, China. At delivery, 667 male singletons were born. They were then followed up at birth (n = 439) and at 6 (n = 411) and 12 months (n = 376) of age when anopenile distance (AGDAP) and anoscrotal distance (AGDAS) were measured. PARTICIPANTS/MATERIALS, SETTING, METHODS A total of 500 male infants who had both maternal plasma concentrations of PFASs and at least one AGD measurement of at three time points were included in the present study. Multiple linear regression models were used to evaluate the potential linear associations between maternal concentrations of PFASs and AGD. MAIN RESULTS AND THE ROLE OF CHANCE Maternal plasma concentrations (ln-transformed) of perfluorooctane sulfonate (PFOS), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUdA) were inversely associated with AGDAS or AGDAP at birth (AGDAS: per ln unit increase in PFAS concentrations: β (95% CI): −0.65 (−1.27 to −0.02) mm for PFOS; −0.58 (−1.11 to −0.06) mm for PFDA; and −0.57 (−1.09 to −0.06) mm for PFUdA; AGDAP: per ln unit increase in PFAS concentrations: β (95% CI): −0.63 (−1.24 to −0.01) mm for PFDA and − 0.76 (−1.36 to −0.16) mm for PFUdA). At 6 months of age, per unit increase in maternal ln concentrations of PFOS and perfluorotridecanoic acid (PFTrDA), AGDAS decreased on average by −2.21 (95% CI: −4.28 to −0.14) and −1.11 (95% CI: −2.17 to −0.06) mm, respectively. Additionally, ln-transformed perfluorooctanoic acid (PFOA) showed nonsignificant but inverse associations with both AGDAS and AGDAP at 6 months of age. We found no significant associations between ln-transformed maternal concentrations of PFASs and either AGDAS or AGDAP at 12 months of age. However, significantly inverse association of ln-transformed PFOA with AGDAP was observed in male infants who never or shortly breastfed (<3 months) at 12 months of age. LIMITATIONS, REASONS FOR CAUTION AGD measurements were performed by different examiners at each follow-up visit, and the intra-examiner variation was not assessed, which might cause intra-rater and inter-rater measurement errors. Additionally, our study may have selection bias since a considerable number of participants withdrew from the cohort although the differences in demographic characteristics were not statistically significant between included mother–infant pairs and those excluded. No statistical correction was made for multiple comparisons. WIDER IMPLICATIONS OF THE FINDINGS Our findings may have important implications for the early development of genital health in male infants since PFASs can be detected in almost all pregnant women and infants worldwide. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by grants from the National Key Research and Development program of China (2018YFC1002801 and 2016YFC1000505), the Science and Technology Commission of Shanghai Municipality (16ZR1430100), the National Natural Science Foundation of China (81428011), and the Innovation-Oriented Science and Technology Grant from National Health Commission Key Laboratory of Reproduction Regulation (CX2017-06). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER N/A.

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