Efavirenz in Human Breast Milk, Mothers', and Newborns' Plasma

Schneider, Serge; Peltier, Alexandra; Gras, Alain; Arendt, Vic; Karasi-Omes, Christine; Mujawamariwa, Anastasie; Ndimubanzi, Patrick Cyaga; Ndayisaba, Gilles; Wennig, Robert

doi:10.1097/qai.0b013e31817bbc21

Cited by 46 publications

(39 citation statements)

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“…This likely explains the emergence of resistance to these drugs in breast-feeding HIVinfected children of mothers who take those drugs (12). Efavirenz has also been demonstrated to transfer to breast-feeding infants in biologically significant concentrations (9). Zidovudine appears to transfer to breast-feeding infants in low quantities (7).…”

Section: Vol 55 2011 Nelfinavir Transfer To Breast Milk and Infantsmentioning

confidence: 99%

“…Antiretrovirals cross from maternal plasma to breast milk and from breast milk to the infant in different concentrations (4,5,7,8,9,10). The Kisumu Breastfeeding study (KiBS) was a phase IIb open-label single-arm PMTCT trial of maternal triple-antiretroviral regimens administered from 34 weeks' gestation to 6 months postpartum while infants exclusively breast-fed.…”

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confidence: 99%

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Nelfinavir and Its Active Metabolite, Hydroxy- t -Butylamidenelfinavir (M8), Are Transferred in Small Quantities to Breast Milk and Do Not Reach Biologically Significant Concentrations in Breast-Feeding Infants Whose Mothers Are Taking Nelfinavir

Weidle

Zeh

Martin

et al. 2011

Antimicrob Agents Chemother

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Antiretroviral drugs cross from maternal plasma to breast milk and from breast milk to the infant in different concentrations. We measured concentrations of nelfinavir and its active metabolite (M8) in maternal plasma and breast milk from women and in dried blood spots collected from their infants at delivery and postnatal weeks 2, 6, 14, and 24 in the Kisumu Breastfeeding Study, Kisumu, Kenya. Nelfinavir-based antiretroviral regimens given to mothers as prevention of mother-to-child HIV transmission (PMTCT) do not expose the breast-feeding infant to biologically significant concentrations of nelfinavir or M8.Maternal antiretroviral medications taken during breastfeeding as prevention of mother-to-child HIV transmission (PMTCT) reduce HIV viral load in the breast milk of nursing mothers (5). Antiretrovirals cross from maternal plasma to breast milk and from breast milk to the infant in different concentrations (4,5,7,8,9,10). The Kisumu Breastfeeding study (KiBS) was a phase IIb open-label single-arm PMTCT trial of maternal triple-antiretroviral regimens administered from 34 weeks' gestation to 6 months postpartum while infants exclusively breast-fed. The study was conducted in Kisumu, Kenya, with women and their infants enrolled between July 2003 and November 2006 (11). We demonstrated in a prior KiBS substudy that nevirapine, lamivudine, and zidovudine were present in the breast milk of lactating mothers prescribed those medications and that nevirapine and lamivudine were transferred to infants via breast-feeding in biologically significant concentrations, as evidenced by the emergence of resistance to lamivudine and nevirapine, respectively, among strains of HIV infecting the infants (7, 12). However, breastfeeding HIV-infected infants from the same substudy whose mothers received nelfinavir did not develop protease inhibitor resistance (12). The aim of this study was to describe concentrations of nelfinavir and its active metabolite, hydroxy-t-butylamidenelfinavir (M8), in maternal plasma, breast milk, and infant dried blood spots collected during the administration of nelfinavir to nursing mothers. MATERIALS AND METHODSA subset of mothers participating in KiBS with a CD4 count of Ͼ250 cells/l received nelfinavir mesylate (1,250 mg twice daily; Viracept, Hoffman-La Roche Ltd, Germany) and zidovudine-lamivudine (300 mg/150 mg twice daily; Combivir, GlaxoSmithKline, United Kingdom) (11). Maternal plasma, breast milk, and infant dried blood spots were collected at delivery and postnatal weeks 2, 6, 14, and 24 from a nonrandom subset of sequentially enrolled subjects participating in a breast milk substudy (7). Nelfinavir was dispensed in pill bottles with MEMS (medication event monitoring system) caps (Aardex, Ltd., Union City, CA), which were used to determine the dosing times for the last maternal antiretroviral dose prior to sampling; timing was confirmed by pharmacy staff. Prior to analysis, plasma and breast milk specimens were stored at Ϫ70°C and dried blood spots were stored at Ϫ20°C. Included in this a...

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Section: Vol 55 2011 Nelfinavir Transfer To Breast Milk and Infantsmentioning

confidence: 99%

mentioning

confidence: 99%

Nelfinavir and Its Active Metabolite, Hydroxy- t -Butylamidenelfinavir (M8), Are Transferred in Small Quantities to Breast Milk and Do Not Reach Biologically Significant Concentrations in Breast-Feeding Infants Whose Mothers Are Taking Nelfinavir

Weidle

Zeh

Martin

et al. 2011

Antimicrob Agents Chemother

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“…In plasma, the inter patient variability of antiretroviral drugs has been reported by us [11,12] and by others [22,23] and has been attributed to genetic influences, diet and/or presence of other drugs and diseases [24][25][26]. In saliva, the parameters responsible for drug concentration variations may be salivary flow rate, salivary pH, and drug pharmacokinetics.…”

Section: Discussionmentioning

confidence: 99%

“…One milliliter of saliva or plasma was then mixed to 1 ml ammonium buffer at pH 9.5 and Mebeverine which served as internal standard. Unbound ARVs were extracted with solid phase extraction cartridges as described earlier [11,12]. After evaporating the extracts to dryness under nitrogen at 40°C, the residues were reconstituted in 100 l ammonium formate buffer (pH 3.8) for quantitative analysis.…”

Section: Sample Collection and Preparationmentioning

confidence: 99%

Evaluation of Saliva as an Alternative Matrix for Monitoring Plasma Zidovudine, Lamivudine and Nevirapine Concentrations in Rwanda

Gras¹,

Schneider²,

Karasi³

et al. 2011

CHR

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Saliva may provide interesting advantages as matrix for compliance measurements, pharmacokinetic studies and therapeutic drug monitoring in resource limited countries. We investigated the feasibility of using saliva for compliance monitoring of zidovudine (ZDV), lamivudine (3TC) and nevirapine (NVP) in 29 HIV-1 infected patients from Rwanda. ZDV, 3TC and NVP drug levels were quantified by an LC/MS-MS method in plasma and stimulated saliva samples and compared using Bland-Altman analysis. Seven patients demonstrated undetectable saliva ZDV levels while five out of these seven also showed no 3TC salivary concentrations. For the other samples, we observed a good agreement between salivary and plasma concentrations of each antiretroviral drug. A significant relation between the difference in saliva and plasma ZDV concentrations and the average ZDV concentration in the two matrices was deduced as follows: y = -380.15 + 1.79 x. The log saliva and plasma concentration difference of both 3TC and NVP was consistent across the range of average log concentration. Overall, we showed large agreement limits suggesting a wide inter patient variability that may result in non-reliable plasma level predictions from saliva drug measurements. Therefore, our results indicate that saliva may serve as a valuable tool only for NVP compliance testing because of its high salivary concentration.

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“…29 Rwandan infants of mothers receiving efavirenzbased HAART achieved median efavirenz concentrations of 0.87 mg/l through breastmilk ingestion, just below the recommended target trough concentration of >1 mg/l. 30 Transfer of NNRTIs from mothers receiving HAART may therefore result in substantial exposure in their breastfed infants along with potential benefit for prevention of HIV transmission, the risk of side-effects and the risk of developing viral resistance to NNRTIs *Whole blood concentrations from 2 to 14 weeks after birth. † Plasma concentrations 6 weeks to 6 months after birth.…”

Section: Impact Of Antituberculosis Treatmentmentioning

confidence: 99%

Pharmacokinetics of antiretroviral drugs in infancy

McIlleron

Gous

2009

South. Afr. j. HIV med.

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Infancy (from birth until 1 year of age) is a time of rapid changes in the body of a child. These changes affect pharmacokinetics in many ways. The CHER study 1 showed that early antiretroviral (ARV) treatment reduces mortality and disease progression among infants acquiring HIV infection before 12 weeks of age. As a result the World Health Organization has recently revised treatment initiation recommendations in children less than 1 year of age: all infants under 12 months of age with confirmed HIV infection should be started on ARV therapy, irrespective of clinical or immunological stage. 2 Dosing in infants is challenging because drug concentrations are highly variable, there is frequently scant pharmacokinetic information on young children, and few suitable drug formulations are available. Furthermore, adherence to treatment is reliant on the caregiver rather than the patient. Peri-and postnatal HIV transmission are reduced by maternal highly active ARV treatment (HAART). However, the benefits and risks to breast-fed infants of exposure to maternal ARV drugs during lactation are poorly understood.In this article we review the pharmacokinetics of ARV drugs relevant to South African infants, and highlight some of the challenges to delivering ARV treatment in safe and effective doses.Growth and development are accompanied by changes that influence drug concentrations. As these developmental changes begin in utero, post-conceptional age is a better descriptor of maturation than postnatal age. Size and age explain a considerable part of the pharmacokinetic variability. However, there is a non-linear relationship between clearance and size. Consequently, simple proportional adjustment of the adult dose based on weight leads to underestimation of the maintenance dose required in children. Dose calculation methods based on scaling of clearance do not account for changes during early infancy in multiple processes affecting drug absorption, distribution, metabolism and elimination. In recent years there has been a trend to provide simplified dosing guidelines using weight bands, which provide many practical advantages. Ideally dosing would also account for differences in lean body size and maturity within the weight bands.Drug absorption is highly variable and difficult to predict. It is determined by multiple interacting factors including enteric pH, gastric motility, intestinal transit time, the physico-chemical properties of the drug, intestinal metabolic capacity and activity of drug transporters. Gastric pH rapidly declines and then rises again during the first few days of life. Acidity then increases over several months, reaching adult levels (pH 2 -3) between 2 and 7 years. Frequent feeding with milk or formula may influence gastric pH. The absorption of atazanavir is reduced at a higher pH and it should be taken with food to enhance bio-availability. Although by 36 weeks' gestational age an infant has developed intestinal motility patterns similar to those in adults, motility is irregular and variable, and the...

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Efavirenz in Human Breast Milk, Mothers', and Newborns' Plasma

Cited by 46 publications

References 23 publications

Nelfinavir and Its Active Metabolite, Hydroxy- t -Butylamidenelfinavir (M8), Are Transferred in Small Quantities to Breast Milk and Do Not Reach Biologically Significant Concentrations in Breast-Feeding Infants Whose Mothers Are Taking Nelfinavir

Nelfinavir and Its Active Metabolite, Hydroxy- t -Butylamidenelfinavir (M8), Are Transferred in Small Quantities to Breast Milk and Do Not Reach Biologically Significant Concentrations in Breast-Feeding Infants Whose Mothers Are Taking Nelfinavir

Evaluation of Saliva as an Alternative Matrix for Monitoring Plasma Zidovudine, Lamivudine and Nevirapine Concentrations in Rwanda

Pharmacokinetics of antiretroviral drugs in infancy

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