scholarly journals A236 LINACLOTIDE IS NOT DETECTABLE IN BREAST MILK OF LACTATING WOMEN: AN OPEN-LABEL, PHASE 1 STUDY

2021 ◽  
Vol 4 (Supplement_1) ◽  
pp. 285-287
Author(s):  
N Crittenden ◽  
D McGeeney ◽  
Y Assouline-Dayan ◽  
K Boutros ◽  
M Syrzycka ◽  
...  
Keyword(s):  
Breast Milk ◽  
Phase 1 ◽  
Cumulative Exposure ◽  
Human Breast Milk ◽  
Open Label ◽  
Idiopathic Constipation ◽  
Once Daily ◽  
Lactating Women ◽  
Amino Acid Peptide ◽  
Institutional Review

Abstract Background Linaclotide (LIN) is a guanylate cyclase-C agonist approved to treat adults with irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC). As LIN is a 14-amino acid peptide, no absorption from the gastrointestinal tract is expected following oral administration. However, LIN levels in human breast milk have not been determined. Aims To determine the levels of LIN and its active metabolite, MM-419447, excreted in breast milk after multiple once-daily doses of LIN (72 µg, 145 μg, or 290 μg) in lactating women. Methods This was a multicenter, open-label, multidose, Phase 1, milk-only lactation study (NCT02220348) in lactating women aged 18–45 years who were actively breastfeeding or pumping for ≥4 weeks and were already taking LIN 72 μg, 145 μg, or 290 μg therapeutically for IBS-C or CIC. Participants continued their LIN dose once daily for the 3 study days, with breast milk extractions at −1 to 0 hours (pre-dose) on Day 1 and −1 to 0 hours and 0–2, 2–4, 4–8, 8–12, 12–16, and 16–24 hours after dosing on Day 3. The pharmacokinetic endpoints were the cumulative amount of LIN and MM-419447 and the percentage dose of LIN excreted into the breast milk over the dosing interval. Adverse events (AEs) were monitored. The study has institutional review board approval. Results Seven women were enrolled in the study (IBS-C, n=1; CIC, n=6) and received LIN (72 μg, n=5; 145 μg, n=1; and 290 μg, n=1). Mean age was 28 (range: 19–35), mean weight was 70 kg (standard deviation [SD]: 12 kg), and mean body mass index was 26 kg/m2 (SD: 4 kg/m2); the majority were white (n=6). Concentrations of LIN and MM-419447 in breast milk samples were below the quantitation limits (<0.25 ng/mL and <1.00 ng/mL, respectively) at all time points for all participants. Cumulative exposure for each dose was 216 μg (72 μg dose), 435 μg (145 μg dose), and 870 μg (290 μg dose). One treatment-emergent AE was reported (mild rash). Conclusions The data collected in this study provide no evidence that breastfeeding infants receive LIN or MM-419447 through breast milk as their concentrations were below the quantitation limit following multiple once-daily doses of LIN 72 μg, 145 μg, or 290 μg. Funding Agencies This study was sponsored by Allergan plc, Dublin, Ireland (prior to acquisition by AbbVie Inc.). Writing and editorial assistance were provided to the authors by Stephanie J. Rippon, MBio, Jane Beck, MA, and Rebecca Fletcher, BA(Hons), of Complete HealthVizion, Inc., Chicago, IL, USA and funded by Allergan plc (prior to acquisition by AbbVie Inc.).

scholarly journals Pharmacokinetics of Dapivirine Transfer into Blood Plasma, Breast Milk, and Cervicovaginal Fluid of Lactating Women Using the Dapivirine Vaginal Ring

2019 ◽  
Vol 63 (3) ◽  
Author(s):  
Lisa M. Noguchi ◽  
Craig Hoesley ◽  
Cliff Kelly ◽  
Rachel Scheckter ◽  
Katherine Bunge ◽  
...  
Keyword(s):  
Breast Milk ◽  
Hiv Infection ◽  
Phase 1 ◽  
Vaginal Ring ◽  
Adult Women ◽  
Open Label ◽  
Lactating Women ◽  
Sexually Transmitted ◽  
Hiv Prevention Strategies ◽  
Cervicovaginal Fluid

ABSTRACT Breastfeeding (BF) women are an important population for biomedical HIV prevention strategies, but they are rarely included in trials. The 25-mg dapivirine vaginal ring (VR) reduced women’s risk of sexually transmitted HIV infection in two phase 3 trials conducted in Africa. We conducted a phase 1, open-label study (MTN-029/IPM 039) of dapivirine VR use among lactating women in Pittsburgh, PA, and Birmingham, AL, USA. MTN-029/IPM 039 enrolled 16 healthy adult women who had already weaned their infants but were still able to express breast milk. Women were instructed to use the VR continuously for 14 days and provided milk, plasma, and cervicovaginal fluid (CVF) samples for pharmacological analysis. No infants were exposed to the drug, but infant dosage was estimated according to FDA guidance. Adverse events (AEs) were collected at all contacts. The study was completed with 100% participant retention. Median dapivirine concentrations were 676 pg/ml in breast milk, 327 pg/ml in plasma (milk/plasma ratio ∼2.0), and 36.25 ng/mg in CVF. Six participants experienced 10 total AEs, none of which required VR discontinuation. The estimated mean daily infant dosage was 74.3 ng/kg/day. In this first study of dapivirine exposure during lactation, dapivirine VR use was associated with lower concentrations of detectable dapivirine in milk and plasma than in CVF samples and a favorable safety profile. Estimated daily levels of infant dapivirine exposure were also low. Additional studies are needed to evaluate longer periods of dapivirine VR use among BF mother-infant pairs living in regions with higher incidence of sexually transmitted HIV infection. (This study has been registered at ClinicalTrials.gov under registration no. NCT02808949.)

Pharmacokinetics of Dapivirine Transfer into Blood Plasma, Breast Milk, and Cervicovaginal Fluid of Lactating Women Using the Dapivirine Vaginal Ring

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Breast Milk ◽  
Hiv Infection ◽  
Phase 1 ◽  
Adult Women ◽  
Open Label ◽  
Lactating Women ◽  
Express Breast Milk ◽  
Sexually Transmitted ◽  
Fda Guidance ◽  
Favorable Safety

Breastfeeding (BF) women are an important population for biomedicalHIV prevention strategies, but they are rarely included in trials. The 25-mg dapivirinevaginal ring (VR) reduced women’s risk of sexually transmitted HIV infection in twophase 3 trials conducted in Africa. We conducted a phase 1, open-label study (MTN-029/IPM 039) of dapivirine VR use among lactating women in Pittsburgh, PA, andBirmingham, AL, USA. MTN-029/IPM 039 enrolled 16 healthy adult women who hadalready weaned their infants but were still able to express breast milk. Women wereinstructed to use the VR continuously for 14 days and provided milk, plasma, andcervicovaginal fluid (CVF) samples for pharmacological analysis. No infants were exposedto the drug, but infant dosage was estimated according to FDA guidance. Adverseevents (AEs) were collected at all contacts. The study was completed with100% participant retention. Median dapivirine concentrations were 676 pg/ml inbreast milk, 327 pg/ml in plasma (milk/plasma ratio ?2.0), and 36.25 ng/mg in CVF.Six participants experienced 10 total AEs, none of which required VR discontinuation.The estimated mean daily infant dosage was 74.3 ng/kg/day. In this first studyof dapivirine exposure during lactation, dapivirine VR use was associated with lowerconcentrations of detectable dapivirine in milk and plasma than in CVF samples anda favorable safety profile. Estimated daily levels of infant dapivirine exposure werealso low. Additional studies are needed to evaluate longer periods of dapivirine VRuse among BF mother-infant pairs living in regions with higher incidence of sexuallytransmitted HIV infection. (This study has been registered at ClinicalTrials.gov underregistration no. NCT02808949.)

Excretion of Iohexol and Metrizoate in Human Breast Milk

1987 ◽  
Vol 28 (5) ◽  
pp. 523-526 ◽  
Author(s):  
S. T. Nielsen ◽  
I. Matheson ◽  
J. N. Rasmussen ◽  
K. Skinnemoen ◽  
E. Andrew ◽  
...  
Keyword(s):  
Breast Milk ◽  
Low Dose ◽  
Decay Curve ◽  
Human Breast Milk ◽  
Human Breast ◽  
Blood Samples ◽  
Lactating Women ◽  
Milk Samples ◽  
Slow Decay ◽  
Contrast Medium Injection

Six lactating women undergoing contrast media examination had milk and blood taken to determine the rate and extent of excretion of iohexol (Omnipaque) (four mothers) and metrizoate (Isopaque) (two mothers). Blood samples were taken up to 45 minutes and milk samples up to 48 hours after the contrast medium injection. The excretion was low, reaching a maximum at 3 to 6 hours and showing a slow decay curve (t 1/2 = 15 to 108 hours). One mother, who was weaning her baby, showed a different excretion pattern. The amount excreted during 24 hours was about 0.5 per cent of the weight adjusted maternal dose for both iohexol and metrizoate. It is not likely, that such a low dose of poorly absorbed drug would cause any adverse effects in the infant, unless it is hypersensitive to the drug already. The authors consider breast feeding to be acceptable for mothers receiving iohexol or metrizoate.

scholarly journals SARS-CoV-2 antibodies detected in human breast milk post-vaccination

2021 ◽  
Author(s):  
Jill K. Baird ◽  
Shawn M. Jensen ◽  
Walter J. Urba ◽  
Bernard A. Fox ◽  
Jason R. Baird
Keyword(s):  
Breast Milk ◽  
Time Course ◽  
Medical Center ◽  
Vaccine Dose ◽  
The United States ◽  
Human Breast Milk ◽  
Policy Makers ◽  
Post Vaccination ◽  
Lactating Women ◽  
Efficacy Research

ABSTRACTImportanceThe SARS-CoV-2 pandemic has infected over a hundred million people worldwide, with almost 2.5 million deaths at the date of this publication. In the United States, Pfizer-BioNTech and Moderna vaccines were first administered to the public starting in December 2020, and no lactating women were included in the initial trials of safety/efficacy. Research on SARS-CoV-2 vaccination in lactating women and the potential transmission of passive immunity to the infant through breast milk is needed to guide patients, clinicians and policy makers during the worldwide effort to curb the spread of this virus.ObjectiveTo determine whether SARS-CoV-2 specific immunoglobins are found in breast milk post-vaccination, and to characterize the time course and types of immunoglobulins present.DesignProspective cohort studySettingProvidence Portland Medical Center, Oregon, USAParticipantsSix lactating women who planned to receive both doses of the Pfizer-BioNTech or Moderna vaccine between December 2020 and January 2021. Breast milk samples were collected pre-vaccination and at 11 additional timepoints, with last sample at 14 days post 2nd dose of vaccine.ExposureTwo doses of Pfizer-BioNTech or Moderna SARS-CoV-2 vaccine.Main Outcome(s) and Measure(s)Levels of SARS-CoV-2 specific IgA and IgG immunoglobulins in breast milk.ResultsIn this cohort of 6 lactating women who received 2 doses of SARS-CoV-2 vaccine, we observed significantly elevated levels of SARS-CoV-2 specific IgG and IgA antibodies in breast milk beginning at Day 7 after the initial vaccine dose, with an IgG-dominant response.Conclusions and RelevanceWe are the first to show that maternal vaccination results in SARS-CoV-2 specific immunoglobulins in breast milk that may be protective for infants.

Higher Absorption of Vitamin C from Food than from Supplements by Breastfeeding Mothers at Early Stages of Lactation

2016 ◽  
Vol 86 (3-4) ◽  
pp. 81-87
Author(s):  
Dorota Martysiak-Żurowska ◽  
Maciej Zagierski ◽  
Ewa Woś-Wasilewska ◽  
Agnieszka Szlagatys-Sidorkiewicz
Keyword(s):  
Liquid Chromatography ◽  
Breast Milk ◽  
Vitamin C ◽  
Daily Intake ◽  
Human Breast Milk ◽  
Dietary Intakes ◽  
Human Breast ◽  
Natural Sources ◽  
Lactating Women ◽  
Lactation Stage

Abstract.The aim of the present study was to determine the effect of vitamin C supply in the diet of lactating women on vitamin C concentrations in human milk (n = 97) sampled at different stages of lactation. Vitamin C levels were measured by liquid chromatography. Dietary intake of vitamin C was determined based on 3-day food dairies kept by breastfeeding mothers. Maternal dietary intakes of vitamin C from natural sources on lactation day 90 (n = 18) were significantly higher than on lactation days 15 (n = 42) and 30 (n = 37). The number of women taking vitamin C supplements decreased in successive stages of lactation. The average daily intake of vitamin C was estimated at 119 mg, but nearly 20% of mothers consumed less than 50 mg of vitamin C per day. No significant correlations were observed between lactation stage and vitamin C levels in breast milk (r = 0.110, p = 0.064). The average vitamin C concentrations in human breast milk were determined at 50.9 mg / L, and were not higher than 80.6 mg / L regardless of lactation stage and maternal intake of vitamin C. Vitamin C excretion into breast milk is regulated to prevent exceeding saturation level. The vitamin C concentration in milk was positive correlated with maternal intake of vitamin C from food, in the case of non-supplemented diet (r = 0.402, p = 0.041). Our results suggest that vitamin C occurring in food is much better absorbed and passes into breast milk than vitamin C from supplements.

Escalation portion of phase II study to evaluate the safety, pharmacokinetics, and clinical activity of the PI3K/mTOR inhibitor paxalisib (GDC-0084) in glioblastoma (GBM) with unmethylated O6-methylguanine-methyltransferase (MGMT) promotor status.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2550-2550
Author(s):  
Patrick Y. Wen ◽  
John Frederick De Groot ◽  
James D. Battiste ◽  
Samuel Aaron Goldlust ◽  
James Stuart Garner ◽  
...  
Keyword(s):  
Oral Mucositis ◽  
Dose Escalation ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Current Phase ◽  
Clinical Activity ◽  
High Grade ◽  
Newly Diagnosed ◽  
Open Label ◽  
Once Daily

2550 Background: Paxalisib (previously GDC-0084) is a potent, oral, selective, brain-penetrant, small molecule inhibitor of class I phosphoinositide 3-kinase and mammalian target of rapamycin. The PI3K pathway is upregulated in ~85% of GBM cases and paxalisib has shown efficacy in preclinical models. A phase I study (NCT01547546) investigated paxalisib dosed once daily in 47 patients with recurrent high-grade gliomas and established a maximum tolerated dose (MTD) of 45mg once daily. The current phase Il study aims to explore the safety, tolerability, and clinical activity of paxalisib in newly diagnosed GBM and an unmethylated MGMT promotor following surgery and temozolomide chemoradiation per Stupp regimen. Methods: Part 1 of this study is an open-label, dose-escalation phase to assess the safety, tolerability and MTD. Dose-escalation started at 60mg and progressed in 15mg increments using a 3+3 design. Part 2 is an expansion cohort recruiting 20 patients randomized to administration in fed or fasted states at the MTD. Results: Part 1 is complete and reported here. Nine patients were recruited and an MTD of 60mg was determined. DLTs were hyperglycemia and oral mucositis. AEs were generally reversible and consistent with the PI3K inhibitor class with the most common events were rash, oral mucositis, and fatigue. PK at the MTD was broadly consistent with the data published for the phase 1 study. For eight response-evaluable patients in Part I the median progression-free survival (PFS) was 8.4 months, and 25% of patients remained progression free after 15 months of follow-up. Part 2 is ongoing. Conclusions: A higher MTD of 60mg was identified in newly diagnosed GBM with unmethylated MGMT promotor status than the 45mg MTD previously identified in recurrent high-grade glioma. An encouraging PFS signal is described in this poor-prognosis, unmethylated MGMT patient population. Clinical trial information: NCT03522298 .

scholarly journals No Clinically Relevant Drug-Drug Interactions between Methadone or Buprenorphine-Naloxone and Antiviral Combination Glecaprevir and Pibrentasvir

2017 ◽  
Vol 61 (10) ◽  
Author(s):  
Matthew P. Kosloski ◽  
Weihan Zhao ◽  
Armen Asatryan ◽  
Jens Kort ◽  
Pierre Geoffroy ◽  
...  
Keyword(s):  
Nonstructural Protein ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Opiate Withdrawal ◽  
Protein Inhibitor ◽  
Open Label ◽  
Once Daily ◽  
Hcv Genotype 1 ◽  
Trough Plasma

ABSTRACT The combination of glecaprevir (formerly ABT-493), a nonstructural protein 3/4A (NS3/4A) protease inhibitor, and pibrentasvir (formerly ABT-530), an NS5A protein inhibitor, is being developed as treatment for HCV genotype 1 to 6 infection. The pharmacokinetics, pharmacodynamics, safety, and tolerability of methadone or buprenorphine-naloxone when coadministered with the glecaprevir-pibrentasvir combination in HCV-negative subjects on stable opioid maintenance therapy were investigated in a phase 1, single-center, two-arm, multiple-dose, open-label sequential study. Subjects received methadone (arm 1) or buprenorphine-naloxone (arm 2) once daily (QD) per their existing individual prescriptions alone (days 1 to 9) and then in combination with glecaprevir at 300 mg QD and pibrentasvir at 120 mg QD (days 10 to 16) each morning. Dose-normalized exposures were similar with and without glecaprevir and pibrentasvir for (R)- and (S)-methadone (≤5% difference) and for buprenorphine and naloxone (≤24% difference); the norbuprenorphine area under the curve was 30% higher with glecaprevir and pibrentasvir, consistent with maximum and trough plasma concentrations that increased by 21% to 25%. No changes in pupil response, short opiate withdrawal scale score, or desire for drugs questionnaire were observed when glecaprevir and pibrentasvir were added to methadone or buprenorphine-naloxone therapy. No dose adjustment is required when glecaprevir and pibrentasvir are coadministered with methadone or buprenorphine-naloxone.

scholarly journals Excretion of Moxidectin into Breast Milk and Pharmacokinetics in Healthy Lactating Women

2011 ◽  
Vol 55 (11) ◽  
pp. 5200-5204 ◽  
Author(s):  
Joan M. Korth-Bradley ◽  
Virginia Parks ◽  
Stephan Chalon ◽  
Ian Gourley ◽  
Kyle Matschke ◽  
...  
Keyword(s):  
Breast Milk ◽  
Adverse Events ◽  
World Health ◽  
Terminal Phase ◽  
Absolute Amount ◽  
Upper Respiratory Tract ◽  
Open Label ◽  
Time Curve ◽  
Lactating Women ◽  
Standard Breakfast

ABSTRACTMoxidectin, registered worldwide as a veterinary antiparasitic agent, is currently under development for humans for the treatment of onchocerciasis in collaboration with the World Health Organization. The objective of this study was to assess the pharmacokinetics of moxidectin in healthy lactating women, including the excretion into breast milk. Twelve women, ages 23 to 38 years, weighing 54 to 79 kg, all more than 5 months postpartum, were enrolled, following their plan to wean their infants and provision of informed consent. A single 8-mg, open-label dose was administered orally after consumption of a standard breakfast. Complete milk collection was done for approximately 28 days, and plasma samples were collected for 90 days. Moxidectin concentrations were measured by high-performance liquid chromatography (HPLC) with fluorescence detection, with a validated range of 0.08 to 120 ng/ml. Noncompartmental pharmacokinetic methods were used to find the following results: peak concentration in plasma (Cmax), 87 ± 25 ng/ml; time toCmax(tmax), 4.18 ± 1.59 h; terminal-phase elimination half-life (t1/2), 832 ± 321 h; total area under the concentration-time curve (AUC), 4,046 ± 1,796 ng·h/ml; apparent oral dose clearance (CL/F), 2.35 ± 1.07 l/h; ratio of CL/Fto the terminal-phase disposition rate constant, λz(Vλz/F), 2,526 ± 772 liters; percentage of maternal dose excreted in milk, 0.701 ± 0.299%; absolute amount excreted in milk, 0.056 ± 0.024 mg; relative infant dose, 8.73 ± 3.17% of maternal dose assuming complete absorption; clearance in milk (CLmilk), 0.016 ± 0.009 liter/h. Nine of 12 subjects reported adverse events, all of which were considered treatment emergent but not drug related and were mostly reported during the long outpatient period 8 to 90 days after dose administration. The most frequently reported adverse events were headache and nausea (n= 4), oropharyngeal pain (n= 2), rhinitis, viral pharyngitis, and viral upper respiratory tract infection (n= 2).

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