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.)

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.)

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.).

BMS-986205, an indoleamine 2, 3-dioxygenase 1 inhibitor (IDO1i), in combination with nivolumab (nivo): Updated safety across all tumor cohorts and efficacy in advanced bladder cancer (advBC).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 358-358 ◽  
Author(s):  
Jason J. Luke ◽  
Josep Tabernero ◽  
Anthony Joshua ◽  
Jayesh Desai ◽  
Andrea I. Varga ◽  
...  
Keyword(s):  
Phase 1 ◽  
Preliminary Evidence ◽  
Stevens Johnson Syndrome ◽  
Tumor Escape ◽  
Open Label ◽  
Indoleamine 2 ◽  
Johnson Syndrome ◽  
Heavily Pretreated ◽  
Grade 3 ◽  
Favorable Safety

358 Background: Nivo (anti–PD-1) has shown durable responses and manageable safety (ORR, 19.6%; grade 3‒4 treatment-related AEs [TRAEs], 18%) in advBC (Sharma et al. Lancet Oncol 2017), but prolonging survival in more pts requires additional approaches to overcome tumor evasion mechanisms. IDO1 allows tumor escape through kynurenine (KYN) production, which stimulates regulatory T cells and suppresses effector T-cell proliferation. Anti─PD-1 can upregulate IDO1, supporting the rationale for combining nivo with an IDO1i. BMS-986205 is a selective, potent, once-daily (QD) oral IDO1i that works early in the IDO1 pathway to reduce KYN production. BMS-986205 + nivo showed favorable safety and efficacy in heavily pretreated pts with select solid tumors (Luke et al. SITC 2017; NCT02658890). Updated safety across all tumor cohorts and efficacy in the immuno-oncology (I-O)–naive advBC cohort are reported. Methods: Dose-escalation methods in this phase 1/2a, open-label study were previously described; during expansion, pts received BMS-986205 100 or 200 mg QD + nivo 240 mg IV Q2W or 480 mg IV Q4W. Objectives included safety and ORR by RECIST v1.1 (includes unconfirmed responses). Results: As of Mar 2018, 516 pts received BMS-986205 + nivo; 45% had ≥2 prior regimens. TRAEs occurred in 57% of pts (grade 3‒4, 12%), the most common being fatigue (15%) and nausea (12%); 19 pts (4%) discontinued due to TRAEs, and 3 pts ( < 1%) died due to a TRAE (myocarditis, Stevens-Johnson syndrome, and hepatic failure). In all treated pts and within the advBC cohort (n = 30), the frequency and severity of TRAEs and rate of discontinuation due to TRAEs was lower with the 100- vs 200-mg BMS-986205 dose. Among the 27 pts with I-O–naive advBC, with a median duration of follow-up of 24 wk, ORR was 37% (3 CRs, 7 PRs), and the DCR was 56%; ORR in pts with tumor PD-L1 ≥1% (Dako PD-L1 IHC 28-8 pharmDx assay; n = 14) vs < 1% (n = 10) was 50% vs 30%. Conclusions: BMS-986205 + nivo was well tolerated in heavily pretreated pts, and tolerability was improved with the 100-mg BMS-986205 dose. Preliminary evidence of efficacy was observed in advBC, supporting further evaluation of BMS-986205 + nivo. Clinical trial information: NCT02658890.

An open-label phase 1 clinical trial of the anti-α4β7 monoclonal antibody vedolizumab in HIV-infected individuals

2019 ◽  
Vol 11 (509) ◽  
pp. eaax3447 ◽  
Author(s):  
Michael C. Sneller ◽  
Katherine E. Clarridge ◽  
Catherine Seamon ◽  
Victoria Shi ◽  
Marek D. Zorawski ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Monoclonal Antibody ◽  
Hiv Infection ◽  
Phase 1 ◽  
Single Subject ◽  
Lymphoid Tissues ◽  
Plasma Viremia ◽  
Open Label ◽  
Phase 1 Clinical Trial ◽  
Open Label Phase

Despite the substantial clinical benefits of antiretroviral therapy (ART), complete eradication of HIV has not been possible. The gastrointestinal tract and associated lymphoid tissues may play an important role in the pathogenesis of HIV infection. The integrin α4β7 facilitates homing of T lymphocytes to the gut by binding to the mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expressed on venules in gut-associated lymphoid tissue. CD4+ T cells with increased expression of α4β7 are susceptible to HIV infection and may be key players in subsequent virus dissemination. Data from nonhuman primate models infected with simian immunodeficiency virus (SIV) have suggested that blockade of the α4β7/MAdCAM-1 interaction may be effective at preventing SIV infection and may have beneficial effects in animals with established viral infection. To explore whether these findings could be reproduced in HIV-infected individuals after interruption of ART, we conducted an open-label phase 1 clinical trial of vedolizumab, a monoclonal antibody against α4β7 integrin. Vedolizumab infusions in 20 HIV-infected individuals were well tolerated with no serious adverse events related to the study drug. After interruption of ART, the median time to meeting protocol criteria to restart therapy was 13 weeks. The median duration of plasma viremia of <400 copies/ml was 5.4 weeks. Only a single subject in the trial experienced prolonged suppression of plasma viremia after interruption of ART. These results suggest that blockade of α4β7 may not be an effective strategy for inducing virological remission in HIV-infected individuals after ART interruption.

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).

Final results of controlled IL-12 monotherapy in adults with grade III or IV gliomas.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3040-3040
Author(s):  
E. Antonio Chiocca ◽  
Rimas Vincas Lukas ◽  
John Yu ◽  
Bakhtiar Yamini ◽  
Nancy Ann Oberheim Bush ◽  
...  
Keyword(s):  
Transcriptional Control ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Intratumoral Injection ◽  
Interleukin 12 ◽  
Open Label ◽  
Dose Escalation Study ◽  
Group V ◽  
Favorable Safety ◽  
Grade Iii

3040 Background: Interleukin-12 (IL-12), a master regulator of the immune system, results in anti-tumor responses in preclinical models, but safe use requires tightly controlled production. This phase 1 trial (NCT02026271) is the first to evaluate the safety and tolerability of Ad-RTS-hIL-12 (Ad) under transcriptional control with veledimex (V) in adults with grade III or IV gliomas. Methods: Multicenter, phase 1, open-label, 3 + 3 dose escalation study of Ad (a single intratumoral injection, 2 × 1011 viral particles, Day 0) with oral V dosing (Days 0 to 14) of 10, 20, 30, and 40 mg in subjects with rGBM. Results: 38 subjects were treated (resection group: V 10 mg (n = 6); 20 mg (n = 15); 30 mg (n = 4); 40 mg (n = 6); and, stereotactic group: V 20 mg, n = 7). The adverse event profile of Ad+ V, was predictable and controllable, with the main adverse reactions (ARs) being mild to moderate. All ARs were manageable and reversible upon withholding V. We observed increased peak (mean ± SEM) serum recombinant IL-12 and downstream endogenous IFN-g: V 10mg 21.4 ± 11.7 pg/mL and 14.6 ± 7.1 pg/mL; V 20 mg 25.8 ± 7.1 pg/mL and 57.0 ± 26.5 pg/mL; V 30 mg 65.7 ± 45.5 pg/mL and 60.7 ± 50.0 pg/mL; V 40mg 108.8 ± 41.0 pg/mL and 167.5 ± 70.9 pg/mL, V 20mg (stereotactic) 25.1 ± 7.2 pg/mL and 69.8 ± 48.5 pg/mL, respectively. In the V 20 mg cohort , there was an increase in tumor-associated T cells (CD3+CD8+%) from pre-Ad (mean ± SEM) 0.6 ± 0.4 to biopsy (~5 mons) 6.3 ± 5.0 and production of IFN-g 97.2 ± 85.3 pg/g (n = 2). Median overall survival (mOS) in the V 20 mg cohort (resection, n = 15) was 12.7 mons (mean follow-up, 13.1 mons). Subjects with unifocal disease (n = 6) who received low-dose (≤ 20mg total) dexamethasone during active dosing (Days 0-14) had an mOS of 17.8 mons. Tumor response data will be presented. Conclusions: Results of Controlled IL-12 in rGBM are promising, with V-dependent and proportional increases in IL-12 and IFN-g resulting in immune activation, with a favorable safety profile and encouraging survival. The 20 mg V dose is the recommended phase 2 dose. Controlled IL-12 is being evaluated in a monotherapy substudy (n = 36, V 20 mg) and two combination studies with immune checkpoint inhibitors for rGBM. Clinical trial information: NCT02026271 .

Efficacy, safety, tolerability, and pharmacokinetics of EPI-506 (ralaniten acetate), a novel androgen receptor (AR) N-terminal domain (NTD) inhibitor, in men with metastatic castration-resistant prostate cancer (mCRPC) progressing after enzalutamide and/or abiraterone.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5032-5032
Author(s):  
Kim N. Chi ◽  
Ulka N. Vaishampayan ◽  
Michael S. Gordon ◽  
David C. Smith ◽  
Erin Rudsinski ◽  
...  
Keyword(s):  
Phase 1 ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Once Daily ◽  
Castration Resistant ◽  
Transcription Inhibitor ◽  
Grade 3 ◽  
Favorable Safety ◽  
Dose Levels ◽  
Anti Tumor Activity

5032 Background: EPI-506 (ralaniten acetate) is a first-in-class small molecule transcription inhibitor of the AR NTD. Nonclinical studies demonstrated activity against both full length and resistance-related AR species, including AR-v7. Methods: Open-label, single-arm, Phase 1/2 study evaluating EPI-506 administered orally once-daily. The Phase 1 is a 3+3 design to establish the safety, pharmacokinetic (PK) profile, and recommended phase 2 dose of EPI-506. Anti-tumor activity is also evaluated. Inclusion criteria included: mCRPC with progression after ≥1 line of hormonal therapy or chemotherapy, and progression on enzalutamide and/or abiraterone. Results: Eighteen patients (pts) have been enrolled in the dose escalation phase over 5 dose levels (80, 160, 320, 640, 1280 mg). Median age was 71 (range 58-87). Prior treatments included enzalutamide only (N = 7), abiraterone only (N = 2) or both (N = 9). Six pts have had prior chemotherapy. Seven pts have discontinued due to disease progression and 2 pts due to adverse events (AEs): Grade 4 elevated amylase (related) and Grade 4 gastrointestinal bleeding (unrelated). Median exposure was 98.5 days (range 26-338). Most frequently reported treatment emergent AEs were diarrhea (N = 7), nausea (N = 5) and fatigue (N = 3). One Grade 3 AE (AST elevation) at 1280 mg and one Grade 4 AE (increased amylase) at 640 mg were reported. PK data demonstrate a dose-proportional profile for Cmax and AUC coupled with an initial negative food effect up to 640 mg. At week 4 of continuous dosing, 3 of 18 evaluable pts demonstrated PSA declines ranging from 9 to 18% receiving doses ≥640 mg. Conclusions: EPI-506 is well-tolerated with a favorable safety profile. PK indicates dose-proportionality. PSA declines have been observed at doses associated with sub-therapeutic exposure in preclinical studies. This study is the first to evaluate targeting the AR NTD, a region critical for transcriptional function of all known AR species. Clinical trial information: NCT02606123.

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