Pharmacokinetics of Antiretroviral Drugs in Lactating Women and Breastmilk Fed Infants Under 6 Months of Age in Botswana (BMS02)

The purpose of this study is to characterize the pharmacokinetics (PK) of understudied drugs administered to lactating women, receiving antiretroviral drugs per SOC as prescribed by their healthcare provider, and their co-enrolled infants ≤180 days of age who receive maternal breastmilk.

Study Overview

• Status: Recruiting
• Conditions: HIV Infections; Lactating Women on Select DOI; Breastmilk Fed Infants of Mothers on Select DOI
• Intervention / Treatment: Drug: Dolutegravir; Drug: Emtricitabine; Drug: Tenofovir Disoproxil Fumarate; Drug: Lamivudine

Detailed Description

Prospective, single-site, open label, PK and safety study. Co-enrollment of lactating women ≥18 years of age receiving drugs of interest (DOIs) per standard of care (SOC), as prescribed by their healthcare providers, and their infants who receive maternal breastmilk ≤180 days postpartum.

To understand drug transfer into breastmilk and determine subsequent infant exposure, biological samples will be collected from lactating women (blood and breastmilk) and infants (blood). The opportunistic design of this study will allow for a minimal risk study, an expanded enrollment net, evaluation of antiretroviral drugs, and capitalization of procedures performed per SOC to maximize study efficiency and data collection and minimize potential risk to participants. The data collected through this initiative will provide valuable PK, dosing, and safety information for drugs in this vulnerable population in order to inform public health.

• Study Type: Observational
• Enrollment (Estimated): 200

Contacts and Locations

• Study Contact: Name: Jessalyn Byrd, MEd, NCC; Phone Number: 919-668-5297; Email: jessalyn.byrd@duke.edu

Study Locations

• South Africa
  • Gaborone
    • Botswana, Gaborone, South Africa
      • Recruiting
      • Botswana-UPenn Partnership
      • Contact: Merrian Brooks, DO; Phone Number: +26772468329; Email: BROOKSM2@chop.edu
      • Contact: Charity Boiditswe; Phone Number: +26771869568; Email: boiditswesc@bup.org.bw
      • Principal Investigator: Merrian Brooks, DO
      • Sub-Investigator: Jonathan Strysko, MD
    • Botswana, Gaborone, South Africa
      • Not yet recruiting
      • Lesirane Clinic
      • Contact: Merrian Brooks, DO; Phone Number: +26772468329; Email: BROOKSM2@chop.edu
      • Contact: Charity Boiditswe; Phone Number: +26771869568; Email: boiditswesc@bup.org.bw
    • Botswana, Gaborone, South Africa
      • Not yet recruiting
      • Mogoditshane Clinic KDC
      • Contact: Merrian Brooks, DO; Phone Number: +26772468329; Email: BROOKSM2@chop.edu
      • Contact: Charity Boiditswe; Phone Number: +26771869568; Email: boiditswesc@bup.org.bw
    • Botswana, Gaborone, South Africa
      • Not yet recruiting
      • Old Naledi Clinic
      • Contact: Merrian Brooks, DO; Phone Number: +26772468329; Email: BROOKSM2@chop.edu
      • Contact: Charity Boiditswe; Phone Number: +26771869568; Email: boiditswesc@bup.org.bw

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Approximately 50 eligible lactating women and their breastmilk fed infants per DOI will be co-enrolled. Participants may be enrolled for one or more DOIs with a single consent. The co-enrollment of mothers and more than 1 infant (multiple birth) is permitted.

Description

Inclusion Criteria Mothers/Infants:

1. Lactating women ≥18 years of age who are receiving at least one DOI per SOC who are ≤180 days postpartum, and their infants (≤180 days of age) who receive maternal breastmilk.
2. Informed consent, according to local IRB/REB/IEC guidelines, prior to any study-related procedures.
3. If the mother is receiving more than one DOI, the mother must have taken all DOIs that she is receiving concomitantly for the 6 doses prior to sample collection.
4. Mother participant is fluent in English or Setswana.

5. Willing to provide at least 1 of the below required samples between the co-enrolled mother/infant pair:

   • Maternal breastmilk
   • Infant blood

Exclusion Criteria Mothers/Infants:

1. Any concomitant condition which, in the opinion of the participant's healthcare provider, the site principal investigator (PI), a research nurse, or designee conducting the study, would preclude participation in the study.
2. Known pregnancy of mother during sample collection.
3. Mother has pumped any breastmilk at all in between the last 6 direct infant feedings prior to sample collection.
4. Infant was fed breastmilk in any manner besides nursing at mother's breast for any of the last 6 feedings prior to sample collection.
5. Previous enrollment on this study.

Study Plan

How is the study designed?

Design Details

• Observational Models: Other
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Drug of Interest; Lactating moms receiving one or more antiretroviral drugs and their breastmilk fed infants per standard of care.

Drug: Dolutegravir; Dolutegravir will be administered in accordance with local SOC as prescribed by the lactating woman's healthcare provider. Not prescribed for this study.; Other Names: Dolutegravir Sodium; DTG; Drug: Emtricitabine; Emtricitabine will be administered in accordance with local SOC as prescribed by the lactating woman's healthcare provider. Not prescribed for this study.; Other Names: FTC; Drug: Tenofovir Disoproxil Fumarate; Tenofovir Disoproxil Fumarate will be administered in accordance with local SOC as prescribed by the lactating woman's healthcare provider. Not prescribed for this study.; Other Names: TDF; Tenofovir DF; Drug: Lamivudine; Lamivudine will be administered in accordance with local SOC as prescribed by the lactating woman's healthcare provider. Not prescribed for this study.; Other Names: 3TC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Drug concentration in maternal plasma	Drug concentration of a DOI in maternal plasma	Baseline
Drug concentration in maternal breastmilk	Drug concentration of a DOI in maternal breastmilk	Baseline
Drug concentration in infant plasma	Drug concentration of a DOI in infant plasma	Baseline
Milk/Plasma ratio	The drug exposure of selected DOIs will be evaluated using milk/plasma ratio	Baseline
Estimated daily infant dose	The drug exposure of selected DOIs will be evaluated using the estimated daily infant dose	Baseline
Relative infant dose	The drug exposure of selected DOIs will be evaluated using relative infant dose	Baseline
Infant/maternal exposure ratio	The drug exposure of selected DOIs will be evaluated using infant/maternal exposure ratio	Baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety ESIs	Safety ESIs for infants collected from the medical record at the time of sample collection	Baseline

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
PK of selected DOIs in lactating women and breastmilk fed infants as measured by Clearance (CL) or apparent clearance (CL/F).	Clearance (CL) or apparent clearance (CL/F)	Baseline
PK of selected DOIs in lactating women and breastmilk fed infants as measured by volume of distribution (V) or apparent volume of distribution (V/F)	Volume of distribution (V) or apparent volume of distribution (V/F)	Baseline
PK of selected DOIs in lactating women and breastmilk fed infants as measured by elimination Half-life (t1/2).	Elimination Half-life (t1/2)	Baseline
PK of selected DOIs in lactating women and breastmilk fed infants as measured by elimination rate constant (kel).	Elimination rate constant (kel)	Baseline
PK of selected DOIs in lactating women and breastmilk fed infants as measured by absorption rate constant (ka).	Absorption rate constant (ka)	Baseline
PK of selected DOIs in lactating women and breastmilk fed infants as measured by area under the curve (AUC).	Area under the curve (AUC)	Baseline
PK of selected DOIs in lactating women and breastmilk fed infants as measured by maximum concentration (CMAX).	Maximum concentration (CMAX)	Baseline
PK of selected DOIs in lactating women and breastmilk fed infants as measured by time to reach maximum concentration (TMAX).	Time to reach maximum concentration (TMAX)	Baseline
Correlation of PK parameters (drug concentration in maternal breastmilk) with maternal BMI	Correlation of drug concentration of each DOI in maternal breastmilk with maternal BMI	Baseline
Correlation of PK parameters (drug concentration in maternal plasma) with maternal BMI	Correlation of drug concentration of each DOI in maternal plasma with maternal BMI	Baseline
Correlation of PK parameters (drug concentration in infant plasma) with maternal BMI	Correlation of drug concentration of each DOI in infant plasma with maternal BMI	Baseline
Correlation of PK parameters (milk/plasma ratio) with maternal BMI	Correlation of milk/plasma ratio of each DOI with maternal BMI	Baseline
Correlation of PK parameters (estimated daily infant dose) with maternal BMI	Correlation of estimated daily infant dose of each DOI with maternal BMI	Baseline
Correlation of PK parameters (relative infant dose) with maternal BMI	Correlation of relative infant dose of each DOI with maternal BMI	Baseline
Correlation of PK parameters (infant/maternal exposure ratio) with maternal BMI	Correlation of infant/maternal exposure ratio for each DOI with maternal BMI	Baseline
Safety ESIs for infants	Will be collected from the medical record at the time of sample collection	Baseline

Collaborators and Investigators

• Sponsor: Duke University
• Collaborators: The Emmes Company, LLC
• Investigators: Principal Investigator: Matt Kelly, MD, Duke University; Principal Investigator: Kevin Watt, MD, University of Utah; Principal Investigator: Stephen Balevic, MD, Duke University; Principal Investigator: Angelique Boutzoukas, MD, Duke University

Publications and helpful links

General Publications

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• Danforth KN, Tworoger SS, Hecht JL, Rosner BA, Colditz GA, Hankinson SE. Breastfeeding and risk of ovarian cancer in two prospective cohorts. Cancer Causes Control. 2007 Jun;18(5):517-23. doi: 10.1007/s10552-007-0130-2. Epub 2007 Apr 21.
• Chasela CS, Hudgens MG, Jamieson DJ, Kayira D, Hosseinipour MC, Kourtis AP, Martinson F, Tegha G, Knight RJ, Ahmed YI, Kamwendo DD, Hoffman IF, Ellington SR, Kacheche Z, Soko A, Wiener JB, Fiscus SA, Kazembe P, Mofolo IA, Chigwenembe M, Sichali DS, van der Horst CM; BAN Study Group. Maternal or infant antiretroviral drugs to reduce HIV-1 transmission. N Engl J Med. 2010 Jun 17;362(24):2271-81. doi: 10.1056/NEJMoa0911486.
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• Gardiner SJ, Kristensen JH, Begg EJ, Hackett LP, Wilson DA, Ilett KF, Kohan R, Rampono J. Transfer of olanzapine into breast milk, calculation of infant drug dose, and effect on breast-fed infants. Am J Psychiatry. 2003 Aug;160(8):1428-31. doi: 10.1176/appi.ajp.160.8.1428.
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• Kobbe R, Schalkwijk S, Dunay G, Eberhard JM, Schulze-Sturm U, Hollwitz B, Degen O, Teulen M, Colbers A, Burger D. Dolutegravir in breast milk and maternal and infant plasma during breastfeeding. AIDS. 2016 Nov 13;30(17):2731-2733. doi: 10.1097/QAD.0000000000001259. No abstract available.
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• Dickinson L, Kintu K, Coombs J, et al. Population pk of dolutegravir in plasma, cord, and breastmilk: results from DolPHIN-1. Presented at: Conference on Retroviruses and Opportunistic Infections 2019. Seattle, Washington. . 2019. https://www.croiconference.org/abstract/population-pk-dolutegravir-plasma-cord-and-breastmilk-results-dolphin-1/
• Palombi L, Pirillo MF, Marchei E, Jere H, Sagno JB, Luhanga R, Floridia M, Andreotti M, Galluzzo CM, Pichini S, Mwenda R, Mancinelli S, Marazzi MC, Vella S, Liotta G, Giuliano M. Concentrations of tenofovir, lamivudine and efavirenz in mothers and children enrolled under the Option B-Plus approach in Malawi. J Antimicrob Chemother. 2016 Apr;71(4):1027-30. doi: 10.1093/jac/dkv435. Epub 2015 Dec 17.
• Mugwanya KK, Hendrix CW, Mugo NR, Marzinke M, Katabira ET, Ngure K, Semiyaga NB, John-Stewart G, Muwonge TR, Muthuri G, Stergachis A, Celum CL, Baeten JM. Pre-exposure Prophylaxis Use by Breastfeeding HIV-Uninfected Women: A Prospective Short-Term Study of Antiretroviral Excretion in Breast Milk and Infant Absorption. PLoS Med. 2016 Sep 27;13(9):e1002132. doi: 10.1371/journal.pmed.1002132. eCollection 2016 Sep.
• Benaboud S, Pruvost A, Coffie PA, Ekouevi DK, Urien S, Arrive E, Blanche S, Theodoro F, Avit D, Dabis F, Treluyer JM, Hirt D. Concentrations of tenofovir and emtricitabine in breast milk of HIV-1-infected women in Abidjan, Cote d'Ivoire, in the ANRS 12109 TEmAA Study, Step 2. Antimicrob Agents Chemother. 2011 Mar;55(3):1315-7. doi: 10.1128/AAC.00514-10. Epub 2010 Dec 20.
• Bierhoff M, Smolders EJ, Tarning J, Burger DM, Spijker R, Rijken MJ, Angkurawaranon C, McGready R, White NJ, Nosten F, van Vugt M. Pharmacokinetics of oral tenofovir disoproxil fumarate in pregnancy and lactation: a systematic review. Antivir Ther. 2019;24(7):529-540. doi: 10.3851/IMP3341.
• Gouraud A, Millaret A, Bernard N, et al. Tenofovir exposure through breast feeding: Serum concentrations in neonates and clinical follow-up. Fundam Clin Pharmacol 2012;26 (Suppl 1):9.
• ViiV Healthcare Company. TIVICAY PD- dolutegravir sodium tablet, for suspension TIVICAY- dolutegravir sodium tablet, film coated [package insert]. U.S. Dept. of Health and Human Services, Food and Drug Administration. June 12, 2020.
• AvKARE. TENOFOVIR DISOPROXIL FUMARATE- tenofovir disoproxil fumarate tablet, film coated [package insert]. U.S. Dept. of Health and Human Services, Food and Drug Administration. April 21, 2020.
• Gini J, Penchala SD, Amara A, Challenger E, Egan D, Waitt C, Lamorde M, Orrell C, Myer L, Khoo S, Else LJ. Validation and clinical application of a novel LC-MS method for quantification of dolutegravir in breast milk. Bioanalysis. 2018 Dec;10(23):1933-1945. doi: 10.4155/bio-2018-0085. Epub 2018 Nov 19.
• GlaxoSmithCline. EPIVIR-lamivudine tablets for oral use [package insert]. U.S. Dept. of Health and Human Services, Food and Drug Administration. September, 2017.
• GlaxoSmithCline. EPIVIR- lamivudine oral solution [package insert]. U.S. Dept. of Health and Human Services, Food and Drug Administration. September, 2017.
• Mirochnick M, Thomas T, Capparelli E, Zeh C, Holland D, Masaba R, Odhiambo P, Fowler MG, Weidle PJ, Thigpen MC. Antiretroviral concentrations in breast-feeding infants of mothers receiving highly active antiretroviral therapy. Antimicrob Agents Chemother. 2009 Mar;53(3):1170-6. doi: 10.1128/AAC.01117-08. Epub 2008 Dec 29.
• Waitt CJ, Garner P, Bonnett LJ, Khoo SH, Else LJ. Is infant exposure to antiretroviral drugs during breastfeeding quantitatively important? A systematic review and meta-analysis of pharmacokinetic studies. J Antimicrob Chemother. 2015 Jul;70(7):1928-41. doi: 10.1093/jac/dkv080. Epub 2015 Apr 8.
• Davis NL, Corbett A, Kaullen J, Nelson JAE, Chasela CS, Sichali D, Hudgens MG, Miller WC, Jamieson DJ, Kourtis AP. Antiretroviral Drug Concentrations in Breastmilk, Maternal HIV Viral Load, and HIV Transmission to the Infant: Results From the BAN Study. J Acquir Immune Defic Syndr. 2019 Apr 1;80(4):467-473. doi: 10.1097/QAI.0000000000001941.
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Helpful Links

• UNICEF Botswana Key Demographic Indicators
• FDA: Clinical Lactation Studies: Considerations for Study Design Guidance for Industry

Study record dates

Study Major Dates

• Study Start (Actual): January 9, 2024
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: April 23, 2021
• First Submitted That Met QC Criteria: April 23, 2021
• First Posted (Actual): April 28, 2021

Study Record Updates

• Last Update Posted (Actual): February 29, 2024
• Last Update Submitted That Met QC Criteria: February 28, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Urogenital Diseases; Genital Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; HIV Integrase Inhibitors; Integrase Inhibitors; Tenofovir; Emtricitabine; Lamivudine; Dolutegravir
• Other Study ID Numbers: Pro00107262; HHSN275201800003I (Other Grant/Funding Number: National Institute of Child Health and Human Development)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: After the study is completed, information about the study, including de-identified study data, will be submitted to the NIH data repository (https://dash.nichd.nih.gov and referred to below as "DASH"). With NIH approval, the data submitted to DASH may be used by other researchers for future research. The study data submitted to DASH will be de-identified, meaning it will not include any information that can identify the participant. The study team may also share the de-identified study data with other researchers. When the participant's de-identified study data are provided to other researchers for the purposes of future research, it will be done without obtaining additional permission from the participant.
• IPD Sharing Time Frame: Data will be uploaded to the repository within 2 years of study completion. Biological samples will be stored indefinitely. If a participant decides to withdraw from the study, they will be instructed per the ICF to contact the site investigator. Study data and samples that have been recorded / collected prior to withdrawal will continue to be used, but no new data or samples will be collected.
• IPD Sharing Access Criteria: In order to have access, researchers have to complete a Data access request. NICHD will review the request and either approve or deny it. IRB approval must be obtained by the researcher to access the data.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No