Plasma and breast milk pharmacokinetics of emtricitabine, tenofovir and lamivudine using dried blood and breast milk spots in nursing African mother-infant pairs

Catriona Waitt, Adeniyi Olagunju, Shadia Nakalema, Isabella Kyohaire, Andrew Owen, Mohammed Lamorde, Saye Khoo, Catriona Waitt, Adeniyi Olagunju, Shadia Nakalema, Isabella Kyohaire, Andrew Owen, Mohammed Lamorde, Saye Khoo

Abstract

Background: Breast milk transfer of first-line ART from mother to infant is not fully understood.

Objectives: To determine the concentrations of lamivudine, emtricitabine and tenofovir in maternal blood, breast milk and infant blood from breastfeeding mother-infant pairs.

Methods: Intensive pharmacokinetic sampling of maternal dried blood spots (DBS), dried breast milk spots (DBMS) and infant DBS from 30 Ugandan and 29 Nigerian mothers receiving first-line ART and their infants was conducted. DBS and DBMS were collected pre-dose and at 5-6 timepoints up to 12 h following observed dosing. Infant DBS were sampled twice during this period. Lamivudine, emtricitabine and tenofovir were quantified using LC-MS/MS, with non-compartmental analysis to calculate key pharmacokinetic parameters.

Results: Peak concentrations in breast milk from women taking lamivudine and emtricitabine occurred later than in plasma (4-8 h compared with 2 h for lamivudine and 2-4 h for emtricitabine). Consequently, the milk-to-plasma (M:P) ratio of lamivudine taken once daily was 0.95 (0.82-1.15) for AUC0-12, whereas for AUC12-20 this was 3.04 (2.87-4.16). Lamivudine was detectable in 36% (14/39) of infants [median 17.7 (16.3-22.7) ng/mL]. For 200 mg of emtricitabine once daily, the median M:P ratio was 3.01 (2.06-3.38). Three infants (19%) had measurable emtricitabine [median 18.5 (17.6-20.8) ng/mL]. For 300 mg of tenofovir once daily, the median M:P ratio was 0.015 (0-0.03) and no infant had measurable tenofovir concentrations.

Conclusions: Emtricitabine and lamivudine accumulate in breast milk and were detected in breastfeeding infants. In contrast, tenofovir penetrates the breast milk to a small degree, but is undetectable in breastfeeding infants.

Figures

Figure 1.
Figure 1.
Correlation plots for concentration of lamivudine (a) and tenofovir (b) from maternal plasma and mDBS. 3TC, lamivudine; TFV, tenofovir.
Figure 2.
Figure 2.
PK profiles of lamivudine in breast milk and estimated plasma. 3TC, lamivudine; BM, breast milk.
Figure 3.
Figure 3.
PK profiles of emtricitabine in breast milk and estimated plasma. FTC, emtricitabine; BM, breast milk.
Figure 4.
Figure 4.
PK profiles of tenofovir in breast milk and estimated plasma. TFV, tenofovir; BM, breast milk.

References

    1. United Nations Children’s Fund (UNICEF). For Every Child, End AIDS. Seventh Stocktaking Report, 2016. New York, NY, USA: UNICEF, 2016. .
    1. WHO. Guideline. Updates on HIV and Infant Feeding. The Duration of breastfeeding and Support From Health Services to Improve Feeding Practices Among Mothers Living With HIV. Geneva, Switzerland: WHO, 2016. .
    1. WHO. Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection. Recommendations for a Public Health Approach—Second Edition. Geneva, Switzerland: WHO, 2016. .
    1. Fogel JM, Mwatha A, Richardson P. et al. Impact of maternal and infant antiretroviral drug regimens on drug resistance in HIV-infected breastfeeding infants. Pediatr Infect Dis J 2013; 32: e164–9.
    1. Zeh C, Weidle PJ, Nafisa L. et al. HIV-1 drug resistance emergence among breastfeeding infants born to HIV-infected mothers during a single-arm trial of triple-antiretroviral prophylaxis for prevention of mother-to-child transmission: a secondary analysis. PLoS Med 2011; 8: e1000430..
    1. Nachega JB, Uthman OA, Mofenson LM. et al. Safety of tenofovir disoproxil fumarate-based antiretroviral therapy regimens in pregnancy for HIV-infected women and their infants: a systematic review and meta-analysis. J Acquir Immune Defic Syndr 2017; 76: 1–12.
    1. Olagunju A, Bolaji O, Amara A. et al. Breast milk pharmacokinetics of efavirenz and breastfed infants’ exposure in genetically defined subgroups of mother-infant pairs: an observational study. Clin Infect Dis 2015; 61: 453–63.
    1. Corbett AH, Kayira D, White NR. et al. Antiretroviral pharmacokinetics in mothers and breastfeeding infants from 6 to 24 weeks post partum: results of the BAN Study. Antivir Ther 2014; 19: 587–95.
    1. Benaboud S, Pruvost A, Coffie PA. et al. 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; 55: 1315–7.
    1. Mirochnick M, Taha T, Kreitchmann R. et al. Pharmacokinetics and safety of tenofovir in HIV-infected women during labor and their infants during the first week of life. J Acquir Immune Defic Syndr 2014; 65: 33–41.
    1. Palombi L, Pirillo MF, Marchei E. et al. Concentrations of tenofovir, lamivudine and efavirenz in mothers and children enrolled under the Option B-Plus approach in Malawi. J Antimicrob Chemother 2016; 71: 1027–30.
    1. Olagunju A, Amara A, Waitt C. et al. Validation and clinical application of a method to quantify nevirapine in dried blood spots and dried breast-milk spots. J Antimicrob Chemother 2015; 70: 2816–22.
    1. Olagunju A, Khoo S, Owen A.. Pharmacogenetics of nevirapine excretion into breast milk and infants’ exposure through breast milk versus postexposure prophylaxis. Pharmacogenomics 2016; 17: 891–906.
    1. Olagunju A, Bolaji OO, Amara A. et al. Development, validation and clinical application of a novel method for the quantification of efavirenz in dried breast milk spots using LC-MS/MS. J Antimicrob Chemother 2015; 70: 555–61.
    1. Waitt C, Dilly Penchala S, Olagunju A. et al. Development, validation and clinical application of a method for the simultaneous quantification of lamivudine, emtricitabine and tenofovir in dried blood and dried breast milk spots using LC-MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci 2017; 1060: 300–7.
    1. Zheng JH, Guida LA, Rower C. et al. Quantitation of tenofovir and emtricitabine in dried blood spots (DBS) with LC-MS/MS. J Pharm Biomed Anal 2014; 88: 144–51.
    1. Waitt CJ, Garner P, Bonnett LJ. et al. Is infant exposure to antiretroviral drugs during breastfeeding quantitatively important? A systematic review and meta-analysis of pharmacokinetic studies. J Antimicrob Chemother 2015; 70: 1928–41.
    1. Mugwanya KK, Hendrix CW, Mugo NR. et al. 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; 13: e1002132.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever