A Study to Evaluate the Effects of Genetic Factors on the Pharmacokinetics of Antiretroviral Drugs During Pregnancy and Lactation

NCT02269462 | Completed

• 1 other identifier: BC60000
• Study Type: observational
• Target: 460
• Locations: 1 country
• Sites: 3

Brief Summary

Mother-to-child transmission of HIV (MTCT) during pregnancy and breastfeeding is prevented with maternal antiretroviral drugs (ARV) and infant nevirapine post-exposure prophylaxis (PEP). However, the pharmacokinetics of certain ARVs is associated with marked inter-individual variability. This variability has been associated with single nucleotide polymorphisms (SNPs) in genes encoding metabolising enzymes, transporters and transcriptional regulators. Pregnancy is also associated with additional changes in pharmacokinetics. The resulting sub-therapeutic or supra-therapeutic drug exposures may have serious consequences for virological control, MTCT, emergence of drug resistance, and toxicity. Foetal and infant exposure to maternal ARV during pregnancy and breastfeeding is believed to play a role in the prevention of mother-to-child transmission of HIV (PMTCT). However, such exposures may also result in toxicity. For example, efavirenz is contraindicated in children less than 3 years old or 10kg but transferred to breastfed babies through breast milk. On the other hand, double exposure to nevirapine from breast milk and PEP may also predispose breastfed infants to nevirapine-associated toxicity. In the proposed study, the influence of selected SNPs in certain drug disposition genes on the pharmacokinetics of efavirenz and nevirapine during pregnancy and lactation, as well as the level of infant exposure to both drugs through breast milk, will be studied. Mathematical models will be developed to predict potential dose optimisation strategies during pregnancy, and to predict infant exposure to maternal drugs through breast milk.

Conditions

HIV; Pregnancy; Breastfeeding

Outcome Measures

Primary Outcomes (8)

• Clearance over systemic availability (Cl/F) during pregnancy.

  Patients will be followed for an average of 6 months for the preliminary and intensive pharmacokinetic phase which will occur mainly between the second and third trimester of pregnancy.

• Area under the concentration-time curve (AUC0-24 for efavirenz, AUC0-12 for nevirapine) during pregnancy.

  Patients will be followed for an average of 6 months for the preliminary and intensive pharmacokinetic phase which will occur mainly between the second and third trimester of pregnancy.

• Minimum plasma drug concentration (Cmin) during pregnancy.

  Patients will be followed for an average of 6 months for the preliminary and intensive pharmacokinetic phase which will occur mainly between the second and third trimester of pregnancy.

• Maximum plasma drug concentration (Cmax) during pregnancy.

  Patients will be followed for an average of 6 months for the preliminary and intensive pharmacokinetic phase which will occur mainly between the second and third trimester of pregnancy.

• Plasma and breast milk clearance over systemic availability (Cl/F) during lactation.

  Pharmacokinetic visits in the preliminary or intensive pharmacokinetic phase will occur mainly from 1 week to 26 weeks postpartum.

• Plasma and breast milk area under the concentration-time curve (AUC0-24 for efavirenz, AUC0-12 for nevirapine) during lactation.

  Pharmacokinetic visits in the preliminary or intensive pharmacokinetic phase will occur mainly from 1 week to 26 weeks postpartum.

• Plasma and breast milk minimum drug concentration (Cmin) during lactation.

  Pharmacokinetic visits in the preliminary or intensive pharmacokinetic phase will occur mainly from 1 week to 26 weeks postpartum.

• Plasma and breast milk maximum plasma drug concentration (Cmax) during lactation.

  Pharmacokinetic visits in the preliminary or intensive pharmacokinetic phase will occur mainly from 1 week to 26 weeks postpartum.

Secondary Outcomes (2)

• Rate of mother-to-child transmission of HIV.

  Infants will be followed up from birth until 18 months of age when all exposure to breastfeeding would have stopped.

• Effect of pregnancy on CD4 count change (immunological recovery).

  CD4 counts will be determined every 6 months during pregnancy and postpartum, starting from recruitmnent.

Study Arms (4)

Pregnant women - efavirenz

Pregnant women taking 600 mg efavirenz daily as part of combination antiretroviral therapy for PMTCT and for their own health

Drug: Efavirenz

Nursing mothers - efavirenz

Nursing mothers taking 600 mg efavirenz daily as part of combination antiretroviral therapy for PMTCT and for their own health and their breastfed babies

Drug: Efavirenz

Pregnant women - nevirapine

Pregnant women taking 200 mg nevirapine twice daily as part of combination antiretroviral therapy for PMTCT and for their own health

Drug: Nevirapine

Nursing mothers - nevirapine

Nursing mothers taking 200 mg nevirapine twice daily as part of combination antiretroviral therapy for PMTCT and for their own health and their breastfed babies

Drug: Nevirapine

Interventions

Efavirenz DRUG

600 mg once daily in combination with other drugs (e.g. tenofovir and emtricitabine)

Nursing mothers - efavirenz; Pregnant women - efavirenz

Nevirapine DRUG

200 mg twice daily in combination with other drugs (e.g. tenofovir and emtricitabine)

Nursing mothers - nevirapine; Pregnant women - nevirapine

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

HIV positive pregnant women and nursing mothers taking efavirenz or nevirapine as part of HAART to prevent mother-to-child transmission of HIV and/or for their own health and their breastfed infants.

You may qualify if:

• HIV positive
• breastfeeding
• enrolled in PMTCT programme
• started efavirenz- or nevirapine-containing regimen during pregnancy

You may not qualify if:

• exclusive replacement feeding
• mixed feeding before 6 months
• severe maternal or infant illness
• maternal or infant treatment with other drugs or herbal medication with known or uncertain interaction with study drug

Sponsors & Collaborators

• Adeniyi Olagunju: lead
• University of Liverpool: collaborator
• Obafemi Awolowo University Teaching Hospital: collaborator

Study Sites (3)

St Monica's Hospital

Adikpo, Benue State, Nigeria

Location

Bishop Murray Medical Centre

Makurdi, Benue State, Nigeria

Location

St Mary's Hospital

Okpoga, Benue State, Nigeria

Location

Related Publications (7)

• Olagunju A, Bolaji OO, Amara A, Waitt C, Else L, Soyinka J, Adeagbo B, Adejuyigbe E, Siccardi M, Back D, Owen A, Khoo S. 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 Feb;70(2):555-61. doi: 10.1093/jac/dku420. Epub 2014 Oct 17.

  PMID: 25326089 RESULT

• Olagunju A, Amara A, Waitt C, Else L, Penchala SD, Bolaji O, Soyinka J, Siccardi M, Back D, Owen A, Khoo S. Validation and clinical application of a method to quantify nevirapine in dried blood spots and dried breast-milk spots. J Antimicrob Chemother. 2015 Oct;70(10):2816-22. doi: 10.1093/jac/dkv174. Epub 2015 Jun 24.

  PMID: 26108608 RESULT

• Olagunju A, Bolaji O, Amara A, Else L, Okafor O, Adejuyigbe E, Oyigboja J, Back D, Khoo S, Owen A. Pharmacogenetics of pregnancy-induced changes in efavirenz pharmacokinetics. Clin Pharmacol Ther. 2015 Mar;97(3):298-306. doi: 10.1002/cpt.43. Epub 2015 Jan 20.

  PMID: 25669165 RESULT

• Olagunju A, Bolaji O, Amara A, Waitt C, Else L, Adejuyigbe E, Siccardi M, Back D, Khoo S, Owen A. Breast milk pharmacokinetics of efavirenz and breastfed infants' exposure in genetically defined subgroups of mother-infant pairs: an observational study. Clin Infect Dis. 2015 Aug 1;61(3):453-63. doi: 10.1093/cid/civ317. Epub 2015 Apr 16.

  PMID: 25882300 RESULT

• Olagunju A, Bolaji O, Neary M, Back D, Khoo S, Owen A. Pregnancy affects nevirapine pharmacokinetics: evidence from a CYP2B6 genotype-guided observational study. Pharmacogenet Genomics. 2016 Aug;26(8):381-9. doi: 10.1097/FPC.0000000000000227.

  PMID: 27195527 RESULT

• Olagunju A, Khoo S, Owen A. Pharmacogenetics of nevirapine excretion into breast milk and infants' exposure through breast milk versus postexposure prophylaxis. Pharmacogenomics. 2016 Jun;17(8):891-906. doi: 10.2217/pgs-2015-0016. Epub 2016 Jun 7.

  PMID: 27268507 RESULT

• Waitt C, Diliiy Penchala S, Olagunju A, Amara A, Else L, Lamorde M, Khoo S. 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 Aug 15;1060:300-307. doi: 10.1016/j.jchromb.2017.06.012. Epub 2017 Jun 17.

  PMID: 28651173 RESULT

MeSH Terms

Conditions

Breast Feeding

Interventions

efavirenz; Nevirapine

Condition Hierarchy (Ancestors)

Feeding Behavior; Behavior

Intervention Hierarchy (Ancestors)

Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Adeniyi Olagunju

  Obafemi Awolowo University, Nigeria

  PRINCIPAL INVESTIGATOR

• Andrew Owen, PhD

  University of Liverpool, United Kingdom

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Lecturer

Study Record Dates

• First Submitted: October 2, 2014
• First Posted: October 21, 2014
• Study Start: December 1, 2012
• Primary Completion: October 1, 2013
• Study Completion: November 1, 2013
• Last Updated: September 6, 2017

Record last verified: 2017-09

Locations

NG (3)