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

September 1, 2017 updated by: Adeniyi Olagunju

Role of Pharmacogenetics in Efavirenz and Nevirapine Pharmacokinetics, Efficacy and Safety in Mother-infant Pairs During Pregnancy and Lactation

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Study design: This is an observational study that will be conducted in two phases. In the preliminary phase, associations between selected SNPs in drug disposition genes and mid-dose plasma and breast milk efavirenz and nevirapine concentrations will be explored in an unselected cohort of HIV positive pregnant women and nursing mothers and their breastfed infants taking either drug as part of combination antiretroviral therapy for PMTCT. In the second phase, the SNP independently associated with the highest predictive power will be used to stratify pregnant women and mother-infant pairs into three groups: non-carriers, heterozygotes, and homozygotes. Randomly selected pregnant women or mother-infant pairs from each group were re-recruited and invited for the intensive pharmacokinetic phase.

Samples collection: In the preliminary phase, mid-dose paired dried blood spots (DBS) (and dried breast milk spots in nursing mothers) samples will be collected at a single, recorded time point post dose. In the intensive pharmacokinetic phase, DBS (and dried breast milk spots in nursing mothers) samples will be collected at multiple time points after an observed dose of efavirenz or nevirapine. Samples will be shipped at room temperature to the Department of Molecular and Clinical Pharmacology, University of Liverpool, United Kingdom for analysis.

DNA extraction and SNP genotyping: Genomic DNA will be extracted using available commercial kits in accordance with the manufacture's protocol and genotyping will be performed by allelic discrimination real-time polymerase chain reaction using TaqMan® chemistry-based assays.

Drug quantification and pharmacokinetic analysis: Liquid chromatography-mass spectrometry methods will be developed for the quantification of efavirenz and nevirapine in DBS and dried breast milk spots. Pharmacokinetic parameters will be determined using standard procedures.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
460

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Nigeria
    • Benue State
      • Adikpo, Benue State, Nigeria
        • St Monica's Hospital
      • Makurdi, Benue State, Nigeria
        • Bishop Murray Medical Centre
      • Okpoga, Benue State, Nigeria
        • St Mary's Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

14 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

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.

Description

Inclusion Criteria:

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

Exclusion Criteria:

  • 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort

Group / Cohort

A group or subgroup of participants in an observational study that is assessed for biomedical or health outcomes.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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
600 mg once daily in combination with other drugs (e.g. tenofovir and emtricitabine)
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
600 mg once daily in combination with other drugs (e.g. tenofovir and emtricitabine)
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
200 mg twice daily in combination with other drugs (e.g. tenofovir and emtricitabine)
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
200 mg twice daily in combination with other drugs (e.g. tenofovir and emtricitabine)

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Time Frame
Clearance over systemic availability (Cl/F) during pregnancy.
Time Frame: 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.
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.
Time Frame: 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.
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.
Time Frame: 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.
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.
Time Frame: 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.
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.
Time Frame: Pharmacokinetic visits in the preliminary or intensive pharmacokinetic phase will occur mainly from 1 week to 26 weeks postpartum.
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.
Time Frame: Pharmacokinetic visits in the preliminary or intensive pharmacokinetic phase will occur mainly from 1 week to 26 weeks postpartum.
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.
Time Frame: Pharmacokinetic visits in the preliminary or intensive pharmacokinetic phase will occur mainly from 1 week to 26 weeks postpartum.
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.
Time Frame: Pharmacokinetic visits in the preliminary or intensive pharmacokinetic phase will occur mainly from 1 week to 26 weeks postpartum.
Pharmacokinetic visits in the preliminary or intensive pharmacokinetic phase will occur mainly from 1 week to 26 weeks postpartum.

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Time Frame
Rate of mother-to-child transmission of HIV.
Time Frame: Infants will be followed up from birth until 18 months of age when all exposure to breastfeeding would have stopped.
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).
Time Frame: CD4 counts will be determined every 6 months during pregnancy and postpartum, starting from recruitmnent.
CD4 counts will be determined every 6 months during pregnancy and postpartum, starting from recruitmnent.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Adeniyi Olagunju

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Obafemi Awolowo University Teaching Hospital
University of Liverpool

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Adeniyi Olagunju, Obafemi Awolowo University, Nigeria
  • Principal Investigator: Andrew Owen, PhD, University of Liverpool, United Kingdom

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
December 1, 2012

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
October 1, 2013

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
November 1, 2013

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
October 2, 2014

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
October 16, 2014

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
October 21, 2014

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
September 6, 2017

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
September 1, 2017

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
September 1, 2017

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • BC60000

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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