Pharmacokinetic Study of Antiretroviral Drugs and Related Drugs During and After Pregnancy

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2016 by National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor:
Collaborator:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00042289
First received: July 26, 2002
Last updated: April 20, 2016
Last verified: April 2016
  Purpose
The purpose of this study is to evaluate the pharmacokinetics (PKs) of antiretroviral (ARV) and tuberculosis (TB) medications in pregnant women and their infants. (Pharmacokinetics are the various interactions between a drug and the body.) This study will also evaluate the PKs of certain ARVs in postpartum women before and after starting hormonal contraceptives. The PKs of these drugs will be evaluated by measuring the amount of medicine present in blood and/or vaginal secretions.

Condition Intervention Phase
HIV Infections
Drug: atazanavir/cobicistat
Drug: darunavir/ritonavir
Drug: darunavir/cobicistat
Drug: etravirine
Drug: elvitegravir/cobicistat
Drug: dolutegravir
Drug: tenofovir alafenamide fumarate (TAF)
Drug: TAF/cobicistat
Drug: TAF/ritonavir
Drug: efavirenz
Drug: lopinavir/ritonavir
Drug: nevirapine
Drug: rifampicin
Drug: ethambutol
Drug: isoniazid
Drug: pyrazinamide
Drug: kanamycin
Drug: amikacin
Drug: capreomycin
Drug: moxifloxacin
Drug: levofloxacin
Drug: ofloxacin
Drug: ethionamide/prothionamide
Drug: terizidone/cycloserine
Drug: para-aminosalicylic acid (PAS)
Drug: high dose isoniazid (INH)
Drug: bedaquiline
Drug: clofazamine
Drug: delamanid
Drug: linezolid
Drug: pretomanid
Drug: atazanavir/ritonavir/tenofovir
Drug: ethinyl estradiol oral contraceptive
Drug: etonogestrel implant
Phase 4

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Pharmacokinetic Properties of Antiretroviral and Related Drugs During Pregnancy and Postpartum

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • Drug parameter: Area under the curve from 0 to 12 hours (AUC 0-12) [ Time Frame: Measured at intensive PK visit ] [ Designated as safety issue: No ]
    Timing of intensive PK visit depends on participant's study arm; may occur during 2nd trimester; 3rd trimester; and either 2 to 6 weeks, 2 to 8 weeks, or 6 to 12 weeks postpartum.

  • Drug parameter: Area under the curve from 0 to 24 hours (AUC 0-24) [ Time Frame: Measured at intensive PK visit ] [ Designated as safety issue: No ]
    Timing of intensive PK visit depends on participant's study arm; may occur during 2nd trimester; 3rd trimester; and either 2 to 6 weeks, 2 to 8 weeks, or 6 to 12 weeks postpartum.

  • Drug parameter: Maximum concentration (Cmax) [ Time Frame: Measured at intensive PK visit ] [ Designated as safety issue: No ]
    Timing of intensive PK visit depends on participant's study arm; may occur during 2nd trimester; 3rd trimester; and either 2 to 6 weeks, 2 to 8 weeks, or 6 to 12 weeks postpartum.

  • Drug parameter: Pre-dose concentration (Cdose) [ Time Frame: Measured at intensive PK visit ] [ Designated as safety issue: No ]
    Timing of intensive PK visit depends on participant's study arm; may occur during 2nd trimester; 3rd trimester; and either 2 to 6 weeks, 2 to 8 weeks, or 6 to 12 weeks postpartum.

  • Drug parameter: Minimum concentration (Cmin) [ Time Frame: Measured at intensive PK visit ] [ Designated as safety issue: No ]
    Timing of intensive PK visit depends on participant's study arm; may occur during 2nd trimester; 3rd trimester; and either 2 to 6 weeks, 2 to 8 weeks, or 6 to 12 weeks postpartum.

  • Drug parameter: Time after administration of drug when maximum plasma concentration is reached (Tmax) [ Time Frame: Measured at intensive PK visit ] [ Designated as safety issue: No ]
    Timing of intensive PK visit depends on participant's study arm; may occur during 2nd trimester; 3rd trimester; and either 2 to 6 weeks, 2 to 8 weeks, or 6 to 12 weeks postpartum.

  • Drug parameter: Clearance over systemic availability (Cl/F) [ Time Frame: Measured at intensive PK visit ] [ Designated as safety issue: No ]
    Timing of intensive PK visit depends on participant's study arm; may occur during 2nd trimester; 3rd trimester; and either 2 to 6 weeks, 2 to 8 weeks, or 6 to 12 weeks postpartum.

  • Drug parameter: Volume of distribution over systemic availability (V/F) [ Time Frame: Measured at intensive PK visit ] [ Designated as safety issue: No ]
    Timing of intensive PK visit depends on participant's study arm; may occur during 2nd trimester; 3rd trimester; and either 2 to 6 weeks, 2 to 8 weeks, or 6 to 12 weeks postpartum.

  • Drug parameter: Half-life (t1/2) [ Time Frame: Measured at intensive PK visit ] [ Designated as safety issue: No ]
    Timing of intensive PK visit depends on participant's study arm; may occur during 2nd trimester; 3rd trimester; and either 2 to 6 weeks, 2 to 8 weeks, or 6 to 12 weeks postpartum.

  • ARV concentrations in vaginal secretions [ Time Frame: Measured at intensive PK visit ] [ Designated as safety issue: No ]
    Timing of intensive PK visit depends on participant's study arm; may occur during 2nd trimester; 3rd trimester; and either 2 to 6 weeks, 2 to 8 weeks, or 6 to 12 weeks postpartum.

  • ARV concentrations in plasma [ Time Frame: Measured at intensive PK visit ] [ Designated as safety issue: No ]
    Timing of intensive PK visit depends on participant's study arm; may occur during 2nd trimester; 3rd trimester; and either 2 to 6 weeks, 2 to 8 weeks, or 6 to 12 weeks postpartum.

  • For contraceptives: plasma concentration [ Time Frame: Measured at 2-12 weeks postpartum (prior to contraceptive initiation) and again 6-7 weeks after contraceptive initiation. ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Ratio of cord blood concentration to maternal blood concentration [ Time Frame: Measured at time of delivery ] [ Designated as safety issue: No ]
  • Ratio of unbound/total drug concentrations [ Time Frame: Measured at time of delivery ] [ Designated as safety issue: No ]
    Ratio will be measured for the highly-bound ARVs, including atazanavir, darunavir, efavirenz, etravirine, lopinavir, nelfinavir, and tipranavir

  • Rate of detection of study drugs in vaginal secretions [ Time Frame: Measured at intensive PK visit ] [ Designated as safety issue: No ]
    Timing of intensive PK visit depends on participant's study arm; may occur during 2nd trimester; 3rd trimester; and either 2 to 6 weeks, 2 to 8 weeks, or 6 to 12 weeks postpartum.

  • Ratio of vaginal drug concentrations to simultaneous blood concentrations [ Time Frame: Measured at intensive PK visit ] [ Designated as safety issue: No ]
    Timing of intensive PK visit depends on participant's study arm; may occur during 2nd trimester; 3rd trimester; and either 2 to 6 weeks, 2 to 8 weeks, or 6 to 12 weeks postpartum.

  • Rate of detection of HIV RNA/DNA in vaginal secretions and comparison to level in blood [ Time Frame: Measured at intensive PK visit ] [ Designated as safety issue: No ]
    Timing of intensive PK visit depends on participant's study arm; may occur during 2nd trimester; 3rd trimester; and either 2 to 6 weeks, 2 to 8 weeks, or 6 to 12 weeks postpartum.

  • ARV exposure (as measured by area under the curve or other PK parameters) during pregnancy and postpartum according to genotype [ Time Frame: Measured at intensive PK visit ] [ Designated as safety issue: No ]
    Timing of intensive PK visit depends on participant's study arm; may occur during 2nd trimester; 3rd trimester; and either 2 to 6 weeks, 2 to 8 weeks, or 6 to 12 weeks postpartum.

  • Adverse events of grade 3 or higher [ Time Frame: Measured through 24 weeks postpartum ] [ Designated as safety issue: Yes ]
  • Infant neurological events of grade 1 or higher [ Time Frame: Measured through 24 weeks of life ] [ Designated as safety issue: Yes ]
  • Adverse pregnancy outcome: preterm birth [ Time Frame: Measured through delivery ] [ Designated as safety issue: Yes ]
  • Adverse pregnancy outcome: low birth weight [ Time Frame: Measured at delivery ] [ Designated as safety issue: Yes ]
  • Adverse pregnancy outcome: fetal demise [ Time Frame: Measured through 24 weeks postpartum ] [ Designated as safety issue: Yes ]
  • Adverse pregnancy outcome: congenital anomalies [ Time Frame: Measured through 24 weeks of life ] [ Designated as safety issue: Yes ]
  • Infant HIV infection status [ Time Frame: Measured through 24 weeks of life ] [ Designated as safety issue: No ]

Estimated Enrollment: 1786
Study Start Date: March 2003
Estimated Primary Completion Date: June 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Women taking ARVs without TB treatment

HIV-infected pregnant women will be assigned to this arm if receiving one or more of the following ARV drugs/drug combinations but not receiving TB treatment: atazanavir/cobicistat, darunavir/ritonavir, darunavir/cobicistat, etravirine, elvitegravir/cobicistat, dolutegravir, tenofovir alafenamide fumarate (TAF), TAF/cobicistat, TAF/ritonavir, efavirenz, or lopinavir/ritonavir.

Note: As of February 2016, the study will no longer enroll women receiving etravirine or increased dose lopinavir/ritonavir.

Drug: atazanavir/cobicistat
Women will receive atazanavir/cobicistat as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: darunavir/ritonavir
Women will receive darunavir/ritonavir as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: darunavir/cobicistat
Women will receive darunavir/cobicistat as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: etravirine
Women will receive etravirine as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: elvitegravir/cobicistat
Women will receive elvitegravir/cobicistat as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: dolutegravir
Women will receive dolutegravir as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: tenofovir alafenamide fumarate (TAF)
Women will receive TAF as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: TAF/cobicistat
Women will receive TAF/cobicistat as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: TAF/ritonavir
Women will receive TAF/ritonavir as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: efavirenz
Women will receive efavirenz as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: lopinavir/ritonavir
Women will receive lopinavir/ritonavir as prescribed by their clinicians. (Dosage will vary for each participant.)
Experimental: Women taking ARVs with TB treatment

HIV-infected pregnant women will be assigned to this arm if receiving efavirenz, lopinavir/ritonavir, or nevirapine and TB treatment with at least one of the following TB drugs at study entry: rifampicin, ethambutol, isoniazid, or pyrazinamide.

Note: As of February 2016, the study will no longer enroll women receiving nevirapine.

Drug: efavirenz
Women will receive efavirenz as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: lopinavir/ritonavir
Women will receive lopinavir/ritonavir as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: nevirapine
Women will receive nevirapine as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: rifampicin
Women will receive rifampicin as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: ethambutol
Women will receive ethambutol as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: isoniazid
Women will receive isoniazid as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: pyrazinamide
Women will receive pyrazinamide as prescribed by their clinicians. (Dosage will vary for each participant.)
Experimental: Women taking no ARVs with TB treatment
HIV-uninfected pregnant women will be assigned to this arm if receiving at least two of the following first-line TB drugs at study entry: ethambutol, isoniazid, pyrazinamide, or rifampicin.
Drug: ethambutol
Women will receive ethambutol as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: isoniazid
Women will receive isoniazid as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: pyrazinamide
Women will receive pyrazinamide as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: rifampicin
Women will receive rifampicin as prescribed by their clinicians. (Dosage will vary for each participant.)
Experimental: Women with/without ARVs w/TB treatment for drug-resistant TB
HIV-infected and HIV-uninfected pregnant women with or without ARVs will be assigned to this arm if receiving at least two of the following second-line TB drugs at study entry: kanamycin, amikacin, capreomycin, moxifloxacin, levofloxacin, ofloxacin, ethionamide/prothionamide, terizidone/cycloserine, para-aminosalicylic acid (PAS), high dose isoniazid (INH), bedaquiline, clofazamine, delamanid, linezolid, or pretomanid.
Drug: kanamycin
Women will receive kanamycin as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: amikacin
Women will receive amikacin as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: capreomycin
Women will receive capreomycin as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: moxifloxacin
Women will receive moxifloxacin as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: levofloxacin
Women will receive levofloxacin as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: ofloxacin
Women will receive ofloxacin as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: ethionamide/prothionamide
Women will receive ethionamide/prothionamide as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: terizidone/cycloserine
Women will receive terizidone/cycloserine as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: para-aminosalicylic acid (PAS)
Women will receive PAS as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: high dose isoniazid (INH)
Women will receive high dose INH as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: bedaquiline
Women will receive bedaquiline as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: clofazamine
Women will receive clofazamine as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: delamanid
Women will receive delamanid as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: linezolid
Women will receive linezolid as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: pretomanid
Women will receive pretomanid as prescribed by their clinicians. (Dosage will vary for each participant.)
Experimental: Women taking ARVs with postpartum hormonal contraceptives

HIV-infected women 2-12 weeks postpartum will be assigned to this arm if receiving one of the following ARV drug combinations and starting postpartum contraceptives: atazanavir/ritonavir/tenofovir, darunavir/cobicistat, atazanavir/cobicistat, or efavirenz AND starting combined oral contraceptives formulated with ethinyl estradiol; or atazanavir/ritonavir/tenofovir, efavirenz, atazanavir/cobicistat, or darunavir/cobicistat AND starting etonogestrel implant.

Note: As of February 2016, the study will no longer enroll women receiving atazanavir/ritonavir/tenofovir or efavirenz AND starting etonogestrel implant.

Drug: atazanavir/cobicistat
Women will receive atazanavir/cobicistat as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: darunavir/cobicistat
Women will receive darunavir/cobicistat as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: efavirenz
Women will receive efavirenz as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: atazanavir/ritonavir/tenofovir
Women will receive atazanavir/ritonavir/tenofovir as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: ethinyl estradiol oral contraceptive
Women will receive ethinyl estradiol oral contraceptive as prescribed by their clinicians. (Dosage will vary for each participant.)
Drug: etonogestrel implant
Women will receive etonogestrel implant as prescribed by their clinicians. (Dosage will vary for each participant.)

Detailed Description:

Pregnant women experience unique physiological changes that may result in clinically significant alterations in drug PKs. Unfortunately, there have been few clinical trials to study the PKs of ARV, TB, and hormonal contraceptive drugs in pregnant women. The development of appropriate dosing regimens for the HIV-infected pregnant woman is critical to the health of both mother and fetus. Overdosing may lead to maternal adverse events and increased risk of fetal toxicity, while underdosing may lead to inadequate virologic control, increased risk of developing drug resistance mutations, and a higher rate of perinatal HIV transmission. This study will evaluate the PKs of ARVs used during pregnancy; evaluate TB drugs used during pregnancy, both in women who are HIV-positive and also taking ARVs and in women who are HIV-negative and not taking ARVs; and evaluate the PKs of hormonal contraceptive medications taken along with ARVs.

There will be five main groups of study arms: HIV-infected pregnant women taking ARVs without TB treatment, HIV-infected pregnant women taking ARVs with first-line TB treatment, HIV-uninfected pregnant women taking no ARVs with first-line TB treatment, HIV-infected and HIV-uninfected pregnant women with or without ARVs with second-line TB treatment for drug-resistant TB, and HIV-infected postpartum women taking ARVs and hormonal contraceptives. Participants will not receive medications through this study—they will continue on ARV, TB, and/or contraceptive medications prescribed by their health care providers.

Women who are 20 0/7 weeks to 37 6/7 weeks pregnant will be enrolled in this study and will remain in the study for up to 12 weeks after delivery. Postpartum women will be enrolled at 2 to 12 weeks after delivery and followed until 6 to 7 weeks after starting contraceptives. Infants will be followed for 16 to 24 weeks of life. At all study visits, participants will undergo a medical history, a physical exam, and blood collection. At some visits, women in some arms will undergo a vaginal swab. Blood collection from the mother and the detached umbilical cord will occur during delivery. Intensive PK sampling will be performed at study visits during the second and third trimester of pregnancy and/or postpartum, depending on the study arm. Additional study visits may occur depending on the ARV drug regimen prescribed.

  Eligibility

Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Maternal Inclusion Criteria:

  • Participant must belong to one of the following 5 groups:

    1. HIV-infected pregnant women greater than or equal to 20 weeks gestation NOT on TB treatment receiving one or more of the ARV drugs/drug combinations specified in the protocol
    2. HIV-infected pregnant women greater than or equal to 20 weeks gestation receiving one of the ARV drugs/drug combinations specified in the protocol and TB treatment with at least one of the TB drugs, specified in the protocol, at study entry
    3. HIV-uninfected pregnant women greater than or equal to 20 weeks gestation receiving at least two of the first-line TB drugs, specified in the protocol, at study entry
    4. HIV-infected and HIV-uninfected pregnant women greater than or equal to 20 weeks gestation receiving at least two of the second-line TB drugs, specified in the protocol, at study entry
    5. HIV-infected women 2 to 12 weeks (14 to 84 days) post-delivery receiving one of the ARV drug combinations listed in the protocol AND starting postpartum contraceptives as listed in the protocol
  • The woman must be stable on the ARV drug/drug combination and/or TB drug combination for at least 2 weeks prior to PK sampling
  • If a woman is receiving a specific generic ARV formulation, the protocol team has approved this formulation
  • HIV-infected pregnant women must be planning to continue on current ARV regimen until postpartum PK sampling is completed. HIV-infected postpartum women on hormonal contraceptives must be planning to continue on ARV and contraceptive regimens until final PK sampling is completed.
  • For HIV-infected women: confirmed HIV infection, documented by positive results from two samples collected at different time points prior to study entry. More information on this criterion can be found in the protocol.
  • HIV-uninfected pregnant women must have documented negative HIV antibody test during current pregnancy. Note: adequate source documentation, including the date of specimen collection, date of testing, test performed, and test result, must be available.
  • Participants enrolling in the 3rd trimester must enroll by 37 6/7 weeks gestation
  • Participant can provide legal informed consent per local regulations
  • If a woman has completed this study and becomes pregnant again, she may re-enroll in the study only if she is enrolled in a different arm than that studied during her initial enrollment

Maternal Exclusion Criteria:

  • Women on medicines known to interfere with absorption, metabolism, or clearance of the drug being evaluated (see protocol for more information). Rifampicin is permitted for women being evaluated for TB and ARV drug interactions.
  • If pregnant, carrying multiple fetuses
  • Clinical or laboratory toxicity that, in the opinion of the site investigator, would be likely to require a change in the medicine regimen during the period of study

Infant Enrollment Criteria:

  • All infants of mothers enrolled during pregnancy (meeting criteria specified above) are enrolled, in utero, immediately after maternal enrollment.

Infant Requirements for Washout Pharmacokinetic Sampling:

  • Born to HIV-infected mother enrolled during pregnancy in an ARV arm (does not include infants born to HIV-uninfected mothers receiving TB drugs)
  • Birth weight greater than 1000 grams
  • Is NOT receiving disallowed medications described in Section 7 of the protocol
  • Does not have any severe congenital malformation or other medical condition not compatible with life or that would interfere with study participation or interpretation, as judged by the site investigator
  • Born after singleton delivery (not after multiple birth)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00042289

Contacts
Contact: Emily F. Demske 301-628-3322

  Show 91 Study Locations
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators
Study Chair: Mark Mirochnick, MD Boston Medical Center
  More Information

Additional Information:
Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00042289     History of Changes
Other Study ID Numbers: P1026s  10040  IMPAACT P1026s  IMPAACT P1025 
Study First Received: July 26, 2002
Last Updated: April 20, 2016
Health Authority: United States: Food and Drug Administration

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Pregnancy
Pharmacokinetics
Treatment Experienced

Additional relevant MeSH terms:
3-keto-desogestrel
Amikacin
Aminosalicylic Acid
Atazanavir
Bedaquiline
Capreomycin
Clofazimine
Contraceptive Agents
Contraceptives, Oral
Cycloserine
Darunavir
Dolutegravir
Efavirenz
Estradiol
Ethambutol
Ethinyl Estradiol
Ethionamide
Etravirine
Isoniazid
Kanamycin
Levofloxacin
Linezolid
Lopinavir
Moxifloxacin
Nevirapine
Norgestimate, ethinyl estradiol drug combination
Ofloxacin
Prothionamide
Pyrazinamide
Rifampin

ClinicalTrials.gov processed this record on May 02, 2016