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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor:
Collaborator:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00042289
First received: July 26, 2002
Last updated: August 19, 2014
Last verified: August 2014
  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: Current ARV medications
Drug: Current TB medications
Drug: Current hormonal contraceptive medications
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, rilpivirine, 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: 1300
Study Start Date: March 2003
Estimated Primary Completion Date: May 2016 (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: darunavir/ritonavir, didanosine delayed release, etravirine, maraviroc, nelfinavir, rilpivirine,tipranavir/ritonavir, efavirenz, or lopinavir/ritonavir (with dose information specified in the protocol).
Drug: Current ARV medications
Pregnant women will continue on ARV medications as prescribed by their clinicians.
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 rifampicin-containing TB treatment with at least one of the following TB drugs: ethambutol, isoniazid, or pyrazinamide (with dose information specified in the protocol).
Drug: Current ARV medications
Pregnant women will continue on ARV medications as prescribed by their clinicians.
Drug: Current TB medications
Pregnant women will continue on TB medications as prescribed by their clinicians.
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 drugs: ethambutol, isoniazid, pyrazinamide, or rifampicin (with dose information specified in the protocol).
Drug: Current TB medications
Pregnant women will continue on TB medications as prescribed by their clinicians.
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: lopinavir/ritonavir and starting combined oral contraceptives formulated with ethinyl estradiol, atazanavir/ritonavir/tenofovir and starting combined oral contraceptives formulated with ethinyl estradiol, lopinavir/ritonavir and starting etonogestrel implant, or atazanavir/ritonavir/tenofovir and starting etonogestrel implant (dose information specified in the protocol).
Drug: Current ARV medications
Pregnant women will continue on ARV medications as prescribed by their clinicians.
Drug: Current hormonal contraceptive medications
Pregnant women will continue on hormonal contraceptive medications as prescribed by their clinicians.

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 dosing regimens that are most effective in preventing perinatal HIV transmission and in maintaining the health of both mother and fetus; 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 four main groups of study arms: HIV-infected pregnant women taking ARVs without TB treatment, HIV-infected pregnant women taking ARVs with TB treatment, HIV-uninfected pregnant women taking no ARVs with TB treatment, and HIV-infected pregnant women taking ARVs with postpartum 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 34 6/7 weeks pregnant will be enrolled in this study and will remain in the study for 24 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 until 24 weeks of life. At all study visits, women 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 between 2 and 3 weeks, 2 and 8 weeks, or 6 and 12 weeks postpartum, with the first sampling occurring within 72 hours of enrollment. The timing of antepartum and postpartum PK samplings will vary by 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

Inclusion Criteria:

  • Participant must belong to one of the following 4 groups:

    1. HIV-infected pregnant woman at least 20 weeks gestation and NOT on TB treatment, receiving one or more of the ARV drugs/drug combinations specified in the protocol
    2. HIV-infected pregnant woman at least 20 weeks gestation receiving one of the ARV drugs/drug combinations specified in the protocol and rifampicin-containing TB treatment with at least one of the TB drugs, specified in the protocol, at study entry
    3. HIV-uninfected pregnant woman at least 20 weeks gestation receiving at least two TB drugs, specified in the protocol, at study entry
    4. HIV-infected woman 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
  • HIV-infected pregnant women must be planning to continue on current ARV regimen until postpartum PK sampling is completed
  • HIV-infected pregnant women must be enrolled in the P1025 study if available at the potential participant's site
  • For HIV-infected women who are not co-enrolled in the P1025 study: documentation of HIV-1 infection by historical data or defined as positive results from two samples collected at different time points. 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
  • Participants enrolling in the 3rd trimester must enroll by 34 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

Exclusion Criteria:

  • Women on medicines known to interfere with absorption, metabolism, or clearance of the ARV 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
  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 89 Study Locations
Sponsors and Collaborators
Investigators
Study Chair: Mark Mirochnick, MD Boston Medical Center
  More Information

Additional Information:
Publications:

Additional 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: August 19, 2014
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:
HIV Infections
Acquired Immunodeficiency Syndrome
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Contraceptive Agents
Contraceptives, Oral, Combined
Reproductive Control Agents
Physiological Effects of Drugs
Pharmacologic Actions
Therapeutic Uses
Contraceptives, Oral
Contraceptive Agents, Female

ClinicalTrials.gov processed this record on August 19, 2014