Pharmacokinetics of Antiretroviral Agents in HIV-Infected Pregnant Women: Abacavir Sulfate, Etravirine, Emtricitabine, and Drug Combination Study

The primary objective of this study is to describe the **pharmacokinetics** of antiretroviral agents in the 3rd trimester of pregnant HIV-infected women and at post-partum, with a focus on agents for which no or limited pharmacokinetic data during pregnancy are available. Additionally, the study aims to determine pharmacokinetics in the infant in cases of post-exposure prophylaxis with one of the tested agents. This is clinically relevant as it addresses the gap in understanding how these medications are processed in pregnant women and their infants, which is crucial for optimizing treatment regimens and ensuring safety and efficacy.

Secondary objectives include:

• Describing the safety of antiretroviral agents during pregnancy and their efficacy in terms of viral load response of the mother and prevention of mother-to-child transmission.
• Describing breastmilk transfer and exposure in the child if breastfeeding occurs.
• For the raltegravir once-daily regimen, additional objectives include describing pharmacokinetics in the infant after birth, investigating the relation between progesterone levels and raltegravir pharmacokinetic changes during pregnancy, and assessing the safety and efficacy of reformulated once-daily raltegravir tablets.
• For the cabotegravir/rilpivirine LA regimen, additional objectives include describing pharmacokinetics over the duration of pregnancy and in the infant after birth, as well as breastmilk transfer and exposure in the child if breastfeeding occurs.

The clinical trial involves a total of **48 participants** who are **HIV-infected**. The study population is exclusively composed of **female subjects** who are pregnant, as the trial aims to investigate the pharmacokinetics of antiretroviral agents during pregnancy. Participants are at least 18 years of age, ensuring they are adults capable of providing informed consent. The trial population was selected based on their HIV status, confirmed by a positive HIV antibody test and an antigen test, and their treatment with a combination antiretroviral therapy (cART) regimen that includes specific agents under investigation. Participants are required to adhere to food intake recommendations, if applicable, which may influence the pharmacokinetics of the medications being studied. The study focuses on a vulnerable population, given the inclusion of pregnant women, to better understand the pharmacokinetics of antiretroviral agents during the 2nd and 3rd trimesters and post-partum periods.

The clinical trial is designed to evaluate the **pharmacokinetics** of antiretroviral agents in **HIV-infected** pregnant women, focusing on the third trimester and postpartum periods. This study employs a randomized, double-blind, controlled methodology to ensure the reliability and validity of the results. The trial is expected to run until December 31, 2025, with recruitment having commenced on November 22, 2009. Participants will be involved in the study for a maximum treatment period of 14 to 26 days, depending on the specific antiretroviral agent being tested.

Study visits are structured to include an initial screening visit, where eligibility is confirmed through a positive **HIV** antibody test and antigen test. Participants must be at least 18 years old, pregnant, and on a combination antiretroviral therapy (cART) regimen containing at least one of the agents under investigation. The screening visit is followed by multiple follow-up visits to monitor pharmacokinetic parameters such as AUC0-tau, Cmax, Ctrough, tmax, and thalf. These parameters will be compared during pregnancy and postpartum using mixed model analysis. The end-of-study visit will assess the cord blood/maternal blood concentration ratio at delivery and, if applicable, the half-life in infants after in utero exposure.

Participants are expected to adhere to food intake recommendations and maintain their cART regimen throughout the study. Conditions that may lead to early termination from the study include non-compliance with the study protocol, withdrawal of consent, or any adverse events that compromise the safety of the participant. The primary endpoints focus on pharmacokinetic parameters, while secondary endpoints include maternal viral suppression, infant infection status at birth, and the incidence of serious adverse events (SAEs) and adverse events (AEs) during pregnancy and postpartum.

The clinical trial involves the administration of several **antiretroviral agents** to evaluate their pharmacokinetics in HIV-infected pregnant women. The experimental medications include **Ziagen 300 mg film-coated tablets**, containing the active substance **abacavir sulfate**. These tablets are administered orally with a maximum daily dose of 600 mg, and the treatment period is limited to 14 days. **INTELENCE 200 mg tablets**, containing **etravirine**, are also administered orally with a maximum daily dose of 400 mg over the same treatment period.

**Eviplera 200 mg/25 mg/245 mg film-coated tablets** contain a combination of **emtricitabine, tenofovir disoproxil, and rilpivirine**. These are administered orally with a maximum daily dose of one tablet, also for 14 days. **EDURANT 25 mg film-coated tablets**, containing **rilpivirine**, are administered orally with a maximum daily dose of 25 mg for 14 days. **Telzir 700 mg film-coated tablets**, containing **fosamprenavir calcium**, are administered orally with a maximum daily dose of 1400 mg for 14 days.

**TRIZIVIR 300 mg/150 mg/300 mg film-coated tablets** contain **zidovudine, abacavir sulfate, and lamivudine**. These are administered orally with a maximum daily dose of two tablets for 14 days. **Delstrigo 100 mg/300 mg/245 mg film-coated tablets**, containing **lamivudine, doravirine, and tenofovir disoproxil**, are administered orally with a maximum daily dose of one tablet for 14 days. **Norvir 100 mg film-coated tablets**, containing **ritonavir**, are administered orally with a maximum daily dose of two tablets for 14 days.

**Ritonavir Accord 100 mg filmomhulde tabletten**, also containing **ritonavir**, are administered orally with a maximum daily dose of 200 mg for 14 days. **Descovy 200 mg/10 mg film-coated tablets**, containing **emtricitabine and tenofovir alafenamide**, are administered orally with a maximum daily dose of one tablet for 14 days. **REYATAZ 300 mg hard capsules**, containing **atazanavir**, are administered orally with a maximum daily dose of one capsule for 14 days.

**REKAMBYS 600 mg prolonged-release suspension for injection**, containing **rilpivirine**, is administered via intramuscular injection with a maximum daily dose of 20 mg for 15 days. **Tivicay 50 mg film-coated tablets**, containing **dolutegravir sodium**, are administered orally with a maximum daily dose of 50 mg for 26 days. **REKAMBYS 900 mg prolonged-release suspension for injection**, also containing **rilpivirine**, is administered via intramuscular injection with a maximum daily dose of 20 mg for 15 days.

**Viread 245 mg film-coated tablets**, containing **tenofovir disoproxil**, are administered orally with a maximum daily dose of 245 mg for 14 days. **Emtriva 200 mg hard capsules**, containing **emtricitabine**, are administered orally with a maximum daily dose of 200 mg for 14 days. **Descovy 200 mg/25 mg film-coated tablets**, containing **emtricitabine and tenofovir alafenamide**, are administered orally with a maximum daily dose of one tablet for 14 days.

**CELSENTRI 300 mg film-coated tablets**, containing **maraviroc**, are administered orally with a maximum daily dose of 600 mg for 14 days. **Truvada 200 mg/245 mg film-coated tablets**, containing **emtricitabine and tenofovir disoproxil**, are administered orally with a maximum daily dose of one tablet for 14 days. **Biktarvy 50 mg/200 mg/25 mg film-coated tablets**, containing **emtricitabine, tenofovir alafenamide, and bictegravir**, are administered orally with a maximum daily dose of one tablet for 14 days.

**Odefsey 200 mg/25 mg/25 mg film-coated tablets**, containing **emtricitabine, tenofovir alafenamide, and rilpivirine**, are administered orally with a maximum daily dose of one tablet for 14 days. **STOCRIN 600 mg film-coated tablets**, containing **efavirenz**, are administered orally with a maximum daily dose of 600 mg for 14 days. **Vocabria 400 mg prolonged-release suspension for injection**, containing **cabotegravir**, is administered via intramuscular injection with a maximum daily dose of 20 mg for 15 days.

**INTELENCE 100 mg tablets**, containing **etravirine**, are administered orally with a maximum daily dose of four tablets for 14 days. **Aptivus 250 mg soft capsules**, containing **tipranavir**, are administered orally with a maximum daily dose of 1000 mg for 14 days. **Pifeltro 100 mg film-coated tablets**, containing **doravirine**, are administered orally with a maximum daily dose of 100 mg for 14 days.

**CELSENTRI 150 mg film-coated tablets**, containing **maraviroc**, are administered orally with a maximum daily dose of 600 mg for 14 days. **Kivexa 600 mg/300 mg film-coated tablets**, containing **abacavir sulfate and lamivudine**, are administered orally with a maximum daily dose of two tablets for 14 days. **ISENTRESS 400 mg film-coated tablets**, containing **raltegravir**, are administered orally with a maximum daily dose of 800 mg for 14 days.

**Fuzeon 90 mg/ml powder and solvent for solution for injection**, containing **enfuvirtide**, is administered via subcutaneous injection with a maximum daily dose of 180 mg for 14 days. **Vocabria 600 mg prolonged-release suspension for injection**, containing **cabotegravir**, is administered via intramuscular injection with a maximum daily dose of 20 mg for 15 days. **ISENTRESS 600 mg film-coated tablets**, containing **raltegravir**, are administered orally with a maximum daily dose of 1200 mg for 26 days.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include pharmacokinetic parameters such as AUC0-tau, Cmax, Ctrough, tmax, and thalf for pregnant women, with a comparison of these parameters during pregnancy and post-pregnancy using mixed model analysis. Additionally, the Ctrough during pregnancy should exceed the minimal effective plasma concentration. The study will also evaluate the cord blood/maternal blood concentration ratio at delivery, the determination of half-life in infants after in utero exposure, and the breastmilk/maternal plasma ratio in cases of breastfeeding, along with exposure in the child if breastfeeding occurs.

Secondary endpoints focus on the description of maternal viral suppression during pregnancy and postpartum, the infection status of infants at birth, and the documentation of serious adverse events (SAEs) and adverse events (AEs) reported during pregnancy and postpartum. These endpoints will provide comprehensive data on the efficacy and safety of the antiretroviral agents being studied in HIV-infected pregnant women and their infants.