Modelling the tail-phase pharmacokinetics of long-acting cabotegravir and rilpivirine from early pregnancy to postpartum at steady state

This study utilized virtual population simulations to characterize the prolonged tail-phase pharmacokinetics of long-acting cabotegravir and rilpivirine following discontinuation during early pregnancy, revealing that maternal drug levels persist for several months postpartum and fall below therapeutic thresholds only after gestation week 33, thereby highlighting the need for strategies to mitigate risks associated with discontinuation in this population.

The Gist

The Big Picture: The "Slow-Release" Dilemma

Imagine you are taking a special HIV medication that comes in a long-acting injection. Instead of taking a pill every day, you get a shot once a month (or every two months) that acts like a slow-release time capsule inside your muscle. It slowly leaks medicine into your body over time, keeping you protected without you having to remember a daily routine.

This study looks at what happens when a woman on this medication discovers she is pregnant and decides to stop the shots.

The big question the researchers asked was: "If she stops the shots early in pregnancy, how long does the medicine stay in her body, and does it reach the baby?"

The Problem: The "Backpack" Effect

Think of the injection site in the muscle as a backpack filled with medicine.

• While you are getting shots: Every time you get a new shot, you add more medicine to the backpack. Eventually, the backpack gets full and reaches a "steady state" (it's packed tight).
• When you stop: Even if you stop getting new shots, the backpack doesn't empty instantly. The medicine slowly trickles out of the backpack into your bloodstream for months. This is called the "tail phase."

The researchers wanted to know: If a woman stops the shots when she finds out she is pregnant, does that "backpack" keep feeding medicine to her and her baby for the rest of the pregnancy?

How They Studied It (The Virtual Simulation)

Since we can't ethically stop medicine in real pregnant women just to see what happens, the scientists used a computer simulation.

• They created 100 "virtual" women on their computers.
• They simulated these women getting the shots until their "backpacks" were full (steady state).
• Then, they simulated the women getting pregnant and stopping the shots in the first few weeks.
• They watched the computer models to see how the medicine levels dropped over the next 9 months of pregnancy and 6 months after the baby was born.

What They Found

Here are the key takeaways, translated from "science-speak" to plain English:

1. The Medicine Sticks Around for a Long Time
Even though the women stopped the shots early in pregnancy, the medicine didn't disappear quickly.

• Cabotegravir (CAB): This drug stayed in the mother's blood at high levels for a long time. Even at the time of delivery (when the baby is born), the levels were still detectable.
• Rilpivirine (RPV): This drug also stayed, but it dropped to lower levels faster than CAB.

2. The Baby Gets a "Side Order"
Because the medicine is still leaking out of the mother's muscle "backpack," it crosses the placenta to the baby.

• The Good News: The baby was exposed to the drug, which might offer some protection against HIV.
• The Bad News: By the time the baby is born, the levels of the drug in the baby's blood (cord blood) were often too low to be fully effective against HIV. It's like having a shield that is too thin to stop a bullet. This is risky because if the virus is present, the baby might get infected, or the virus might learn to fight back (resistance).

3. The "Tail" Lasts After Birth
The study found that the medicine stays in the mother's system for 6 months after the baby is born.

• This means if the mother breastfeeds, the baby could still be getting small amounts of this medicine through the milk.
• Since the levels are dropping, the mother might be in a "danger zone" where the drug isn't strong enough to stop HIV, but it's still there. This is a dangerous spot because it can lead to the virus becoming resistant to the drug.

The "So What?" for Real Life

This study highlights a tricky situation for women who get pregnant while on long-acting HIV shots:

• You can't just "turn it off": Unlike a daily pill where you stop taking it and it's gone in a day or two, these long-acting shots have a long "tail." You can't stop the flow immediately.
• The Risk of Resistance: If a woman stops the shots and doesn't switch to a different, effective treatment (like daily pills) immediately, the low levels of the old drug might let the HIV virus wake up and become resistant to the medicine.
• The Baby's Exposure: The baby is exposed to the drug for the whole pregnancy, but the levels might not be high enough to be a perfect shield.

The Bottom Line

The researchers are saying: "If you are on these long-acting shots and get pregnant, you need a plan."

You can't just stop the shots and hope for the best. Because the medicine lingers in your body like a slow-dripping faucet, you and your baby will be exposed to it for months. Doctors need to help women switch to a different treatment (like daily pills) before the levels drop too low, to ensure both mom and baby stay safe and the virus doesn't become resistant.

In short: The "slow-release" feature is great for convenience, but it becomes a complex puzzle when pregnancy happens, requiring careful medical guidance to manage the lingering "tail" of the drug.

Technical Summary

1. Problem Statement

Long-acting injectable (LAI) antiretrovirals, specifically the combination of cabotegravir (CAB) and rilpivirine (RPV), offer significant adherence benefits for HIV treatment and prevention. However, a critical clinical challenge arises when women of childbearing age become pregnant while on these regimens. Due to a lack of definitive safety data, many women choose to discontinue LAI therapy upon discovering pregnancy.

The core problem addressed is the "tail-phase" phenomenon: because LAIs are administered as intramuscular depots with slow release, drug concentrations decline gradually over months after the final injection. If a woman discontinues LA-CAB/RPV early in pregnancy, the drug continues to be released from the muscle depot throughout gestation and potentially into the postpartum period. This creates two major risks:

1. Fetal Exposure: The developing fetus is exposed to the drug without the benefit of therapeutic efficacy (if levels drop below the effective threshold) or clear safety data.
2. Resistance Risk: As drug levels fall below the therapeutic threshold (subtherapeutic) but remain detectable, there is a risk of virologic rebound and the selection of drug-resistant HIV strains, particularly for rilpivirine (a non-nucleoside reverse transcriptase inhibitor).

Previous studies had not fully quantified the maternal and fetal "tail-exposures" specifically for women who had reached steady state prior to conception and then discontinued early in pregnancy.

2. Methodology

The study utilized Physiologically-Based Pharmacokinetic (PBPK) modelling to simulate drug disposition across the continuum of pregnancy and postpartum.

• Model Platform: SimBiology (MATLAB R2019a).
• Model Validation: The PBPK models were previously validated against clinical datasets for oral and LA-CAB/RPV in adults, and oral LA-CAB/RPV in pregnant women.
• Simulation Scenarios:
  • Virtual Population: 100 non-pregnant women per scenario (median age 26.5 years).
  • Dosing Regimens: Two approved maintenance dosing schedules were simulated:
    • Every 4 weeks (Q4W): 400 mg CAB / 600 mg RPV.
    • Every 8 weeks (Q8W): 600 mg CAB / 900 mg RPV.
  • Protocol:
    1. Initiation of LA-CAB/RPV in non-pregnant state until steady state was achieved.
    2. Continuation of dosing through conception.
    3. Discontinuation at Week 1 of pregnancy (early pregnancy).
    4. Simulation of the "tail-phase" from Week 1 through delivery (Week 40) and up to 6 months postpartum.
• Model Architecture:
  • Pre-pregnancy/Postpartum: Adult female PBPK model.
  • First Trimester (Weeks 1–13): Pregnancy model without a fetal sub-model.
  • Second/Third Trimester (Weeks 14–40): Pregnancy model with a fetal sub-model to estimate cord blood concentrations.
• Key Metrics:
  • Residual drug mass in the muscle depot.
  • Maternal and fetal plasma concentrations.
  • Time to fall below therapeutic thresholds: 4×PA-IC90 (therapeutic target) and PA-IC90 (minimum effective concentration).
  • Cord-to-maternal blood ratios.

3. Key Contributions

• First Quantification of Fetal Tail-Exposure: This is the first study to model fetal exposure to LA-CAB/RPV specifically in the scenario where the mother reached steady state pre-conception and discontinued early in pregnancy.
• Differentiation of Regimens: It provides distinct pharmacokinetic profiles for both Q4W and Q8W dosing schedules, highlighting differences in depot size and washout rates.
• Clinical Threshold Analysis: The study maps the timeline of when drug levels drop below clinically relevant thresholds (4×PA-IC90 and PA-IC90) for both mother and fetus, offering data to guide the duration of oral "bridge" therapy.
• Depot Kinetics: It quantifies the residual drug mass in the muscle depot at various stages (steady state, end of 1st trimester, delivery), illustrating the slow release mechanism driving the tail-phase.

4. Key Results

Pharmacokinetic Tails and Depot Kinetics:

• The tail-phase is driven by the residual drug in the muscle depot. At steady state, the depot contained ~380% (Q4W) and ~170% (Q8W) of a single maintenance dose.
• Even after discontinuation at Week 1, drug levels remained detectable in maternal plasma up to 6 months postpartum.

Maternal Exposure:

• Therapeutic Thresholds: By the time of delivery (Week 40), 0% of the virtual cohort maintained concentrations above the 4×PA-IC90 for either drug.
• Time to Subtherapeutic Levels (4×PA-IC90):
  • CAB: Median 30.1 weeks (Q4W) and 27.4 weeks (Q8W) after the last dose.
  • RPV: Median 13.3 weeks (Q4W) and 11.0 weeks (Q8W) after the last dose.
• Postpartum Levels: At 6 months postpartum, median concentrations were 125 ng/mL (CAB) and 7.84 ng/mL (RPV) for Q4W dosing.

Fetal Exposure (Cord Blood):

• CAB: Cord-to-maternal ratios were >1.0 in the second and third trimesters. Cord concentrations remained above the PA-IC90 (166 ng/mL) at delivery (Median ~764 ng/mL for Q4W).
• RPV: Cord-to-maternal ratios were <1.0. Cord concentrations fell below the PA-IC90 (12 ng/mL) by delivery (Median ~10.2 ng/mL for Q4W).
• Timing: Fetal exposure to CAB remained above therapeutic levels until approximately gestation week 33, while RPV levels dropped below therapeutic targets much earlier.

Table Summary (Selected Data Points):

Metric	Q4W (CAB)	Q4W (RPV)	Q8W (CAB)	Q8W (RPV)
% > 4×PA-IC90 at Delivery	0%	0%	0%	0%
% > PA-IC90 at Delivery	100%	38%	100%	5%
Cord Concentration at Delivery (Median)	764 ng/mL	10.2 ng/mL	652 ng/mL	8.56 ng/mL

5. Significance and Clinical Implications

• Informed Counseling: Clinicians must inform women of childbearing potential that discontinuing LA-CAB/RPV early in pregnancy does not immediately stop fetal exposure. The drug will persist in the system throughout gestation.
• Resistance Prevention: The study highlights a "danger window" where drug levels are subtherapeutic but detectable. For women on LA-CAB for PrEP who become pregnant, the authors recommend switching to oral PrEP immediately upon discontinuation of the injection to prevent resistance selection.
  • Specific Recommendation: Oral coverage should ideally be maintained until at least 27 weeks after the last dose for Q8W regimens to ensure levels do not linger in the subtherapeutic zone.
• Breastfeeding Considerations: Residual drug levels persist 6 months postpartum, suggesting potential exposure to infants via breastfeeding, though the benefit-risk ratio of this exposure remains unclear.
• Regulatory Impact: These findings support the need for specific guidelines regarding the management of women on LAI therapies who become pregnant, emphasizing the necessity of bridging therapies to cover the tail-phase.

In conclusion, this study provides critical quantitative data demonstrating that the "tail" of long-acting injectables extends well beyond pregnancy, necessitating proactive clinical management to ensure both maternal viral suppression and fetal safety.