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Stephen Balevic, MD, explains hydroxychloroquine PK and exposure-response in pregnancies with lupus and the importance of adhering to treatment both during pregnancy and postpartum.
Rheumatology Network interviewed Stephen Balevic, MD, an adult and pediatric rheumatologist at Duke University and clinical researcher at the Duke Clinical Research Institute (DCRI), to discuss his study, “Hydroxychloroquine PK and exposure-response in pregnancies with lupus: the importance of adherence for neonatal outcomes.”
Rheumatology Network: What first sparked your team's interest to study hydroxychloroquine (HCQ) levels and medication adherence in this patient population?
Stephen Balevic, MD: Our treatment armamentarium in pregnant women with lupus is unfortunately very limited. And we know that having active lupus in pregnancy can worsen pregnancy outcomes. For example, there is an increased risk of preterm birth. However, one drug that we know reduces the risk of active disease and is safe in pregnancy is hydroxychloroquine. That really underscores the reason why we must make sure pregnant women are taking hydroxychloroquine regularly and at the right dose. Now, a very important point is that we can't assume that medication dosing in pregnancy is the same or should be the same as in non-pregnant women. There's a number of changes to the body that occur during pregnancy that can affect how the body handles a drug, or what we call pharmacokinetics (PK). For example, the kidney filtration system can increase by 30% or 40% by the third trimester. So that means medications like hydroxychloroquine could leave the body quicker and therefore require a dosage adjustment. That is why we really wanted to do this study.
RN: Why is it so critical that patients with SLE adhere to their medication prior to pregnancy, during pregnancy, and into postpartum?
SB: To really get all the benefits from hydroxychloroquine, it's very important that enough of the medication actually in the body, which means, of course, taking it very regularly and as prescribed. If lupus becomes active during pregnancy, sometimes other medications, like glucocorticoids, might be necessary. But these medications have their own risks and side effects, so it is best to have a lupus pregnancy where the disease is not active at the start and stays inactive throughout the pregnancy and postpartum period. Hydroxychloroquine is one of our key medications to help us do that. We also know that adherence to medications in lupus is very hard for our patients. Many of our patients don't feel well and are often overwhelmed with the number of medications that they have to take. Additionally, many women who are pregnant may feel nauseated or may have concerns about potential side effects to their unborn child. Collectively, that can make medication adherence even worse, but also really underscores why we have to have good communication with our patients because a number of medications, like hydroxychloroquine, are safe and we can reassure them that these medications can be used safely and effectively.
RN: How does a diagnosis of lupus impact a woman who is pregnant or planning to become pregnant?
SB: Although many women with lupus can, with good physician guidance, have healthy pregnancies, lupus does bring a number of challenges. One of the most important guiding principles is good pregnancy planning. A number of medications we use in non-pregnant women with lupus, such as methotrexate or mycophenolate, should not be used in pregnancy. When a pregnancy is being planned, it's important that women work with their rheumatologist to make sure that they are on medications that are safe to use in pregnancy. And secondly, having controlled lupus ideally 6 months before becoming pregnant is also very important and increases the chances of having the healthiest pregnancy possible. That also highlights the importance of very reliable contraception. So, if a woman is sexually active and not intending to become pregnant, having very reliable contraception is super important. And if an unintended pregnancy does happen, it's important that we counsel our patients not to panic and just to contact the rheumatologist right away.
RN: What were the findings of your study?
SB: We learned several important things. First, we did find that pregnancy really changes how hydroxychloroquine is handled in the body. For clinicians, we found the clearance of the medication increases progressively with each trimester. That increased clearance means lower average levels of the medicine in the body, smaller peak concentrations, and a shorter half-life by about 10 days. To maintain the same average level of medication the body, for example, the dosage would need to be increased by about 60% pre-pregnancy compared with the third trimester.
For several reasons that we discussed in the manuscript, the need for dosage adjustment for hydroxychloroquine in pregnancy is not straightforward. At this point, we're not advocating that clinicians change dosage until we have a little bit more data. Secondly, we found that medication non-adherence had the greatest impact on the amount of hydroxychloroquine in the serum. Serum hydroxychloroquine levels that were ≤100 ng/mL were strongly suggestive of medication non-adherence. For example, if there were no missed doses at all, we would expect to see a level that low only about 0.3% of the time in women taking the most common dose of 400 milligrams a day. In other words, even though there's these physiologic changes, really low hydroxychloroquine levels in serum are still pretty uncommon. Conversely, if 60% of hydroxychloroquine doses are missed, we would expect to see those average hydroxychloroquine levels being ≤100 ng/mLabout 25% of the time. And thirdly, we found that women with persistently low serum hydroxychloroquine levels throughout the pregnancy, so that's an average level ≤100 ng/mL, had significantly higher odds of preterm birth. And that was the case even when we controlled for potential confounders, like lupus nephritis, race, and concomitant medications.
The take home message here is that our study suggests that monitoring serum hydroxychloroquine levels during lupus pregnancies can really help identify non-adherence. And that's one way we can easily intervene to hopefully improve adherence and possibly improve pregnancy outcomes.
RN: Were you surprised by the results of the study?
SB: I think the results make sense if we think about the pharmacology of hydroxychloroquine. Yes, we would expect the medication to be affected by pregnancy, but this is the first time we were able to quantify those changes and determine the clinical significance. I think we were surprised to learn that medication non-adherence was so common. We found that about 1 in 4 pregnancy visits had a serum hydroxychloroquine level that was very low and suggestive of non-adherence.
RN: Are there any strengths or limitations of the study that you'd like to highlight?
SB: The major strength of this study was our use of something called PK modeling, which really allowed us to figure out what was happening to hydroxychloroquine in the body due to physiologic changes, what was happening due to medication non-adherence, and what the combined effect was. PK modeling is a very powerful tool that is used frequently by the FDA and other regulatory authorities and industry, and something I hope will be used more commonly in academic rheumatology.
The most important limitation for your readers is the fact that we used the serum and not whole blood to measure hydroxychloroquine levels. Without going into too much detail, hydroxychloroquine does partition into blood cells. Target whole blood levels cannot be compared directly with serum and plasma and vice versa. Most of the existing literature on hydroxychloroquine levels, especially in non-pregnant patients with lupus, have been using whole blood. It’s typically a little bit more precise. I do want to highlight that measuring serum levels, though, does have some advantages in pregnancy. For example, it's usually less impacted by the physiologic anemia that can occur during pregnancy. I must refer readers to the discussion in our manuscript to really know what the strengths and limitations of using whole blood versus serum are, but I think that is an important thing for researchers or clinicians to be aware of.
RN: Does your team plan on doing any further research on this topic?
SB: Yes. This is a growing area where we need more research on optimal dosages of our antirheumatic drugs, especially in vulnerable populations, like pregnant women and in children. We're very fortunate to have our Duke Autoimmunity in Pregnancy Registery, which is an ongoing registry where we collect information from pregnancy. We are planning to study the PK of other drugs in lupus pregnancies as well.
For more information about this study, refer to our recent article.