Response of hydroxychloroquine PK to exposure to lupus during pregnancy

Pregnancy in women with systemic lupus erythematosus is often complicated
by fetal miscarriage, preterm birth, and maternal death in severe cases.
Therefore, it is critical
to optimize medical therapy for lupus pregnancy to promote disease control and improve outcomes.
Hydroxychloroquine (HCQ) is considered by the American College of Rheumatology and the European League Against Rheumatism to be the gold standard immunomodulatory drug for SLE complicated by pregnancy due to its safety, prevention of disease onset and improved pregnancy and neonatal outcomes
.

Despite the importance of maintaining therapeutic drug exposure during pregnancy, few studies have evaluated the pharmacokinetics (PK)
of HCQ in pregnancy.
Pregnancy may further exacerbate medication nonadherence due to frequent nausea and vomiting, concerns about harm to the fetus from medications, mood changes, and life stressors
.
Therefore, drug exposure during pregnancy must be interpreted
in the context of physiological changes, disease effects, and adherence.
Notably, most studies assessing medication adherence and HCQ concentrations use whole blood rather than serum
.
However, in this analysis, the investigators measured serum concentration because serum was readily available from existing biological repositories and retrospective studies, had commercially available assays for clinical monitoring, and avoided potential confusion
with anemia of pregnancy.

Hydroxychloroquine concentration and adherence are based on stock scores for medication adherence self-reported at each visit:

Methods: PK analysis
was performed using data from two observant pregnancy registries.
We recruited pregnant women with SLE to take HCQ at least 3 months before pregnancy and throughout pregnancy, and excluded pregnant women
with multiple pregnancies.
Using the PK model, we performed dose simulations and extrapolated 0%/20%/40%/60% nonadhesion to assess the effect
of adherence versus physiological changes on HCQ concentrations.
We compared the effect
of mean pregnancy non-adherent concentrations (≤100 ng/mL versus >100 ng/mL) on preterm birth using adjusted logistic regression.

Prediction of HCQ pharmacokinetics throughout pregnancy and postpartum:

Results: 56 pregnant women were recruited for 61 pregnancies
.
By the third trimester, the average apparent HCQ clearance increased by 59.
6%.

At a dose of 400 mg/day, patients with complete adhesion can expect HCQ concentrations of only 0.
3% ≤ 100 ng/mL, compared to 24.
2% when 60%
of the dose is missed.
Persistently low HCQ concentrations during pregnancy were associated with a significantly increased chance of preterm birth, controlling for lupus nephritis and ethnicity (OR 11.
2; 95% CI 2.
3 to 54.
2; p=0.
003）
。

Expected percentage of trough concentrations during pregnancy and postpartum, accompanied by medication non-compliance:

In summary, significant changes in HCQ PK during pregnancy were observed, resulting in a shortening of the half-life of the drug by 10 days; However, the effect of drug nonadherence on HCQ exposure was more pronounced
than physiological changes alone.
In addition, the rate of preterm birth was significantly higher
in pregnant women with non-adherent HCQ concentrations.
Therefore, optimizing adherence during pregnancy may be more clinically meaningful
than adjusting HCQ doses to account for physiological changes.
PK modelling suggests that a serum HCQ concentration of ≤ 100 ng/mL suggests non-compliance regardless of gestation and may help identify pregnancies
at risk of adverse outcomes.

References:

Balevic SJ, Weiner D, Clowse MEB, Eudy AM, Maharaj AR, Hornik CP, Cohen-Wolkowiez M, Gonzalez D.
Hydroxychloroquine PK and exposure-response in pregnancies with lupus: the importance of adherence for neonatal outcomes.
Lupus Sci Med.
2022 Jan; 9(1):e000602.
doi: 10.
1136/lupus-2021-000602.
PMID: 34996856; PMCID: PMC8744126.