Pharmacokinetics of Hydroxychloroquine in Pregnancies with Rheumatic Diseases
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Hydroxychloroquine is an oral drug prescribed to pregnant women with rheumatic disease to reduce disease activity and prevent flares. Physiologic changes during pregnancy may substantially alter drug pharmacokinetics. However, the effect of pregnancy on hydroxychloroquine disposition and the potential need for dose adjustment remains virtually unknown.
We performed a population-pharmacokinetic analysis using samples from the Duke Autoimmunity in Pregnancy Registry from 2013 to 2016. We measured hydroxychloroquine concentration using high-performance liquid chromatography/tandem mass spectrometry and analyzed data using non-linear mixed-effect modeling. We calculated differences between pregnancy and postpartum empirical Bayesian estimates using paired t tests. We computed steady-state concentration profiles for hydroxychloroquine during pregnancy and postpartum using individual clinical data and empirical Bayesian estimates developed from the final pharmacokinetic model.
We obtained 145 serum samples from 50 patients, 25 of whom had paired pregnancy and postpartum specimens. Five subjects had average concentrations (pregnancy and postpartum) < 100 ng/mL, consistent with medication non-adherence, and were excluded. The population estimated apparent volume of distribution was 1850 L/70 kg and estimated apparent clearance was 51 L/h. Compared with postpartum, median apparent volume of distribution increased significantly during pregnancy (p < 0.001), whereas apparent clearance and 24-h area under the curve did not change.
We developed a one-compartment population-pharmacokinetic model for hydroxychloroquine in pregnant women with rheumatic disease. Estimates for serum CL were within the expected range for plasma in non-pregnant adults. Because CL and 24-h area under the curve did not change during pregnancy compared with postpartum, our modeling in this small cohort does not support adjusting hydroxychloroquine dose during pregnancy.
Compliance with Ethical Standards
Salary and/or research support for this project was provided by the Rheumatology Research Foundation’s Scientist Development Award, the Thrasher Research Fund, the Derfner Foundation, NIGMS/NICHD (2T32GM086330-06), NICHD (5R01-HD076676-04, HHSN275201000003I), and a Duke Health/Private Diagnostic Clinic ENABLE grant. The National Institutes of Health Sponsored open access.
Conflict of interest
Stephen J. Balevic receives salary and research support from the National Institute of General Medical Sciences and the National Institute of Child Health and Human Development (2T32GM086330-06, 5R01-HD076676-04, HHSN275201000003I), the Rheumatology Research Foundation, and the Thrasher Research Fund. Michael Cohen-Wolkowiez receives support for research from the National Institutes of Health (5R01-HD076676, HHSN275201000003I), National Institute of Allergy and Infectious Diseases/National Institutes of Health (HHSN272201500006I), US Food and Drug Administration (1U18-FD006298), Biomedical Advanced Research and Development Authority (HHSO1201300009C), and from the industry for the drug development in adults and children (http://www.dcri.duke.edu/research/coi.jsp). Amanda M. Eudy is a consultant for GlaxoSmithKline and was previously a graduate research assistant for GlaxoSmithKline. Megan E. B. Clowse and Amanda M. Eudy have received independent medical education Grants from GlaxoSmithKline. Thomas P. Green has no conflicts of interest directly relevant to the contents of this article. Laura E. Schanberg receives research support from the National Institutes of Health (5R01-AR063890-02, 1U19AR069522-01, 1U34AR066294), Patient-Centered Outcomes Research Institute (CER-1408-20534, PPRN-1306-04601), Childhood Arthritis and Rheumatology Research Alliance, and Swedish Orphan Biovitrum AB. She participates in the Data Safety and Monitoring Board for UCB and Sanofi. Megan E. B. Clowse serves as a consultant for UCB and AstraZeneca.
We conducted the study in compliance with the Declaration of Helsinki and the Duke Institutional Review Board approved the protocol.
All subjects included in the study provided informed consent.
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