Pharmacokinetics of Quetiapine Across Pregnancy and Postpartum

Study Overview
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Brief Summary
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The widespread and common use of quetiapine in childbearing and pregnant women demands more data to inform dosing and toxicity in pregnancy. The new FDA Pregnancy and Lactation Labeling Final Rule (PLLR) will go into effect on June 30th, 2015 and will replace the prior A, B, C, D, and X categories. Additionally, the PLLR will require information to aid prescribing decisions in three categories 1) Pregnancy (including labor and delivery), 2) Lactation, and 3) Females and Males of Reproductive Potential. The pregnancy category will include a subsection that will describe pharmacokinetic and pharmacodynamic characteristics of the medication in pregnancy, fetal risk, and data quality. The data collected in this study will update the FDA pregnancy pharmacokinetic section for quetiapine and inform physicians that prescribe to childbearing women.

Detailed Description
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Bipolar Disorder (BD) and Schizophrenia (SCHZ) in pregnancy are associated with pregnancy complications and increased maternal mortality due to physiological and psychosocial changes independent of second-generation antipsychotic (SGA) use. Untreated BD and SCHZ have been associated with an increased risk of placental abnormalities, antepartum hemorrhage, preterm birth, pre-eclampsia, low birth-weight, intrauterine growth retardation, small for gestational age, fetal distress, neonatal hypoglycemia, stillbirth and congenital defects, and the potential for adverse neurodevelopmental outcomes. Severe maternal stress in pregnancy increases the risk for offspring mental disorders, and eye, ear, respiratory, digestive, skin, musculoskeletal, and genitourinary diseases and congenital malformations (i.e., cleft palate, cleft lip). Also, BD and SCHZ illness symptoms are linked to psychosocial consequences that result in poor perinatal outcomes including impulsivity that leads to reckless behavior such as increased indiscriminate sex and exposure to sexually transmitted infections, smoking, increased alcohol and drug use, less prenatal care, and poor nutrition. Furthermore, women with recurrence of mental illness in the perinatal period have increased risk for suicide, a leading cause of maternal death. The only published case of quetiapine plasma concentrations in a pregnant woman included cross-sectional levels of a woman on 300 mg of quetiapine across pregnancy and postpartum. Compared to six months postpartum, the area under the curve decreased by 27%, 42%, and 18% in the first, second, and third trimester, respectively. Given the complexity of the metabolism of quetiapine to a very active metabolite, it is important to understand the altered metabolism of quetiapine and its active metabolite in pregnancy and the implication for dosing adjustments. This study will investigate the longitudinal pharmacokinetics of quetiapine in pregnancy, delivery, and postpartum. The long-term goal of this line of research is to establish psychotropic medication dosing algorithms informed by longitudinal pharmacokinetic data to improve mental health and pregnancy outcomes for mothers with serious mental illness. The primary aims are: 1) Determine the elimination clearance of quetiapine and its major active metabolite, 7-N-desalkyquetiapine, across pregnancy and postpartum; 2) Determine the effect of pharmacokinetic changes on symptoms and toxicity during pregnancy and postpartum, and; 3) Examine the maternal-to-cord plasma concentrations ratios of quetiapine and its major active metabolite, 7-N-desalkylquetiapine.

Official Title
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Pharmacokinetics of Quetiapine Across Pregnancy and Postpartum

Conditions
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Bipolar Disorder

Intervention / Treatment
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* Drug: Quetiapine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-45 years Pregnant, second trimester English-speaking DSM-V diagnosis of Bipolar Disorder or Schizophrenia, any subtype Medically healthy Singleton gestation Exclusion Criteria: Chronic use of drugs for medical disorders, except thyroid replacement for stable hypothyroidism No psychiatrist or obstetrician QIDS-SR 16 positive answer 3 on item 12, I have made specific plans for suicide or have actually tried to take my life within the past week DSM-V diagnosis of substance abuse or dependence in last 6 months, with the exception of cannabis; positive urine drug screen

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Quetiapine<br>Patients taking quetiapine during pregnancy are eligible to participate in the study. Their dose and plasma concentration levels of quetiapine will be monitored throughout pregnancy and up to three months postpartum. | Drug: Quetiapine<br>* Quetiapine concentrations will be observed in women who have already (under the guidance of a physician) decided to continue taking Quetiapine for the treatment of Bipolar Disorder (any subtype) or Schizophrenia during pregnancy.<br>* Other names: Seroquel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in plasma concentration/elimination | For patients taking the immediate release formulation, plasma levels will be obtained beginning at time 0 and at hours, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16. For patients on the extended release formulation, plasma levels will be obtained at time 0 and at hours 0.5, 1, 1.5, 2, 2,5, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, and 24. | 2 timepoints during pregnancy (second and third trimesters), and at four and twelve weeks postpartum | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Arterial and Venous Umbilical Cord Concentration of Quetiapine and 7-N-desalylquetiapine | Arterial and venous cord blood samples will be obtained immediately post-delivery and banked for later analysis | 30 minutes | 
| Cerebrospinal Fluid (CSF) Quetiapine and 7-N-desalkyquetiapine Concentrations |  | CSF to be obtained within 10 minutes of the epidural placement during labor | 
| Scores on Depression assessment, Inventory of Depression Symptomatology- Self Report (IDS-SR) | To determine if there is a pattern of increasing scores on self-report depression assessment (IDS-SR) and declining plasma levels. Increasing scores indicate worsening symptoms or depression episode recurrence. | Participants will complete these assessments an average of every 10 weeks from the time they enter the study, up to 12 weeks postpartum | 
| Scores on anxiety scale, Generalized Anxiety Disorder (GAD-7) | To determine if there is a pattern of increasing scores on GAD-7 and declining plasma levels | Participants will complete these assessments an average of every 10 weeks from the time they enter the study, up to 12 weeks postpartum | 
| Scores on mania assessment, Young Mania Reporting Scale (YMRS) | To determine if there is a pattern of increasing scores on clinician administered mania assessment (YMRS) and declining plasma levels | Participants will complete these assessments an average of every 10 weeks from the time they enter the study, up to 12 weeks postpartum. | 
| Scores on Brief Psychosis Rating Scale (BPRS) | assessment to evaluate psychotic symptoms | Participants will complete these assessments an average of every 10 weeks from the time they enter the study, up to 12 weeks postpartum. | 
| Positive responses on SAFTEE | surveys general and specific side effects including somatic, behavioral, and affective symptoms | Participants will complete these assessments an average of every 10 weeks from the time they enter the study, up to 12 weeks postpartum. | 
| Delivery outcomes as determined by the Peripartum Events Scale (PES) | assessment to quantify stressful events related to delivery. | 4 and 12 weeks postpartum | 
| Scores on the separate domains of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health | Assesses patient perceptions in 5 domains:physical function, pain, emotional distress, social function, and fatigue. | Participants will complete these assessments an average of every 10 weeks from the time they enter the study, up to 12 weeks postpartum. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pregnant, quetiapine, bipolar, women, female, postpartum, seroquel, perinatal, manic-depressive