A Study of the Pharmacology of Oseltamivir (Tamiflu) in Pregnancy

Study Overview
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Brief Summary
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The primary research question of this study is: Does the pharmacokinetics of oseltamivir after a single oral dose differ between the pregnant and non-pregnant women?

Detailed Description
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With the pending threat of pandemic avian influenza, the disproportionate morbidity and mortality documented in previous 20th century pandemics among pregnant women, and the lack of any data for use of these vital antiviral drugs in pregnancy, study of the pharmacology of oseltamivir in pregnancy is imperative. If and when the next pandemic occurs, a better understanding of this drug's safety and pharmacologic profiles for use in pregnancy is critical given the fact that it will be used in this vulnerable patient population. This is a pilot study of the use of oseltamivir in pregnancy. This data will be combined with data from the parallel Pediatric Pharmacology Research Unit (PPRU) studies to put together a portfolio for use in understudied populations. This will allow for a re-thinking of the current status and potentially allow for small trials to be performed with patients who are suffering from influenza in pregnancy, to assess efficacy. The relevance with the pandemic strain and its corresponding Minimum Inhibitory Concentration (MIC) may have direct implications for dosing in pregnancy if lower levels of drug are documented. In addition, depending on the findings from the esterase component of the investigation, future investigation into mechanistic bases for changes in enzyme activity are possible.

Official Title
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A Study of the Pharmacology of Oseltamivir (Tamiflu) in Pregnancy

Conditions
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Pregnancy, Influenza

Intervention / Treatment
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* Drug: Oseltamivir (Tamiflu)
* Procedure: Blood Draws


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For Oseltamivir (Tamiflu) arm: Singleton gestation prior to 24 0/7 weeks gestation Planning to undergo a termination procedure for the incident pregnancy Willingness to take the single-dose medication and to follow study procedures Able to undergo informed consent. For Esterase arm: Singleton gestation greater than 32 completed weeks and less than 40 completed weeks of gestation Absence of severe pregnancy complication that could affect body volume and or metabolism (i.e., preeclampsia, renal dysfunction, hepatic dysfunction [defined as serum creatinine clearance of < 30 ml/min or a known ALT/AST> 2x facility normal value], etc.) Willingness to follow study procedures Able to undergo informed consent The use of medications that may affect renal metabolism is not a contraindication to participation since these subjects are only undergoing PK sampling. Exclusion Criteria: For Oseltamivir (Tamiflu) arm: Known current in utero fetal death Significant medical history and/or medication use as determined by the investigator that has the potential to affect results of the study or put the patient at risk from the single-dosing Known hypersensitivity to the components of the study drug Known hepatic or renal dysfunction (defined as serum creatinine clearance of < 30 ml/min or a known ALT/AST> 2x facility normal value) Chronic use of street drugs (obtained via subject interview and/or medical history) Participation in any other concurrent interventional study. We will ask if they have a history of depression in the past requiring treatment or if they are currently actively depressed. If either of these questions yields a positive response, we will not consider the patient eligible and will not enroll the subject. For Esterase arm: Known current in utero fetal death Significant medical history as determined by the investigator to potentially affect results of the study Chronic use of street drugs (obtained via subject interview and/or medical history Participation in any other concurrent interventional study.

Ages Eligible for Study
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Minimum Age: 18 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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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oseltamivir (Tamiflu)<br> | Drug: Oseltamivir (Tamiflu)<br>* The following procedures will be performed on two occasions: once at least three days prior to the scheduled pregnancy termination procedure and again about eight weeks after the termination procedure. A) Subject will take 75 mg of oseltamivir pill by mouth B) Multiple blood draws (1 teaspoon each) over the next 48 hours after taking oseltamivir. Urine samples also will be collected.<br>|
| Other: Esterase<br> | Procedure: Blood Draws<br>* Two blood draws (1 teaspoon each) will be performed: once during third trimester of pregnancy and again about eight weeks after delivery.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the area under the concentration vs. time curve (AUC 0-7 d) in the first and second trimesters of pregnancy with comparisons to the post-termination non-pregnant follow-up data on these enrollees and historical non-pregnant data. |  | Less than 9 weeks for subjects planning termination; up to 5 months for subjects enrolled during their 3rd trimester. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Non-compartmental model analysis for Cmax, Tmax, Cl/F, Clr,V/F, MRT and t ½. |  | Less than 9 weeks for subjects planning termination; up to 5 months for subjects enrolled during their 3rd trimester. | 
| Plasma concentrations of oseltamivir after single-dosing. |  | Less than 9 weeks for subjects planning termination; up to 5 months for subjects enrolled during their 3rd trimester. | 
| Evaluation of carboxy-esterase levels and activity in all trimesters of pregnancy with comparison to the post-partum internal controls. |  | Less than 9 weeks for subjects planning termination; up to 5 months for subjects enrolled during their 3rd trimester. | 
| Tolerance (side effect profile) of single-dose oseltamivir in pregnancy. |  | Less than 9 weeks for subjects planning termination; up to 5 months for subjects enrolled during their 3rd trimester. |