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

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.

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.