A Study of the Pharmacology of Tamiflu in Pregnancy

The emergence of the novel H1N1 influenza virus has raised concern among public health
officials and the public alike. Although initial reports suggested that the risk of serious
disease or death was less than initially feared, continued experience suggests that the
disease will have a major impact on the public's health. To address this urgent public
health challenge, the centers of the Obstetric-Fetal Pharmacology Research Units Network
(OPRU) will recruit a total of 75 pregnant women (25 per trimester with singletons
pregnancies) who are receiving oseltamivir for supposed influenza infection. When possible,
we will recruit women with twin gestation to determine if fetal number affects the drugs
pharmacokinetics. We do not anticipated a significant number of multi-fetal gestations (<
10) but even limited data might prove useful in this population given the tremendous change
in renal drug clearance that is normally seen in this group of women. An additional 25
healthy non-pregnant women will be studied to define pregnancy- related changes in the PK of
oseltamivir and the carboxylate.

We will study each woman once during therapy, performing steady state pharmacokinetic
analyses. This study will be performed after 3 days of oral therapy to optimize the
possibility that steady state concentrations have been achieved.

We will:

1. collect biological fluids (plasma and urine) to further characterize the pharmacology
of the drug;

2. collect a check swab for DNA to allow study of the impact of single nucleotide
polymorphisms on drug handing and disease expression;

3. develop an assay or partner with others to develop an assay for oseltamivir and the
primary metabolite, oseltamivir carboxylate;

4. compare the pharmacokinetics of oseltamivir and its metabolite in each trimester of
pregnancy to evaluate whether gestational age has an impact on the drug's
pharmacokinetics;

5. assess the impact of fetal number on the drug's pharmacokinetics;

6. ask all participants about GI tolerance to the drug and any side effects they may be
experiencing, especially related to mood and psychiatric well being; and

7. on all pregnant subjects studied, when possible, we will obtain at delivery maternal
and umbilical cord blood to evaluate placental transport especially in those who
deliver proximate (within 3 days) to drug treatment.

Inclusion Criteria:

1. Taking or about to start oral oseltamivir for presumed influenza viral infection or
for prophylaxis

2. Able to give informed consent

3. Pregnant female with singleton or multifetal gestation or healthy
non-pregnant female (ancillary study)

Exclusion Criteria:

1. Unable to take medication orally

2. Renal failure - creatinine > 1.5

3. Hct <28