# Presentation: 724064

## Research Recommendations from the NICHD Workshop on the Need to Study Drugs During Pregnancy

**Research Recommendations from the NICHD Workshop on the Need to Study Drugs During Pregnancy**

**Raymond L. Woosley, MD, PhD**
**President, American Society for Clinical Pharmacology and Therapeutics**
**Associate Dean for Clinical Research**
**Georgetown University Medical Center**
**Washington, DC**

## General Observations, NIHCD Sept. 2000: 

**General Observations, NIHCD Sept. 2000: **

**Pregnancy, a subset of patients that requires special consideration in therapeutics**
**Inadequate data are available to optimally prescribe most medications for these patient**
**Many pregnant patients are not receiving needed medications**
**Many patients require medicines and their fetuses are exposed to unknown risks**

## The Opportunity 

**The Opportunity **

**There are medical conditions unique to pregnancy**
**There are medical conditions more common in pregnancy**
**If risk to the fetus can be prevented, greater use of medications can improve the medical care of pregnant patients**

## Diseases Requiring Treatment During Pregnancy 

**Diseases Requiring Treatment During Pregnancy **

**Thromboembolic Diseases****	****	****	****	****Asthma**
**Hypertension (Preg. Induced and chronic)****	****	****Epilepsy**
**Diabetes Mellitus****	****	****	****	****	****	****Migraine**
**Sexually Transmitted diseases****	****	****	****	****Psychosis**
**Collagen Vascular Diseases****	****	****	****	****Depression**
**Recurrent Pregnancy Loss****	****	****	****	****Anxiety**
**Hyperemesis gravidarum**** **

## Common Problems During Pregnancy Often Requiring Rx 

**Common Problems During Pregnancy Often Requiring Rx **

**Allergy**
**Headaches**
**Colds**
**Sleep**

## The Model for Improved Therapeutics 

**The Model for Improved Therapeutics **

**Basic Research**

**Confirmatory Clinical Trials**

**Therapeutic Guidelines**

**Improved Outcomes**

**Clinical Pharmacologic Research**

## The Adjusted Model for Improved Therapeutics in Pregnancy 

**The Adjusted Model for Improved Therapeutics in Pregnancy **

**Basic Research**

**Confirmatory Clinical Trials**

**Improved Outcomes**

**Exploratory Clinical Pharmacologic Research**

**Meta-Analysis/Clin Trials**

## Exploratory Clinical Pharmacologic Research  Techniques

**Biomarkers**
**Radio-receptor assays (bioassays)**
**Stable Label Isotope PK Studies**
**PK/PD Modeling**
**NonMEM Regression Analyses**
**Computer Simulations**

## Biomarkers

**A measure of drug action that is directly correlated with clinical benefit or harm.**

**ECG Intervals**
**	****QRS – Sodium channel blockers**
**	****QT – Potassium channel blockers**
**EEG Changes – Benzodiazepines**
**Viral Load – Protease inhibitors**
**FIO****2**** – Bronchodilators**

## ECG Interval Measurement

## Sotalol pharmacokinetic simulation

**Time (hours)**

**Concentration (mg/l)**

**0**

**72**

**144**

**216**

**288**

**360**

**432**

**504**

**576**

**648**

**720**

**Arm 1**
**(standard dose escalation)**

**Arm 2**
**(rapid dose escalation)**

## Pharmacodynamic modeling of QTc

**Time (hours)**

**Arm 1**
**(standard dose escalation)**

**Arm 2**
**(rapid dose escalation)**

**400**

**410**

**420**

**430**

**440**

**450**

**460**

**470**

**480**

**490**

**500**

**0**

**48**

**96**

**144**

**192**

**240**

**288**

**336**

**384**

**432**

**480**

**528**

**576**

**624**

**672**

**720**

**QTc (msec)**

***Rebound***

## Define PD relationship to clinical endpoint

**0**

**0.02**

**0.04**

**0.06**

**0.08**

**0.1**

**0.12**

**0**

**20**

**40**

**60**

**80**

**100**

**120**

**140**

**160**

**QTc Prolongation (Msec)**

**TdP Risk in First Month**

## Ibutilide infusion in men and women

**Ibutilide infusion in men and women**

## Ibutilide infusion in men and women

**Menses**

**Ovulation**

**Luteal**

**Males**

**0.0**

**0.5**

**1.0**

**1.5**

**2.0**

**2.5**

**p< 0.05**

**p< 0.05**

**AUC (QTc sec . min)**

## Ibutilide Response Vs Progesterone Concentration

## Active Drug

- Target Tissue

- Active Metabolites
- Active isomers
- Non-Protein Bound

## Classical Pharmacokinetics 

**Classical Pharmacokinetics **

**Twelve Homogenous Subjects**
**Multiple (8-20) blood samples timed the same**

**100-200 Inhomogenous Subjects**
**One blood sample each at random times**
**Logistic Regression Analysis**

**NonMEM Pharmacokinetics **

**(Non-linear Mixed Effect Modeling) **

## Pregnancy 

**Pregnancy **

**A unique medical condition that requires novel research tools and approaches:**
**Modern Clinical Pharmacology Methods**
**Patient Registries, Targeted and Screening**
**Web-based Registries**

## Urgent Needs for Educational Programs

**Urgent Needs for Educational Programs**

**FDA Modified Label and Pregnancy Categories**
**Professional Societies:  Practice guidelines**
**USP-DI Off label indications**
**Medical, Nursing and Pharmacy Schools**
**	****Scientific Facts**
**	****Prescribing Skills**
**	****Attitudes**

## Coordinated Research Needed

**Coordinated Research Needed**

**Maternal Fetal Network**
**Perinatal Centers**
**Pediatric Clinical Pharmacology Research Units**
**Centers for Education and Research on Therapeutics**
**FDA Pharmacoepidemiology Network**
**Pharmaceutical Industry Research**

## Barriers to Progress

**Barriers to Progress**

**Ethics of multiple patients**
**Litigious Society**
**Inadequate Funding for Research**
**Inadequate numbers of trained clinical investigators**
**Inadequate incentives for industry**
**Inadequate funding for FDA**

## Continued Progress Requires a Permanent Forum

**Continued Progress Requires a Permanent Forum**

**A National Center for the Study of Medications During Pregnancy**