# Presentation: 184915

## Drug Therapy During Pregnancy and the Perinatal Period

**Marilynn C. Frederiksen, M.D.**
**Associate Professor Clinical Ob/Gyne**
**Feinberg Medical School,**
**Northwestern University**

## Pregnancy Physiology Potentially Affecting Pharmacokinetics

**Cardiovascular system**
**Plasma volume expansion**
**Increase in cardiac output**
**Regional blood flow changes**
**Respiratory Changes**
**Decrease in albumin concentration**
**Enzymatic activity changes**
**Increase in GFR**
**Gastrointestinal changes**

## Pregnancy Physiology Potentially Affecting Pharmacokinetics

**Cardiovascular system**
**Plasma volume expansion**
**Increase in cardiac output**
**Regional blood flow changes**

## Body Fluid Spaces in Pregnant and Nonpregnant Women

|  | 
WEIGHT
(kg) | 
PLASMA
 VOLUME
(mL/kg) | 
ECF
 SPACE
(L/kg) | 
TBW
(L/kg) |
| --- | --- | --- | --- | --- |
| NONPREGNANT | 
< 70
70 – 80
> 80 | 49 | 
0.189
0.156
0.151 | 
0.516
0.415
0.389 |
|     PREGNANT | 
< 70
70 – 80
> 80 | 67 | 
0.257
0.255
0.240 | 
0.572
0.514
0.454 |

**Frederiksen MC, et al. Clin Pharmacol Ther 1986;40:321-8.**

## Cardiovascular System Changes

**Plasma volume expansion**
**Begins at 6 - 8 weeks gestation**
**Volume of 4700 - 5200 ml peaks at 32 weeks gestation**
**Increase of 1200 - 1600 ml above ****	**** non-pregnant women**

## Cardiovascular System Changes

**Cardiac output increases  30 - 50%**
**50% by 8 weeks gestation**
**Increase in stroke volume and heart rate**
**Stroke volume in early pregnancy**
**Heart rate in later pregnancy**

## Regional Blood Flow Changes

**Increased blood flow to uterus - 20% of cardiac output at term**
**Increased renal blood flow**
**Increased skin blood flow**
**Increased mammary blood flow**
**Decreased skeletal muscle blood flow**

## HEPATIC BLOOD FLOW IN PREGNANCY

**HEPATIC BLOOD FLOW IN PREGNANCY**
**(% CARDIAC OUTPUT)**

**Robson SC, et al. Br J Obstet Gynaecol 1990;97:720-4.**

## Pregnancy Physiology Potentially Affecting Pharmacokinetics

**Cardiovascular system**
**Plasma volume expansion**
**Increase in cardiac output**
**Regional blood flow changes**
**Respiratory Changes**

## Respiratory Changes

**Compensated respiratory alkalosis**
**Lowered P****a****CO****2**
**pH 7.44**

## Pregnancy Physiology Potentially Affecting Pharmacokinetics

**Cardiovascular system**
**Plasma volume expansion**
**Increase in cardiac output**
**Regional blood flow changes**
**Respiratory Changes**
**Decrease in albumin concentration**

## PROTEIN CONCENTRATIONS DURING PREGNANCY AND POSTPARTUM

**PROTEIN CONCENTRATIONS DURING PREGNANCY AND POSTPARTUM**

**Frederiksen MC, et al. Clin Pharmacol Ther 1986;40:321-8.**

## Is The Hypoalbuminemia of Pregnancy Dilutional ?

**[GLOBULIN] IS NOT REDUCED**
**DISTRIBUTION VOLUME DOES NOT AFFECT C****SS**
**THEREFORE, ****↓**** [ALBUMIN] REFLECTS EITHER ****↓ ****SYNTHESIS RATE OR ****↑**** CL****E****.**

## Pregnancy Physiology Potentially Affecting Pharmacokinetics

**Cardiovascular system**
**Plasma volume expansion**
**Increase in cardiac output**
**Regional blood flow changes**
**Respiratory Changes**
**Decrease in albumin concentration**
**Enzymatic activity changes**

## Enzymatic Activity Changes

**Thought to be related to pregnancy hormonal changes**
**N-demethylation inhibited by progesterone, not by estrogen**

## CYP3A4

**Hydroxylation**
**Increased activity during pregnancy**

## CYP1A2

**Activity decreased progressively during pregnancy**
**Progressive lengthening of caffeine half-life**

## Caffeine Clearance – CYP 1A2

**Aldridge A, et al. Semin Perinatol 1981;5:310-4.**

## CYP2C9

**Activity shown to increase during pregnancy**
**Lowered total concentration of phenytoin during pregnancy**

## Phenytoin Plasma Concentrations during and after Pregnancy – CYP 2C9

**Tomson T, et al. Epilepsia 1994;35:122-30.**

## CYP2D6 Activity

**Genetic determined polymorphism**
**Increased clearance of metoprolol observed during pregnancy**
**Increased clearance in homozygous and heterozygous extensive metabolizers**
**No change in homozygous poor metabolizers**

**Wadelius M, etal. Clin Pharmacol Ther 1997; 62: 400.**

## Pregnancy Physiology Potentially Affecting Pharmacokinetics

**Cardiovascular System**
**Plasma Volume Expansion**
**Increase in Cardiac Output**
**Regional Blood Flow Changes**
**Respiratory Changes**
**Decrease in Albumin Concentration**
**Enzymatic Activity Changes**
**Increase in GFR**

## GFR DURING PREGNANCY AND POSTPARTUM

**GFR DURING PREGNANCY AND POSTPARTUM**

**Davison JM, Hytten FE. Br J Obstet Gynaecol Br Commonw 1974;81:588-95.**

## Pregnancy Physiology Potentially Affecting Pharmacokinetics

**Cardiovascular System**
**Plasma Volume Expansion**
**Increase in Cardiac Output**
**Regional Blood Flow Changes**
**Respiratory Changes**
**Decrease in Albumin Concentration**
**Enzymatic Activity Changes**
**Increase in GFR**
**Gastrointestinal Changes**

## Gastrointestinal Changes

**Decreased gastric acidity**
**Gastric emptying**
**Delayed in laboring women**
**No difference between 1st & 3rd ******
**No difference from postpartum**
**Increased orocecal transit time in 3rd ******
**Progesterone effect**
**Pancreatic polypeptide inverse correlation**

## Maternal Physiologic Changes Altering PK of Drugs

**Volume Expansion**

**  **

**CAFFEINE V****d**** (MARKER FOR TBW)**
** ****DURING PREGNANCY AND POSTPARTUM**

**Aldridge A, et al. Semin Perinatol 1981;5:310-4****.**

## THEOPHYLLINE Vd

**THEOPHYLLINE V****d**
** ****DURING PREGNANCY AND POSTPARTUM**

**Frederiksen MC, et al. Clin Pharmacol Ther 1986;40:321-8.**

**V****d**

## Maternal Physiologic Changes Altering PK of Drugs

**Volume expansion**
**Protein binding-increase in free fraction of drugs bound to albumin**

## THEOPHYLLINE PROTEIN BINDING

**THEOPHYLLINE PROTEIN BINDING**
** ****DURING PREGNANCY AND POSTPARTUM**

**Frederiksen MC, et al. Clin Pharmacol Ther 1986;40:321-8.**

**f**

**ALBUMIN**

## Theophylline Protein Binding

**Connelly TJ, et al. Clin Pharmacol Ther 1990;47:68-72.**

## Maternal Physiologic Changes Altering PK of Drugs

**Volume expansion**
**Protein binding**
**Clearance changes**

## THEOPHYLLINE RENAL CLEARANCE

**THEOPHYLLINE RENAL CLEARANCE**
** ****DURING PREGNANCY AND POSTPARTUM**

**Frederiksen MC, et al. Clin Pharmacol Ther 1986;40:321-8.**

**PREGNANT**

**POSTPARTUM**

## THEOPHYLLINE CLH AND CLINT DURING PREGNANCY AND POSTPARTUM

**THEOPHYLLINE CL****H ****AND CL****INT**** DURING PREGNANCY AND POSTPARTUM**

**Frederiksen MC, et al. Clin Pharmacol Ther 1986;40:321-8.**

## THEOPHYLLINE CLEARANCE DURING PREGNANCY AND POSTPARTUM

**THEOPHYLLINE CLEARANCE DURING PREGNANCY AND POSTPARTUM**

**Frederiksen MC, et al. Clin Pharmacol Ther 1986;40:321-8.**

## METHADONE CLEARANCE

**DURING AND AFTER PREGNANCY**
**(Primarily a CYP3A4 Substrate)**

**Pond SM, et al. J Pharmacol Exp Ther 1978;233:1-6.**

## Carbamazepine Plasma Concentrations During Pregnancy(Primarily CYP 3A4 Substrate)

**Tomsom T, et al. Epilepsia 1994; 35:122-30.**

## Phenytoin Plasma Concentrations during and after Pregnancy – CYP 2C9

**Tomson T, et al. Epilepsia 1994;35:122-30.**

## FREE AND TOTAL PHENYTOIN LEVELS(DOSE = 300 MG/DAY)

**[PHENYTOIN] ****μ****g/mL**

## CAFFEINE METABOLITE / PARENT DRUG RATIOS IN PREGNANT AND NON-PREGNANT EPILEPTIC WOMEN

**CAFFEINE METABOLITE / PARENT DRUG RATIOS IN PREGNANT AND NON-PREGNANT EPILEPTIC WOMEN**

**Bologa M, et al. J Pharmacol Exp Ther 1991;257:735-40****.**

*** *****P***** <  .05**
********** P***** <  .005**

## CAFFEINE METABOLITE / PARENT DRUG RATIOS IN HEALTHY PREGNANT AND NON-PREGNANT WOMEN

*****

******

******

*** P < 0.001**

**** P < 0.01**

**Tsutsumi K, et al. Clin Pharmacol Ther 2001; 70: 121.**

**NS**

## Betamethasone PK in Singleton and Twin Pregnancies

| Parameter |    Singleton    |       Twin |
| --- | --- | --- |
| Vd (L) |  67.5 ± 27.9 |   70.9 ± 28.4 |
| Cl (L/h) |    5.7 ± 3.1 |     8.4 ± 6.4 **
 |
| T1⁄2 (h) |    9.0 ± 2.7 |     7.2 ± 2.4 * |

*** P < .017**

**** P < .06**

**Ballabh P, et al. Clin Pharmacol Ther 2002; 71, 39.**

## Lamotrigine Clearance in Pregnancy

**Phase II biotransformation by  glucuronidation**
**Increased clearance in second and third trimesters ( > 65%)**
**May require dose adjustment**
**Rapid decrease in clearance in the first two weeks postpartum**

**Tran TA, et al. Neurology 2002; 59: 251-55.**

## Pharmacokinetics of Cefuroxime in Pregnancy

**Pt Category          V****D****(L)      CI(ml/min)    T(1/2)**
**Pregnant                17.8**_**+**_** 1.9        282**_**+**_**34*   44**_**+**_**5***
**At Delivery             19.3**_**+**_**3.1         259**_**+**_**35*   52**_**+**_**10**
**Postpartum             16.3**_**+**_**2.1        198**_**+**_**27      58**_**+**_**8**
***p<0.05 on comparison to PP**

## Tobramycin Pharmacokinetics

**Cl higher in mid-trimester with a corresponding shorter half-life**
**Cl lower in the third trimester with a corresponding longer half-life**
** **

**Bourget P, et al. J Clin Pharm Ther 1991;16:167-76**

## Metformin PK in Pregnancy

**C****max**** in pregnancy 81% lower than postpartum values**
**Mean metformin concentrations 69% of the postpartum values**
**Mean AUC for metformin during pregnancy is 80% of the postpartum AUC **

**Hughes RCE et al. Diabetes Medicine 23:323-6, 2006.**

## Heparin PK during Pregnancy

**Shorter time to peak heparin concentration and effect**
**Lower peak effect**

- Brancazio et al. Am J Obstet Gynecol 1995; 173: 1240.

## Enoxaprin PK during Pregnancy

**T****max**** shows no change **
**C****max**** lower during pregnancy**
**Cl decreases in late pregnancy**
**Lower anti-factor Xa activity**
**AUC lower during pregnancy**

- Casele, et al. Am J Obstet Gynecol 1999; 181: 1113.

## Maternal Physiologic Changes Altering PK of Drugs

**Volume expansion**
**Protein binding**
**Clearance changes**
**Gastrointestinal changes**

## Oral Ampicllin Pharmacokinetics in Pregnancy

**Parameter         ****	****	****Pregnant       Nonpregnant **
**AUC(cm****2****)          ****	****	****8.2**_**+**_**4.1             12.6**_**+**_**4.3***
**Peak Level (μg/ml)****	****	****2.2**_**+**_**1.0             3.7**_**+**_**1.5***
**Bioavailability (%) ****	****	****45.6**_**+**_**20.2       48.1**_**+**_**19.3****
**	****	****	****	****	****	****	****       ****	****	****	****	****                              ***** P < 0.001      ****	****	****	****	****	****	****    ** NS**

**Philipson A. J Inf Dis 1977;136:370-6.**

## PK of Oral Valacyclovir & Acyclovir

**The pro-drug Valacyclovir converted by first pass metabolism to Acyclovir**
**Non-pregnant Valacyclovir gives 3 - 5 times higher plasma level as Acyclovir**
**Valacyclovir PK study in pregnancy gave plasma levels 3 times higher than Acylovir  **

**Kimberlin DF, et al. Amer J Obstet Gynecol 1998; 179: 846**

## Peripartum Pharmacologic Considerations

**Increased cardiac output**
**Blood flow changes**
**Uterine contractions**
**? Pharmacodynamic changes**

## MORPHINE PHARMACOKINETICS DURING LABOR

**Gerdin E, et al. J Perinat Med 1990;18:479-87.**

**0**

**100**

**200**

** ****300**

**V****d**** (L)**

**p < 0.05**

## Pharmacokinetics of Cefuroxime in Pregnancy

**Category****	****     V****D ****(L)      ****	****        CI (ml/min)          T(1⁄2)**
**Pregnant         17.8**_**+**_** 1.9    ****	****282**_**+**_**34*  ****	****     44**_**+**_**5***
**At Delivery      19.3**_**+**_**3.1    ****	****           259**_**+**_**35*  ****	****     52**_**+**_**10**
**Postpartum      16.3**_**+**_**2.1    ****	****198**_**+**_**27    ****	****     58**_**+**_**8**
***p<0.05 on comparison to PP**

## Postpartum PK Considerations

**Increased cardiac output maintained **
**GFR increased**
**Diuresis**
**Breastfeeding**
**Great variability**

## Postpartum Clindamycin Pharmacokinetics

- Steen B, et al. Br J Clin Pharmacol 1982; 13: 661.

## Del Priore Obstet Gynecol 1996; 87: 994

**Del Priore Obstet Gynecol 1996; 87: 994**

## Drug Studies for Pregnancy

**Pregnancy Specific Drugs**
**Tocolytic agents**
**Oxytocic agents**
**Eclampsia agents**
**Drugs commonly used by women of childbearing potential**
**Antidepressants**
**Asthma drugs**

## Technical Considerations

**Ethical and IRB concerns**
**Serial studies**
**Spanning pregnancy**
**Specific to peripartum period**
**Controls**

## Study Design

**Use population PK analysis**
**Incorporate in vitro protein binding studies**
**Use stable isotopes for bioavailability studies**
**Use established tracer substances as reference markers**

## Teratogenesis

## General Principles of Teratology

**Teratogens act with specificity**
**Teratogens demonstrate a dose-response relationship**
**Teratogens must reach the conceptus**
**Effects depend upon the development stage when exposed**
**Genotype of mother and fetus effect susceptibility**

## General Principles of Teratology

**Teratogens act with specificity**

## PHOCOMELIA DUE TO THALIDOMIDE

**PHOCOMELIA DUE TO THALIDOMIDE**

## General Principles of Teratology

**Teratogens act with specificity**
**Teratogens demonstrate a dose-response relationship**

## DOSE-RESPONSE RELATIONSHIP

**DOSE-RESPONSE RELATIONSHIP**

## General Principles of Teratology

**Teratogens act with specificity**
**Teratogens demonstrate a dose-response relationship**
**Teratogens must reach the conceptus**

## Placental Transport

**Passive diffusion**
**P-glycoprotein expressed on trophoblastic cells of placenta**
**Active transport of P-gp substrates back to the mother**
**Pore system**
**Endocytosis**

## PHARMACOKINETIC MODEL OF MATERNAL-FETAL TRANSPORT

**DOSE**

**CL ****E**

**FETAL**
**EXCRETION +**
**METABOLISM**

## General Principles of Teratology

**Teratogens act with specificity**
**Teratogens demonstrate a dose-response relationship**
**Teratogens must reach the conceptus**
**Effects depend upon the development stage when exposed**

## All or Nothing Period

## Slide 72

## General Principles of Teratology

**Teratogens act with specificity**
**Teratogens demonstrate a dose-response relationship**
**Teratogens must reach the conceptus**
**Effects depend upon the development stage when exposed**
**Genotype of mother and fetus effect susceptibility**

## Phenytoin

**Animal evidence for an arene oxide (epoxide) reactive metabolite**
**Genetic susceptibility to the Dilantin Syndrome related to variation in Epoxide hydrolase activity  **

## Prenatal Diagnosis of the Fetus at Risk

**Prenatal Diagnosis of the Fetus at Risk**

**Buehler BA, et al. N Engl J Med 1990;322:1567-72.**

## Genetic Polymorphisms

**Increased risk of clefting in fetuses carrying atypical allele for transforming growth factor ******** whose mothers smoke**
**Decreased risk for fetal alcohol syndrome in African American women carrying alcohol dehydrogenase isoform 2**

## Mechanisms of Teratogenesis

**All theoretical**
**Most not understood well**
**Implications of a genetic component **

## Thalidomide

**Thalidomide causes DNA oxidation in animals susceptible to teratogenesis**
**Pre-treatment with PBN (free radical trapping agent) reduced thalidomide embryopathy**
**Suggesting that the mechansim is free radical-mediated oxidative DNA damage**

- Parman T,et al. Nature Medicine 1999; 5: 582

## Teratogen?

**Is there a specific pattern of abnormalities?**
**Was the agent present during development of that organ system?**
**Is there a dose-response curve?**
**Could there be a genetic component?**

## Evaluation of Drugs in Breast Milk

**Measure the M / P radio**
**Estimate breast milk dose**
**Estimate infant dose**
**Measure blood level in the infant**

## Drugs in Breast Milk

**Free drug transferred into milk**
**Milk concentrations usually less than serum concentrations**
**Exchange is bi-directional**

## KINETIC ANALYSIS OF THEOPHYLLINE 

**PLASMA**

**MILK**

**KINETIC ANALYSIS OF THEOPHYLLINE **
**PLASMA AND MILK CONCENTRATIONS**

## KINETIC ANALYSIS OF PREDNISOLONE 

**PLASMA**

**MILK**

**KINETIC ANALYSIS OF PREDNISOLONE **
**PLASMA AND MILK CONCENTRATIONS**

**SHADED AREA IS EXPECTED RANGE OF UNBOUND PLASMA CONC.**

## Factors Effecting the Milk / Plasma Concentration Ratio

**Maternal protein binding**
**Protein binding in milk**
**Lipid solubility of drug**
**Physiochemical factors of drug effecting diffusion**

## Drugs Generally Contraindicated during Lactation 

**Antineoplastics**
**Immune suppressants**
**Ergot Alkaloids**
**Gold**
**Iodine**
**Lithium carbonate**
**Radiopharmaceuticals**
**Social drugs & drugs of abuse**
**Certain antibiotics**

## General Recommendations

**Drugs considered safe for pregnancy are usually safe during lactation**
**Decrease the drug dose to the infant by feeding just prior to a dose**
**Infant blood levels can be monitored and should be less than therapeutic **