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Treatment During Pregnancy: Gaps in our Knowledge

Treatment During Pregnancy: Gaps in our Knowledge Donald R Mattison Obstetric and Pediatric Pharmacology Research Branch Center for Research for Mothers and Children NICHD, NIH, HHS mattisod@mail.nih.gov 301 451 3823

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Treatment During Pregnancy: Gaps in our Knowledge

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  1. Treatment During Pregnancy:Gaps in our Knowledge Donald R Mattison Obstetric and Pediatric Pharmacology Research Branch Center for Research for Mothers and Children NICHD, NIH, HHS mattisod@mail.nih.gov 301 451 3823

  2. Announcement on SMFM Web Site2nd Annual Summer Institute Maternal-Fetal PharmacologyJuly 23–29, 2006 in Denver, COhttp://www.circlesolutions.com/summerinstitute • National Institute of Child Health and Human Development • Office of Research on Women’s Health • Institute of Human Development, Child and Youth Health • Canadian Institutes of Health Research

  3. Treatment During Pregnancy:Gaps in our Knowledge • Introduction • Frequency of Drug Use in Pregnancy • Sex Differences in Drug Safety • Sex Differences in Pharmacokinetics • Case Studies • MgSO4 • Antidepressants • Where do we go from here?

  4. Drug Development Applied “In Practice” Clinical Studies “Indication” Basic 3 - 5 years $350 million 4 years $45 - 60 million 2 – 4 years $90 – 150 million Dosing and Safety Safety and Efficacy Pre-Clinical Launch Discovery Phase IV Phase I Phase IIa Phase IIb Phase III • In Obstetrics and Pediatrics the vast majority of clinical • studies (for efficacy and/or safety) are done without knowledge of pharmacokinetics and/or pharmacodynamics • ~75% of drugs used in pediatrics not tested in kids • most drugs used in women and during pregnancy not tested in either nonpregnant or pregnant women Submit New Drug Application (NDA) Apply for Investigational New Drug (IND) Status

  5. Obstetric and Pediatric Pharmacology • Pediatric Pharmacology Research Network • 13 sites, ~180,000 inpatient, > 2 million outpatient, >200 clinical studies • Best Pharmaceuticals for Children Act of 2002 • Collaboration with 15 ICs: 9 clinical trials, 7 pre-clinical studies • Obstetric Pharmacology Research Network • Established Fall 2004: 2 clinical trials, 5/40 opportunistic • 4 Sites: UTMB, Magee, U Washington, Georgetown

  6. Treatment During Pregnancy:Gaps in our Knowledge • Introduction • Frequency of Drug Use in Pregnancy • Sex Differences in Drug Safety • Sex Differences in Pharmacokinetics • Case Studies of Pharmacokinetics and Pharmacodynamics in Pregnancy • MgSO4 • Antidepressants • Where do we go from here?

  7. AJOG 2003; 188: 1039 • Identify medications used in rural ob population • 28 month study • 578 women interviewed across pregnancy • 96% of participants given Rx medication • 93% self medicated with OTC medication • 45% self medicated with Herbal product

  8. Rx consumed by women of reproductive age in this population 0 12% 1 24% 2 22% 3 16% ≥4 26%

  9. Therapeutic Class Antibiotics 35% Respiratory 14% GI 13% Opioids 8% Rx med use did not differ by trimester

  10. OTC Therapeutic Class Analgesics GI Respiratory Use of multiple OTC meds increased across gestation

  11. Herbals • consumed as • “medications” not • dietary supplements • Many indicated • that herbals • recommended • by health care staff • dosing? • efficacy? • safety?

  12. Lancet 2000; 356, 1735 • Survey of records from French Health Insurance Service • 1000 women in SW France • 99% received Rx during pregnancy • mean 13.6 meds per woman • 79% received Rx for a drug for which there was no knowledge of safety

  13. Nature of the drugs may be more worrying • than the numbers taken. • widespread prescription of meds for which • no proven efficacy • dosing may not be appropriate for pregnancy • no data to evaluate fetal effects

  14. AJOG 2002; 187: 333 ~40% in PDR have pregnancy “risk” A 0.7% B 19% C 66% D 7% X 7%

  15. Drugs Prescribed 35% Prenatal Vits 18% Antibiotics 16% Fe 5% Topical Creams 5% Antihistamines 4% Analges/Antipyr FDA Class of Rx A 1% B 71% C 25% D 1% X 1% U 1% Drugs in Pregnancy – 2004, UTMB

  16. Frequency of Use and Indications • Broad multi-agent exposure to Rx, OTC and herbals in women of reproductive age and pregnancy • Labeling for dosing, efficacy and safety during pregnancy inadequate • Literature resources on dosing, efficacy, safety for women – non-pregnant or pregnant - are not available

  17. Treatment During Pregnancy:Gaps in our Knowledge • Introduction • Frequency of Drug Use in Pregnancy • Sex Differences in Drug Safety • Sex Differences in Pharmacokinetics • Case Studies of Pharmacokinetics and Pharmacodynamics in Pregnancy • MgSO4 • Antidepressants • Where do we go from here?

  18. Sex Differences • Sex differences noted in animal models ~1932 • F rats required half the dose of barbiturates, compared to M to induce sleep • Duration of sleep substantially longer in F given same dose as M • Sex differences noted in subsequent studies (pharmacology & toxicology/safety); rat, mouse, rhesus, beagle, cat, rabbit, hamster, goats, cattle, trout, humans • Before 1993 under-representation of F in clinical trials was mandated by US FDA • Excluded from phase I/II clinical trials and did not encourage participation in later phases • Concern focused on two factors; hormonal variations across ovarian cycle & potential for pregnancy

  19. Adverse Drug Reactions F experience more adverse reactions to drugs than M (GAO, 2001) • Evaluated the 10 drugs withdrawn from US market from Jan ’97 – Dec ‘2000 • Eight had evidence of greater health risks in F identified from post-marketing data • 3 introduced before 1993, 5 after 1993 • Two with no evidence of greater health risks in F using post-marketing data • Both introduced after 1993

  20. Adverse Drug Reactions F experience more adverse reactions to therapeutic drugs than M • F overdosed; pk differences • Drug interactions; F take more medications than M • Difference is artifact; F report adverse reactions more frequently • F experience adverse reactions more frequently; pk, pd differences

  21. Adverse Drug Reactions pk differences; F overdosed? • Volume of distribution different • Hepatic metabolism different? • Sex specific CYP’s, drug transporters • ~ Half of drugs on market are metabolized by CYP3A, transported by P glycoprotein (liver, GI?) • pk modestly successful in predicting adverse drug reactions

  22. Adverse Drug Reactions F take more medications than M; drug interactions? • F start medication use earlier, contraceptives and reproductive system • F use ~60% of all medications • Unclear what proportion of adverse events are due to drug interactions

  23. Adverse Drug Reactions F report adverse reactions more frequently; difference is artifact? • Reports of adverse drug reactions is proportional to drug usage by M, F • Adverse reactions reported by F are more severe than those reported by M

  24. Adverse Drug Reactions Adverse events reported by F more frequently than by M (FDA database – voluntary reporting of adverse events) • Torsades de points • QT prolongation • Agranulocytosis • Bleeding • Pancreatitis • Renal toxicity • Liver toxicity

  25. Adverse Drug Reactions Torsades de points, QT prolongation • Torsades de points – fatal heart arrhythmia associated with delayed repolarization and prolonged QT • Androgens enhance repolarization and shorten QT • Decreases M heart susceptibility to QT prolongation effects of drugs

  26. Adverse Drug Reactions Acute Liver Failure • ~2000 cases/yr in US • >50% due to medications • ~75% occur in F • Fatality rate among F ~80% • Unclear if pk or pd differences account for the differential

  27. Treatment During Pregnancy:Gaps in our Knowledge • Introduction • Frequency of Drug Use in Pregnancy • Sex Differences in Drug Safety • Sex Differences in Pharmacokinetics • Case Studies • MgSO4 • Antidepressants • Where do we go from here?

  28. Pharmacokinetic Factors Absorption • GI: • Transit time F≤ M, vary with Progesterone • Transit time increased in pregnancy • Transport and metabolism systems, P glycoprotein (P-gp)? • Skin: F=M • Lungs: proportional to respiratory rate and depth • F minute ventilation < M • Changes during cycle • Pregnant F minute ventilation > M (Progesterone) • Complain of feeling “short of breath” • Inhaled insulin

  29. Pharmacokinetic Factors Distribution • Protein Binding • Albumen F≈M • Alpha 1 acid glycoprotein F<M, • Free fraction drugs F >M • Diminished during pregnancy • Body Composition • Fat content F>M • F from 33% to 48% with aging • M from 18% to 36% with aging • Body water, fat increase across pregnancy

  30. Pharmacokinetic Factors Metabolism (Data – limited/conflicting) • Drug Transporters • P-gp M>F, may decrease hepatic metabolism • Role in transport and metabolism remains unclear • Phase I Enzymes • Oxidation • CYP3A, overlap in substrates with P-gp • Phase II Enzymes • Conjugation • M≥F, UDP-GT, Sulfotransferases, Methyltransferases • M=F, N-Acetyltransferases

  31. Sex Differences Bioavailability • Oral F>M • Transdermal M=F • Bronchial M>F Distribution Volume • Water Sol M>F • Lipid Sol F>M Protein Binding • Albumen F=M • Alpha 1 acid gp M>F

  32. Sex Differences Renal • GFR M>F • Tubular Secretion M>F • Tubular Reabsorption M>F CYPs – Hepatic and ?others • CYP3A F>M • CYP2D M>F Conjugation • Glucur, Methyl M>F • Acetyl F=M

  33. Sex Differences Analysis of data submitted to CDER/FDA • 28% of data sets demonstrated significant sex differences • Sex differences in drug exposure could be greater than 50%

  34. Impact of Pregnancy – pk/pd • Sex differences in pk/pd • ADME • Pregnancy extends & alters impact on ADME • Cardiac output, regional blood flow • Body composition, protein binding • Transport proteins • Phase I and Phase II metabolism • Impact on therapeutic strategies

  35. Pharmacokinetics (PK) “What the body does to the drug” Tools generally well developed Not frequently applied in women, during pregnancy or in children Pharmacodynamics (PD) “What the drug does to the body” Tools are being developed Clinical relevance Efficacy Safety The “Classic” View of PK-PD

  36. Caffeine • Water soluble - Vd ↑, []↓ • Metabolized by CYP1A2* - Metabolism ↓ during pregnancy Weeks Clearance Half-Life • 11 100% 5.3h • 17 68% 9.9h • 24 54% 12.6h • 32 37% 10h • PP 100% 5.5h * Induced by cigarette smoking

  37. Clin Pharmacol Ther 2001; 70: 121 Caffeine Metabolism

  38. Clin Pharmacol Ther 2001; 70: 121 Caffeine Metabolism

  39. Caffeine Metabolism in Pregnancy Metabolic Step Change in Pregnancy • Transport proteins ? • Phase I metabolism • CYP1A2 (M>F) ↓ • XO (M=F) ↔ • 8-Hydroxylation (M?F) ↑ • Phase II metabolism • N Acetyltransferase (M=F) ↓

  40. CYP3A4 • Most abundant CYP450 in liver and GI • 30% of total cytochrome P450 • Broad substrate specificity • Metabolizes >50% of drugs • Activity/amount increased during pregnancy • Caveats • Substrate overlap with P-gp • ? Unbound plasma concentration • Time course across pregnancy undefined

  41. CYP3A4 - Examples Drug Metabolic Change Nifedipine Clearance (CL) ↑30% Carbamazepine Concentration ↓18% Total & unbound [] ↔ Substantial ↓ at term Midazolam CL ↑ Indinavir AUC ↓ CL ↑ - P-gp? Lopinavir CL ↑ - P-gp? Ritonavir Peak/Trough [] ↓ ?binding

  42. CYP2D6 • Second most common enzyme responsible for drug metabolism • >40 drugs • Increases in latter portion of pregnancy • Increase only observed in homozygous and heterozygous extensive metabolizers (EM) • No change or decrease across pregnancy among poor metabolizers (PM)

  43. CYP2D6 - Examples Drug Metabolic Change Dextromethorphan Metab ↑50% EM Metab ↓60% PM Metoprolol CL ↑ w PO admin Protein binding ↔ Fluoxetine Metab ↑ Nortriptyline CL ↑

  44. Phase II - Glucuronidation - Examples Drug Metabolic Change Lamotrigine CL ↑ 2-3x (UGT1A4) Zidovudine CL (↑ 50%) ↔ (UGT2B7) Morphine CL ↑ 70% (UGT2B7) Oxazepam CL ↑ 160% (UGT2B7, 2B15, 1A9)

  45. Increased CYP3A4 CYP2D6 EM, PM CYP2C9 CYP2A6 UGT1A4 UGT2B7 Decreased CYP1A2 Induced smokers CYP2C19 Pregnancy Changes in Phase I & II

  46. Renal Elimination • Drugs Cleared by Renal Mechanisms • Ampicillin, Cefuroxime, Ceftazidime, Cephradine, Cefazolin, Piperacillin, Atenolol, Sotalol, Digoxin, Lithium, …. • Renal Clearance increases 20% - 60% beginning in first trimester

  47. Treatment During Pregnancy:Gaps in our Knowledge • Introduction • Frequency of Drug Use in Pregnancy • Sex Differences in Drug Safety • Sex Differences in Pharmacokinetics • Case Studies • MgSO4 • Antidepressants • Where do we go from here?

  48. Pharmacokinetics (PK) “What the body does to the drug” Tools generally well developed Not frequently applied in women, during pregnancy or in children Pharmacodynamics (PD) “What the drug does to the body” Tools are being developed Clinical relevance Efficacy Safety The “Classic” View of PK-PD

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