* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download "Gaps in our knowledge re pregnancy treatment"
Survey
Document related concepts
Discovery and development of beta-blockers wikipedia , lookup
Orphan drug wikipedia , lookup
Compounding wikipedia , lookup
Polysubstance dependence wikipedia , lookup
Psychopharmacology wikipedia , lookup
Neuropsychopharmacology wikipedia , lookup
Pharmacognosy wikipedia , lookup
Neuropharmacology wikipedia , lookup
Theralizumab wikipedia , lookup
Drug design wikipedia , lookup
Prescription drug prices in the United States wikipedia , lookup
Drug discovery wikipedia , lookup
Prescription costs wikipedia , lookup
Pharmaceutical industry wikipedia , lookup
Drug interaction wikipedia , lookup
Transcript
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 [email protected] 301 451 3823 Announcement on SMFM Web Site 2nd Annual Summer Institute Maternal-Fetal Pharmacology July 23–29, 2006 in Denver, CO http://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 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? Drug Development Basic 3 - 5 years $350 million Discovery Pre-Clinical Clinical Studies “Indication” 4 years $45 - 60 million Dosing and Safety Phase I Phase IIa Applied “In Practice” 2 – 4 years $90 – 150 million Safety and Efficacy Phase IIb Phase III Launch Phase IV In Obstetrics and Pediatrics the vast majority of clinical studies (for efficacy and/or safety) are done without knowledge of Submit New Drug Apply for Investigational New Drug (IND) Status pharmacokinetics and/or pharmacodynamics Application (NDA) • ~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 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 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? 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 Rx consumed by women of reproductive age in this population 0 1 2 3 ≥4 12% 24% 22% 16% 26% Therapeutic Class Antibiotics Respiratory GI Opioids 35% 14% 13% 8% Rx med use did not differ by trimester OTC Therapeutic Class Analgesics GI Respiratory Use of multiple OTC meds increased across gestation Herbals consumed as “medications” not dietary supplements Many indicated that herbals recommended by health care staff • dosing? • efficacy? • safety? 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 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 AJOG 2002; 187: 333 ~40% in PDR have pregnancy “risk” A B C D X 0.7% 19% 66% 7% 7% Drugs in Pregnancy – 2004, UTMB Drugs Prescribed FDA Class of Rx • • • • • • • • • • • • 35% Prenatal Vits 18% Antibiotics 16% Fe 5% Topical Creams 5% Antihistamines 4% Analges/Antipyr A B C D X U 1% 71% 25% 1% 1% 1% 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 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? 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 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 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 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 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 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 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 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 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 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? 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 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 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 Sex Differences Bioavailability – Oral – Transdermal – Bronchial F>M M=F M>F Distribution Volume – Water Sol – Lipid Sol M>F F>M Protein Binding – Albumen – Alpha 1 acid gp F=M M>F Sex Differences Renal – GFR – Tubular Secretion – Tubular Reabsorption M>F M>F M>F CYPs – Hepatic and ?others – CYP3A – CYP2D F>M M>F Conjugation – Glucur, Methyl – Acetyl M>F F=M 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% 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 The “Classic” View of PK-PD 3.5 6 3 5 2.5 Drug Effect Drug Concentration 7 4 3 2 1.5 2 1 1 0.5 0 0 0 5 10 15 20 25 0 2 Time • Pharmacokinetics (PK) • “What the body does to the drug” • Tools generally well developed – Not frequently applied in women, during pregnancy or in children 4 6 8 Drug Concentration • Pharmacodynamics (PD) • “What the drug does to the body” • Tools are being developed • Clinical relevance – Efficacy – Safety 10 Caffeine • Water soluble - Vd ↑, []↓ • Metabolized by CYP1A2* Metabolism ↓ during pregnancy Weeks Clearance Half-Life • 11 • 17 • 24 • 32 • PP 100% 68% 54% 37% 100% * Induced by cigarette smoking 5.3h 9.9h 12.6h 10h 5.5h Clin Pharmacol Ther 2001; 70: 121 Caffeine Metabolism Clin Pharmacol Ther 2001; 70: 121 Caffeine Metabolism 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) ↓ 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 CYP3A4 - Examples Drug Metabolic Change Nifedipine Clearance (CL) ↑30% Carbamazepine Concentration ↓18% Total & unbound [] ↔ Substantial ↓ at term Midazolam CL ↑ Indinavir Lopinavir Ritonavir AUC ↓ CL ↑ - P-gp? CL ↑ - P-gp? Peak/Trough [] ↓ ?binding 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) CYP2D6 - Examples Drug Dextromethorphan Metoprolol Fluoxetine Nortriptyline Metabolic Change Metab ↑50% EM Metab ↓60% PM CL ↑ w PO admin Protein binding ↔ Metab ↑ CL ↑ 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) Pregnancy Changes in Phase I & II Increased Decreased • CYP3A4 • CYP2D6 • CYP1A2 – EM, PM • • • • CYP2C9 CYP2A6 UGT1A4 UGT2B7 – Induced smokers • CYP2C19 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 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? The “Classic” View of PK-PD 3.5 6 3 5 2.5 Drug Effect Drug Concentration 7 4 3 2 1.5 2 1 1 0.5 0 0 0 5 10 15 20 25 0 2 Time • Pharmacokinetics (PK) • “What the body does to the drug” • Tools generally well developed – Not frequently applied in women, during pregnancy or in children 4 6 8 Drug Concentration • Pharmacodynamics (PD) • “What the drug does to the body” • Tools are being developed • Clinical relevance – Efficacy – Safety 10 Magnesium Sulfate • MgSO4 used to treat seizures, ↑BP for ~75 years – Optimum dosing, concentration and therapeutic range undefined – Mg bound to proteins ~50% • Total vs Free in assays – Pk - One vs Two compartment – what does body do to drug – Pharmacodynamics – what does drug do to body - BP PreTermLabor Free Total PreEclampsia Free Total Volume of Distribution Elimination Half-life 15,775 mL 577 min 15,667 mL 610 min 16,675 mL 313 min 24,260 mL 707 min MgSO4 Therapeutics • 2-Compartment model most appropriate • [Mg++] needs to be characterized • Disease state alters disposition • [Mg++] between 2 – 4 mmol/L produce more than half-maximal reduction in systolic & diastolic BP 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? The “Classic” View of PK-PD 3.5 6 3 5 2.5 Drug Effect Drug Concentration 7 4 3 2 1.5 2 1 1 0.5 0 0 0 5 10 15 20 25 0 2 Time • Pharmacokinetics (PK) • “What the body does to the drug” • Tools generally well developed – Not frequently applied in women, during pregnancy or in children 4 6 8 Drug Concentration • Pharmacodynamics (PD) • “What the drug does to the body” • Tools are being developed • Clinical relevance – Efficacy – Safety 10 Depression • Depression common in women of reproductive age – 10% - 16% during pregnancy – 12% - 16% postpartum • Necessary to treat – Maximize therapeutic efficacy – Minimize adverse effects Fluoxetine -------------------------- Norfluoxetine Oxidative N-demethylation CYP2D6 Citalopram----------------------Desmethyl-CIT (DMCIT) CYP 2C19, 2D6, 3A4 DMCIT---------------------Didesmethyl-CIT (DDMCIT) Oxidative N-demethylation CYP2D6 SSRI’s Treating Maternal Depression • Clinical characterization of SSRItreated depression - worsening during pregnancy – Severity increased at 28 – 32 weeks – SSRI dose increased 25% - 80% • Increases in maternal CYP 2D6 – Decrease [SSRI] across pregnancy – ? Other metabolic processes, transport Therapeutic Goals for Obstetrical Pharmacology • Given the class of drugs available what is the drug of choice? • How will results of treatment be judged? – Clinical signs & symptoms – Laboratory tests • How will toxicity & side-effects be evaluated? – Clinical or laboratory • How is treatment duration and schedule determined? Clinical Pharmacology for Obstetric Therapeutics • Absorption – how does pregnancy influence rate & amount reaching blood? • Distribution – how does pregnancy influence how the drug is distributed throughout body to site of therapeutic action & adverse effects? • Metabolism – how does pregnancy influence hepatic & renal mechanisms? • Elimination – pregnancy influences on clearance? Pharmacodynamics in Obstetric Therapeutics • Influence of pregnancy on site of action & adverse effects – Concentration of drug, metabolites at sites of biological action? – Mode or mechanism of action? – Impact on signs, symptoms, laboratory test results? Conclusions • Research Infrastructure – Academic centers with obstetric-pharmacology-basic science collaboration – NICHD - OPRU Network – Encourage research exploring ob-pharm • Education – Educational tools needed – Labeling needs to be improved – on both sides of parturition • Best practices – Therapeutic efficacy for intervention goals are poorly defined • Multi-agency effort needed – – – – Research & Academic infrastructure – NIH Education, Best Practice – AHRQ Clinical resources – HRSA Safety, efficacy and labeling - FDA Announcement on SMFM Web Site 2nd Annual Summer Institute Maternal-Fetal Pharmacology July 23–29, 2006 in Denver, CO http://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