Clinical Discussion of Specific Populations Zhixia (Grace) Yan,

Clinical Discussion of Specific Populations Zhixia (Grace) Yan, Ph.D. Office of Clinical Pharmacology, Division 4 Office of Translational Sciences Center for Drug Evaluation & Research Disclaimer The opinions contained in this presentation are my own and do not necessarily represent the views of the FDA. 2 One Size Does Not Fit All www.fda.gov 3 Specific Populations

www.fda.gov Women Pregnant women Pediatrics Geriatrics Obese patients Patients with organ dysfunction 4 Phase 1 vs. Phase 3 Demographics Demographic Factor

Phase 1 subjects Age Usually 18-65 Pregnancy Excluded Predominantly Caucasian Race www.fda.gov Renal/Hepatic Function Normal

Weight BMI usually lower than 25 kg/m2 Phase 3 patients Higher % of older patients (>65 yr) Excluded diversity in ethnic background Often have at least minor degrees of impairment Greater % of overweight patients 5 Women

Women appear to be more sensitive to QT interval prolongation following anti-arrhythmic drug administration. Disease progression can also manifest differently between men and women (e.g., multiple sclerosis). Estrogen levels may play a role in altered drug pharmacokinetics in women by affecting gastric emptying (i.e., change drug transit time between non-pregnant women, throughout pregnancy, and at menopause). Women tend to have a lower body weight, higher percentage body fat, and lower plasma volumes than men. Differences in body composition

also influence the absorption and distribution of drugs. 6 Ambien (zolpidem tartrate) in Women Sleeping aid, approved in the U.S. in 1992 FDA Med Watch Safety Alert (2013)1 Lower Doses Recommended for Sleep Drugs Especially for Women Risk: New data show that blood levels in some people who take zolpidem may be high enough in the morning after use to impair activities that require alertness, including driving. This risk is highest for people who take products containing extendedrelease zolpidem. Women are especially vulnerable because zolpidem is cleared from the body more slowly in women than in men. http://www.fda.gov/forconsumers/consumerupdates/ucm340655.htm#2 1

www.fda.gov 7 Pregnant Women Ideally, no drugs would be needed in pregnancy Not realistic Percentage of pregnant women on a prescription medication Estimates vary, but probably between 60-90% Average age of first time mothers in the US 1 1970: 21.4 years 2006: 25.0 years Proportion of first time births to women over 35 is what it was in 1970 8-fold Just like everyone else, women need effective and safe treatment during pregnancy Figures from CBS news; online story dated 8/14/09

1 www.fda.gov 8 Physiological Changes During Pregnancy Changes in body weight and body fat composition Increase in blood volume Altered gastrointestinal motility Increase in glomerular filtration rate Altered hepatic enzyme activity (Cytochrome P450s) All of these factors affect drug pharmacokinetics

Lab measure and vital sign changes as well Respiratory rate Heart rate, BP pCO2 www.fda.gov AST/ALT Hgb and HCT Creatinine 9 Amoxicillin Concentration-Time Profiles in 16 Subjects During Pregnancy and Postpartum 500 mg amoxicillin single oral dose Amoxicillin renal clearance was markedly higher during pregnancy than postpartum www.fda.gov

Andrew et al Clinical Pharmacology and Therapeutics 2007 81(4) pp 547-556 10 Placenta www.fda.gov Drugs taken by a pregnant woman reach the fetus primarily by crossing the placenta. The human placenta is not a semipermeable membrane it is a metabolic organ that makes enzymes and hormones and changes throughout gestation.

The placenta contains drug transporters and efflux pumps. The human placenta is structurally and functionally different from those in rodents and rabbits. 11 melia a effect o The Thalidomide Tragedy Sedative used for morning sickness in late 1950s

Withdrawn from market due to teratogenicity and neuropathy Many children in the 1960's were born with phocomelia as a side effect of the drug thalidomide, resulting in the shortening or absence of limbs. www.fda.gov Thalidomide was not approved in the U.S. for morning sickness due to lack of safety data, but there were thousands of victims worldwide 12 When to conduct a pharmacokinetics

(PK) study in pregnant women? Per the 2004 Draft FDA Guidance1, PK studies in pregnant women are useful in the following situations: Known to be prescribed or used by pregnant women, especially in 2 nd or 3rd trimesters For a new drug or indication, if there is anticipated or actual use in pregnancy Usage is expected to be rare, but the consequences of under- or overdosing are great (e.g., narrow therapeutic range drugs, cancer chemotherapy) Pregnancy is likely to alter significantly the pharmacokinetics of a drug (e.g., renally excreted drug) Guidance for Industry, Pharmacokinetics in Pregnancy Study Design, Data Analysis, and Impact on Dosing and Labeling, Draft Guidance, 2004 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072133.pdf 1 www.fda.gov 13 PK Study Design Considerations for Pregnant Women

Large randomized controlled trials not practical or usually needed Guidance suggests longitudinal or population PK study design Find the right dose Lower or less frequent doses can be considered to minimize fetal risk, while maintaining the efficacy in pregnant women Dose can be adjusted based on PK target or patients response Safety monitoring Maternal effects Fetal effects Animal reproductive studies inform study design Some studies seek to determine whether the animal studies are predictive www.fda.gov

14 What About Lactating Mothers? A Case Study Case Study1: A newborn infant born after an unremarkable pregnancy and delivery (birth weight 3.88 kg) developed difficulty breastfeeding and increased lethargy at 7 days of age. At 11 days of age, he was taken to a pediatrician owing to concerns about his skin color and decreased milk intake. The pediatrician noted that the infant had regained his birth weight. Subsequently on day 13, an ambulance team found the baby cyanotic and without vital signs. Resuscitation was unsuccessful. Review of the medical records revealed that the mother was prescribed Tylenol 3 (codeine 30 mg and acetaminophen 500 mg). Initially she took 2 tablets twice daily, but she halved the dose on postpartum day 2 owing to somnolence and constipation. She continued taking Tylenol 3 for 2 weeks. As reported in Madadi et al Canadian Family Physician 2007 Vol 53 pp 33-35 1

www.fda.gov 15 Case Study Continued Analysis of frozen breast milk from the mother revealed an unexpectedly high morphine concentration. The mother was later determined to be a CYP2D6 ultra-rapid metabolizer, which led to excessive conversion of codeine to morphine by the mother. The morphine was then excreted into the breast milk and consumed by the child. In 2007, FDA issued a public health advisory: when prescribing codeine for a nursing mother, doctors should prescribe the lowest dose for the shortest amount of time to relieve pain or cough1. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm054717.htm 1

www.fda.gov 16 When to conduct a Clinical Lactation Study? Per the 2005 Draft FDA Guidance1, clinical lactation studies are useful in the following situations: A drug under review for approval is expected to be used by women of reproductive age After approval, use of a drug in lactating women becomes evident (e.g., via reports in the medical literature or lay press) A new indication is being sought for an approved drug and there is evidence of use or anticipated use of the drug by lactating women Marketed medications that are commonly used by women of reproductive age (e.g., antidepressants, antihypertensives, antiinfectives, diabetic and pain medications) Guidance for Industry, Clinical Lactation Studies Study Design, Data Analysis, and Recommendations for Labeling, Draft Guidance, 2005 http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm127505.pdf 1 www.fda.gov

17 Clinical Study Design Considerations for Lactating Women Mother-Infant Pair Design Determine the PK of the drug in lactating women Determine the amount of drug transferred into breast milk Show effects of drug on milk production and composition Assess drug exposure and PD in the breast-fed child Lactating Women Only Designs Plasma and milk Milk only Other Design Considerations Longitudinal or multiple arm design Guidance for Industry, Clinical Lactation Studies Study Design, Data

Analysis, andsize, Recommendations Study participants, controls, sample etc for Labeling, Draft Guidance, 2005 http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm127505.pdf 18 Pediatric Population Vulnerable Population cant consent Laws address public health importance for pediatric therapies Established regulations (BPCA and PREA) Is there a need for this product to be developed for use in children? www.fda.gov

19 Are Kids Just Small Adults? Not Exactly! Absorption Gastric acidity, gastric emptying, surface area of absorption Distribution Changes in body composition, total body water, adipose tissue, protein binding Metabolism Differential expression of metabolic enzymes Excretion GFR, tubular secretion and tubular reabsorption can mature at different rates Other Factors

Differences in immune response, CNS development, vital signs, lab values www.fda.gov 20 Renal Function Maturation National Kidney Foundation KDOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification www.fda.gov 21 Hepatic Metabolism is also Variable CYP450 expression is generally low in fetal tissue, but expression increases with age CYP450 Expression is also influenced by diet and exposure to environmental toxins Several common CYP450 enzymes are

polymorphic (2D6, 2C9, 2C19) www.fda.gov 22 Example - Argatroban Anticoagulant for heparin induced thrombocytopenia Predominantly excreted in feces via biliary secretion Metabolized by CYP3A4/5 (metabolites not as potent) Dose initially studied in neonates led to increase in serious bleeding PK analysis showed need for decreased dose in neonates due to lower hepatic metabolism1 1 www.fda.gov : See Madabushi et al J Clin Pharmacol 2011 51(1) pp 19-28

23 Example - Linezolid Single-Dose PK of Linezolid in Pediatrics and Adults1 Age Group Birth to <11 yrs (10 mg/kg) 12 yrs and older (600 mg) Cmax (g/mL)g/mL) AUC (g/mL)g*h/ mL) CL (mL/min/ kg) Full term neonates (28 days) 11.5-12.9

34-55 3.8-5.1 Infants (1-3 months) 11.0 33 5.4 3 months 11 years 15.1 58 3.8

Adolescents (12-17 years) 16.7 95 2.1 Adults 12.5 91 1.7 Dose recommendation for pediatric patients1: Pediatric patients (<11 yrs): 10 mg/kg every 8 hours Pediatric patients (>12 yrs): 600 mg every 12 hours (Same as adults) ZYVOX (linezolid) labeling; http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021130s030,021131s029,021132s034lbl.pdf

1 www.fda.gov 24 Approach to Pediatric Studies Children cannot consent to participate in clinical trials. No such thing as a healthy volunteer Children enrolled in trial must have the potential for direct benefit. www.fda.gov FDA Regulations Protection of Human Subjects 21 CFR 50

Subpart A: General Provisions Subpart B: Informed Consent Subpart D: Safeguards for Children in Clinical Investigations 25 Approach to Pediatric Studies What is the safety knowledge from adult use? Phase 1,2,3 studies in adults may provide evidence of potential safety concerns Adult post-market information may provide insight to rare adverse events of particular interest in pediatrics (Stevens-Johnson) www.fda.gov 26 Pediatric Study Decision Tree

Guidance for Industry - General Clinical Pharmacology Considerations for Pediatric Studies for Drugs and Biological Products, Draft Guidance, 2014 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM425885.pdf 27 PREA: Pediatric Research Equity Act BPCA: Best Pharmaceuticals for Children Act Extended FDAs authority to require and request pediatric studies PREA requires pediatric assessment of drugs/biologics if application is for: new indication, new dosage form, new route of administration, new dosing regimen, or new active ingredient If a company wants the financial benefit of increased exclusivity (BPCA) they MUST have a formal Written Request from FDA and fulfill it. www.fda.gov 28

PREA and BPCA PREA Has helped tremendously in getting medications approved in children BPCA Not required by law Increased exclusivity offered Studies can be more challenging than PREA www.fda.gov 29 Geriatric Population Many age cutoffs to delineate this group, but most in need of special considerations are > 70 years Often enrolled in Phase 3 trials (e.g. chronic diseases) Source: United Nations. World Population Prospects www.fda.gov

30 Major Organ Functions in Geriatric Population Renal Function Decline with age Higher systemic exposure of drugs ADME Altered absorption due to gut motility Liver function Higher systemic exposure www.fda.gov Host Defense Diminished cellmediated immunity

CNS Function Declines with age Less CNS reserve Physical effects (balance, hearing) Psychological effects 31 Ambien (zolpidem tartrate) in Geriatrics Adult dose: 10 mg once daily Geriatric patients and patients with hepatic impairment: 5 mg once daily ADME Cmax, half-life, and exposure increased Converted to inactive metabolites which are then renally eliminated www.fda.gov

32 Geriatric Research Challenges Growing population and getting older Unlikely to participate in early trials Dedicated study or Pop PK approach? Complications of informed consent Impact of co-morbidities and medications (polypharmacy) www.fda.gov 33 Scientific Advances in Specific Population Research Application of modeling and simulation technique Inform design/conduct of clinical studies Improve drug development efficiency

Advances in PK sampling (e.g. dried blood spots) Reduce invasiveness and blood volume (robust PK studies) As science grows so will our understanding of benefit/risk of a medication in specific populations www.fda.gov 34 Tools: References Growth Charts http://www.cdc.gov/growthcharts/ Vital Signs http://clinicalcenter.nih.gov/ccc/pedweb/pedsstaff/age.html

Laboratory Values http://clinicalcenter.nih.gov/ccc/pedweb/pedsstaff/pedlab.html#blo Guidance documents http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidan ces/ucm121568.htm www.fda.gov 35

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