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Azithromycin Pharmacokinetics in Pregnancy

Azithromycin Pharmacokinetics in Pregnancy. James H. Fischer, Pharm.D ., FCCP. May 17, 2011. Azithromycin: Background. Macrolide Commonly administered for community acquired respiratory, skin and gynecological infections Among 15 most frequently prescribed drugs to pregnant women (2004)

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Azithromycin Pharmacokinetics in Pregnancy

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  1. Azithromycin Pharmacokinetics in Pregnancy James H. Fischer, Pharm.D., FCCP May 17, 2011

  2. Azithromycin: Background • Macrolide • Commonly administered for community acquired respiratory, skin and gynecological infections • Among 15 most frequently prescribed drugs to pregnant women (2004) • Dose derived from non-pregnant women & men • Practice disregards how dose requirements affected by pregnancy-related differences: • Pharmacokinetics • Functioning of immune system Piscitelli et al 1992; Andrade et al 2004; Jamieson 2006

  3. Azithromycin: Pharmacokinetics • Distinct profile • Incomplete oral absorption (34%) • Extensively distributes into tissues • Eliminated by hepatobiliary excretion • P-glycoprotein • Multidrug resistance protein-2 (MRP-2) • Only one previous PK study in pregnancy • Women from Papua-New Guinea receiving malarial prophylaxis Ballow et al 1998; Luke & Foulds 1997; Sugie et al 2004; Salmon et al 2010

  4. Objectives • Compare population pharmacokinetics of azithromycin between pregnant women and nonpregnant women of child bearing age • Identify factors contributing to the inter-individual variability in azithromycin pharmacokinetics

  5. Research Team • Co-Principal Investigator Gloria Sarto, M.D., Ph.D. • Brigham & Women’s Hospital, Harvard • Ruth Tuomala, M.D. • Karen McCarthy, R.N. • University of Illinois at Chicago Patricia Fischer, R.N. Mitra Habibi, Pharm.D. Sarah Kilpatrick, M.D. Keith Rodvold, Pharm.D. • University of Wisconsin Thomas Jenkins, M.D. Lori Wollett, R.N. • University of Michigan • Janet Shier, Pharm.D., M.D. • Zan Daley, R.N. • FDA Margaret Miller, Ph.D.

  6. Methods: Study Design • Pilot Study • Goals: • assist in establishing structural model • provide initial PK parameter estimates • 12 healthy adult women of child bearing age • Traditional Multi-Dose Pharmacokinetic Study • 500 mg *1, then 250 mg Q.D. for 4 days • Extensive sampling performed for 96 h following last dose • Typical eligibility criteria (except allowed OC use)

  7. Methods: Study Design • Population Pharmacokinetic Study • Prospective, open-label multicenter design • Participants • Women at least 18 years of age, • Capable of bearing children, • Receiving azithromycin for treatment of infection, and • Either • Pregnant and at least 12 weeks gestational age, or • Nonpregnant and at least 3 months postpartum.

  8. Methods: Study Design • Sparse sampling strategy • 5 samples collected within 4 sampling windows • First 3 with any dose, last 2 with final dose • Drug intake assessed by diary and interviews

  9. Methods: Laboratory Analysis • Azithromycin Plasma Concentrations • HPLC with electrochemical detection • linear: 10 – 505 ng/ml • LLOQ: 10 ng/ml • inter-assay precision: 3.2% to 5.8%

  10. Methods: Pharmacokinetic Analysis • Nonlinear mixed effects modeling (NONMEM) with FOCE method • Subjects with at least one evaluable azithromycin plasma concentration • Data from healthy women included in population PK database • Step 1: Identify structural (base) model • Step 2: Covariate Analysis • Step 3: Model validation

  11. Covariates • Body Size Measures total body weight lean body weight body mass index body surface area • Continuous Variables age gestational age creatinine clearance azithromycin dose • Categorical Variables pregnancy status Ethnicity study site type of infection concurrent medications oral contraceptives renal/hepatic disease administration with food healthy volunteer

  12. Structural Model • Three-Compartment PK model • Inter-individual variability (IIV) • exponential error • Residual variability • proportional error V-p2 CLD-P2 ka CLD-P1 V-p1 Vc [Lag time] CL

  13. Two-Compartment Three-Compartment

  14. Covariates: Oral Clearance (CL/F) • Body Size Measures total body weight lean body weight body mass index body surface area • Continuous Variables age gestational age creatinine clearance azithromycin dose • Categorical Variables pregnancy status ethnicity pregnancy-ethnicity (pregnant non-African Americans) study site type of infection concurrent medications oral contraceptives renal/hepatic disease administration with food healthy volunteer

  15. Covariate Models • Oral Clearance (CL/F) CL/F = 134 L/h + (Ethn × Preg × (-51)) + (OC × (-51)) × LBW/50

  16. Model Predicted CL/F for 50-kg Lean Body Weight (LBW) Woman

  17. Population PK Parameters: Model vs. Bootstrap Estimates

  18. Visual Predictive Check Nonpregnant women Pregnant African American women Pregnant Non-African American women Women receiving oral contraceptives

  19. Influence of Pregnancy and Ethnicity on CL/F * *p<0.05, compared to non-pregnant women who were not receiving oral contraceptives

  20. Influence of Oral Contraceptives on Cl/F * *p<0.05, compared to non-pregnant women who were not receiving oral contraceptives

  21. Conclusions • Ethnicity influences the effect of pregnancy on azithromycin CL/F • Compared to non-pregnant women, azithromycin CL/F during pregnancy is unchanged in African American women and 40% lower in non-African Americans • Concurrent administration of oral contraceptives (OCs) also reduced azithromycin CLoral

  22. Conclusions • Whether ethnicity also impacts the effect of OCs on CL/F requires further study as no African American women were in the OC cohort. • These findings suggest that estrogen or progesterone mediate the effects of pregnancy and OCs on azithromycin CL/F.

  23. Research in Pregnant Women Lessons Learned

  24. IRB Challenges • Vulnerable Population • Options to Participation (other drug options) • Coercion/Undue Influence • Inclusions of subjects < 18 y/o • Risks of Drug Therapy • Restrictions on concurrent drug therapy • Data Safety Monitoring Committee

  25. IRB Challenges • Frequency of Blood Sampling • Translated consent forms • Certificate of Confidentiality • Follow up Data Collection on Newborn • Consent • Blood sampling

  26. Overcoming Challenges • Request Pre-review with IRB staff • Study design: Population PK – missed clinic visit or time limitations have no impact on study integrity • Be prepared for additional scrutiny

  27. Reasons for not participating • Time commitment • Illness in addition to pregnancy – did not want additional burden • Aversion to needle sticks • Discomfort with 24 hr blood pressure monitor • Staff wore first to develop strategies

  28. Subject Recruitment Strategies • Involve Primary Physician • Assure physician that research is independent of clinical care • Provide overview to potential subject • Experienced Study Coordinator • Coordination with clinical care services • Other labs • Ultrasounds • Prolonged monitoring

  29. Subject Recruitment Strategies • Multiple sites • Adequate number of subjects • Diversity of population • Age • Ethnicity • Diagnosis • Liver/renal function • Body size

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