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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

Azithromycin Pharmacokinetics in Pregnancy

James H. Fischer, Pharm.D., FCCP

May 17, 2011

azithromycin background
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

azithromycin pharmacokinetics
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

objectives
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
research team
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.

methods study design
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)
methods study design7
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.
methods study design8
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
methods laboratory analysis
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%
methods pharmacokinetic analysis
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
covariates
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

structural model
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

slide14

Two-Compartment

Three-Compartment

covariates oral clearance cl f
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

covariate models
Covariate Models
  • Oral Clearance (CL/F)

CL/F = 134 L/h + (Ethn × Preg × (-51)) + (OC × (-51)) ×

LBW/50

visual predictive check
Visual Predictive Check

Nonpregnant women

Pregnant African American women

Pregnant Non-African American women

Women receiving oral contraceptives

influence of pregnancy and ethnicity on cl f
Influence of Pregnancy and Ethnicity on CL/F

*

*p<0.05, compared to non-pregnant women who were

not receiving oral contraceptives

influence of oral contraceptives on cl f
Influence of Oral Contraceptives on Cl/F

*

*p<0.05, compared to non-pregnant women who were not receiving oral contraceptives

conclusions
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
conclusions23
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.
irb challenges
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
irb challenges26
IRB Challenges
  • Frequency of Blood Sampling
  • Translated consent forms
  • Certificate of Confidentiality
  • Follow up Data Collection on Newborn
    • Consent
    • Blood sampling
overcoming challenges
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
reasons for not participating
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
subject recruitment strategies
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
subject recruitment strategies30
Subject Recruitment Strategies
  • Multiple sites
    • Adequate number of subjects
    • Diversity of population
      • Age
      • Ethnicity
      • Diagnosis
      • Liver/renal function
      • Body size