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)• 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

• 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

• 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• 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 ChicagoPatricia Fischer, R.N.

Mitra Habibi, Pharm.D.

Sarah Kilpatrick, M.D.

Keith Rodvold, Pharm.D.

• University of WisconsinThomas Jenkins, M.D.

Lori Wollett, R.N.

• University of Michigan– Janet Shier, Pharm.D., M.D.– Zan Daley, R.N.

• FDAMargaret Miller, Ph.D.

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 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 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

• 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

• 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• Body Size Measures

total body weightlean body weightbody mass index

body surface area

• Continuous Variablesagegestational agecreatinine clearanceazithromycin dose

• Categorical Variablespregnancy statusEthnicitystudy sitetype of infectionconcurrent medicationsoral contraceptivesrenal/hepatic diseaseadministration with foodhealthy volunteer

DemographicsNumber 53 pregnant (12-40 weeks GA)

25 non-pregnant

Age (years) 28 (18-49)

Total Body Weight (kg) 76 (45-178)

Ethnicity

African American 19

Caucasian 42

Hispanic 9

Other 8

Creatinine Clearance (ml/min) 110 (37-229)

Indication for Azithromycin

Respiratory tract infection 41

Premature rupture of membranes 14

Chlamydia 8

Other 3

Healthy volunteer 12

Structural Model• Three-Compartment PK model

• Inter-individual variability (IIV)– exponential error

• Residual variability– proportional error

Vcka

V-p1CLD-P1

CL

V-p2

[Lag time]

CLD-P2

Time Following Initial Dose (h)

0 30 60 90 120 150 180 210 240 270 300

We

igh

ted

Resid

uals

-4

-3

-2

-1

0

1

2

3

4

Time Following Initial Dose (h)

0 30 60 90 120 150 180 210 240 270 300

We

igh

ted

Re

sid

ua

ls

-4

-3

-2

-1

0

1

2

3

4

Two-Compartment

Three-Compartment

Covariates: Oral Clearance (CL/F)• Body Size Measures

total body weightlean body weightbody mass index

body surface area

• Continuous Variablesagegestational agecreatinine clearanceazithromycin dose

• Categorical Variablespregnancy statusethnicitypregnancy-ethnicity (pregnant non-African

Americans) study sitetype of infectionconcurrent medicationsoral contraceptivesrenal/hepatic diseaseadministration with foodhealthy volunteer

Covariate Models

• Oral Clearance (CL/F)

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

LBW/50

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

Subjects CL/F (L/h)

Nonpregnant women of any race not receiving oral contraceptives 134

Pregnant African American women 134

Pregnant Non-African American women 83

Nonpregnant women receiving oral contraceptives (OC) 83

Population PK Parameters: Model vs. Bootstrap Estimates

Parameter Final Model Bootstrap (n=1000)

Estimate Median 2.5th - 97.5th Percentiles

ka (h-1) 0.8 --- ---

Lag time (h) 1.3 1.3 1.0 – 1.6

CL/F (l/h/50 kg LBW) 134 133 85 – 176

Pregnancy, non-African Americans -51 -44 -78 – -4

Oral Contraceptive Use -51 -44 -78 – -4

CLD-P1/F (l/h) 401 398 235 - 609

CLD-P2/F (l/h) 120 115 35 - 208

Vc/F (l) 456 436 189 - 716

VP-1/F (l) 1560 1630 925 - 3629

VP-2/F (l) 16100 17400 6124 - 31837

Inter-Individual Variability (CV, %)CL/F 36 34 16 - 49

CLD-P2/F (l/h) 86 86 3 - 133

Vc/F 114 116 75 - 161

VP-1/F 60 60 0.5 - 110

Residual error (%) 32 32 18 - 42

Visual Predictive Check

Time From First Dose (hours)

0 24 48 72 96 120 144 168 192

Azi

thro

myc

in P

lam

sa C

on

cen

trat

ion

s (n

g.m

l)

1

10

100

1000A

Time From First Dose (hours)

0 24 48 72 96 120 144 168 192

Azi

thro

myc

in P

lasm

a C

on

cen

trat

ion

(n

g/m

l)

1

10

100

1000B

Nonpregnant womenPregnant African American women

Pregnant Non-African American womenWomen receiving oral contraceptives

Influence of Pregnancy and Ethnicity on CL/FA

zith

rom

ycin

Ap

par

ent

Cle

aran

ce (

L/h

/50

kg L

BW

)

0

20

40

60

80

100

120

140

160

180

Number:

Pregnant:

Ethnicity:

15

No

All

36

Yes

Non-AfricanAmerican

17

Yes

African American

*

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

not receiving oral contraceptives

Influence of Oral Contraceptives on Cl/FA

zith

rom

ycin

Ap

par

ent

Cle

aran

ce (

L/h

/50

kg L

BW

)

0

20

40

60

80

100

120

140

160

180

Number:

Pregnant:

Ethnicity:

Oral Contraceptives:

15

No

All

No

10

No

Non-AfricanAmerican

Yes

*

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

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

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.

Research in Pregnant Women

Lessons Learned

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 Challenges• Frequency of Blood Sampling• Translated consent forms• Certificate of Confidentiality• Follow up Data Collection on Newborn

– Consent– Blood sampling

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

• 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

• 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 Strategies

• Multiple sites– Adequate number of subjects– Diversity of population

• Age• Ethnicity• Diagnosis• Liver/renal function• Body size