Transcript Steady-State Pharmacokinetic Evaluation of

Steady-State Pharmacokinetic Evaluation
of Emtricitabine in Neonates Exposed to
HIV In Utero
MR Blum,1 D Ndiweni,2 G Chittick,1 N Adda,1
D Kargl,1 and D Josipovic3
1Gilead
Sciences, Inc., Durham, North Carolina, USA; 2Department of Pediatrics,
Johannesburg Hospital, Parktown, South Africa; 3Perinatal HIV Research Unit,
Chris Hani Baragwanath Hospital, Soweto, South Africa
13th Conference on Retroviruses and Opportunistic Infections
February 5-9, 2006
Denver, Colorado
Poster No. 568
Introduction
• Emtricitabine (Emtriva®, FTC) is a potent, once daily (QD)
nucleoside reverse transcriptase inhibitor approved for the
treatment of human immunodeficiency virus (HIV) infection in
adults and children ≥ 3 months old in combination with other
antiretroviral (ARV) agents
• FTC pharmacokinetics (PK) in HIV-exposed infants were
examined following short-term multiple-dose administration
during the first 3 months of life in order to determine an
appropriate dose that would provide a drug exposure similar to
those achieved by regimens shown to be safe and efficacious
in pediatric patients ≥ 3 months old and adult patients
Blum MR, et al. 13th CROI, 2006; #568.
Background
• Main elimination route of FTC is via the kidneys into urine,
primarily as unchanged drug
• Full-term (36 weeks gestation or later) newborn infants
have immature kidney function (glomerular filtration rate
[GFR] = 40 mL/min/1.73m2) with values similar to adults
(GFR = > 90 mL/min/1.73m2) not achieved until > 8 weeks
postpartum.1 Therefore, dose adjustment to reflect
changing renal function was anticipated in this very young
patient
1. Schwartz GJ, Brion LP, Spitzer A. Use of Plasma Creatine Concentration for Estimating Glomerular Filtration Rate in
Infants, Children, and Adolescents. Pediatric Nephrology 1987; 34:571-590.
Blum MR, et al. 13th CROI, 2006; #568.
Objectives
• The primary objectives of the study were to:
– evaluate the PK of FTC over the first 3 months of life following
multiple-dose administration in children born to HIV-1 infected
mothers, and
– determine how the maturing renal function of neonates < 3 months
old affects FTC PK
• The secondary objective was to evaluate the safety of FTC
when administered to neonates < 3 months old
Blum MR, et al. 13th CROI, 2006; #568.
Methods
• Two study centers in South Africa enrolled up to 20 HIV-exposed
neonates born to women with confirmed HIV-1 infection
• Minimum ARV treatment for the women was IV zidovudine (ZDV)
or a single dose of nevirapine during delivery. In practice, women
in or close to the last trimester were identified and treated with
triple ARV drug therapy
• Each child received 6 weeks ZDV for HIV prophylaxis, starting
within 24 hours of birth
• Infants were enrolled in one of four groups in which two 4-day
courses of 3 mg/kg FTC QD, separated by an interval of
≥ 2 weeks, were administered to each infant. The timing of each
course was staggered between the groups (see Table 1) in order to
assure a continuum of PK assessments over the first 12 weeks of
life
Blum MR, et al. 13th CROI, 2006; #568.
Methods (cont’d)
• 48 hour PK evaluations were conducted following last FTC dose of
both FTC courses
• Plasma FTC concentrations were measured using validated
LC/MS/MS method
• PK analysis was conducted using standard non-compartmental
methods and parameters were summarized by age on day of PK
evaluation (0-21, 22-42, and 43-90 days)
• Safety evaluations (physical examination, vital signs and blood for
clinical laboratory testing) were performed at birth, at Weeks 2, 6,
12 and 24, and before and after the first and last dose of each FTC
course
Blum MR, et al. 13th CROI, 2006; #568.
Methods (cont’d)
• HIV-1 DNA and RNA testing was performed at birth and at
Weeks 6, 12 and 24. Positive test excluded child from study;
however, the child was provided ARV drugs though a post-protocol
program. Mothers were also given postpartum access to ARV
drugs through the same program
• Formula was provided to mothers to minimize postpartum
exposure to HIV through breast feeding
Blum MR, et al. 13th CROI, 2006; #568.
Schematic of FTC Dosing Schedule
Study Week
Group
1
2
3
4
1
2
X
3
4
5
6
7
8
9
10
11
12
<--------------X------------->
X
<--------------X------------->
X
<--------------X------------->
X
<----------------------X--------------------->
X = 3 mg/kg QD dose of FTC administered in AM for each of 4 consecutive days
Blum MR, et al. 13th CROI, 2006; #568.
Demographics
• All infants were black South Africans; 64% (16/22) were
male, and birth weights ranged from 2.0 to 3.8 kg
(mean: 2.9 kg)
Blum MR, et al. 13th CROI, 2006; #568.
Safety / Disposition
• Twenty-two infants were enrolled with 20 completing both
FTC courses and PK assessments
• One infant received three doses of first course FTC before
he was lost to follow-up, and a second infant was
discontinued due to anemia (Grade 3) prior to starting his
first course of FTC
• Bronchopneumonia and gastroenteritis in 1 subject and
bronchiolitis in 1 subject, all assessed as unrelated to ZDV
or FTC, were the only serious adverse events reported
• All 20 infants completing the study were determined to be
free of HIV infection at 6 months postpartum
Blum MR, et al. 13th CROI, 2006; #568.
Pharmacokinetics
• FTC exposure (AUC) in neonates receiving 3 mg/kg FTC
QD was in the range of pediatric patients ≥ 3 months old
receiving the recommended dose of 6 mg/kg QD and
adults receiving 200 mg QD (~10 hr*µg/mL)
• FTC AUC decreases with increasing age over the first
3 months of life, which correlates with an increase in total
body clearance (CL/F)
Blum MR, et al. 13th CROI, 2006; #568.
Mean (%CV) FTC PK Parameters by
Age on Day of Assessment
Age Range
(days)
N
Agea
(days)
Cmax
(µg/mL)
Cmin
(µg/mL)
AUC0-24
(hr*µg/mL)
t1/2
(hr)
CL/F
(mL/min)
0-21
18
13, 5-21
1.601
(28)
0.126
(41)
13.44
(28)
12.5
(23)
13
(31)
22-42
10
33, 23-42
1.416
(23)
0.065
(42)
8.55
(15)
11.5
(36)
22
(19)
43-90
12
55, 43-81
1.639
(52)
0.091
(89)
9.27
(48)
11.8
(21)
29
(64)
a. Mean, range
Blum MR, et al. 13th CROI, 2006; #568.
FTC AUC vs. Age in HIV-Exposed Neonates
25
AUC (hr*µg/mL)
20
AUC = -0.0994 * age + 14.032
15
R2 = 0.223
mL
g/10
h
C
(
U
A5
0
0
20
40
60
Age (days)
Blum MR, et al. 13th CROI, 2006; #568.
80
100
FTC CL/F vs. Age in HIV-Exposed Neonates
90
CL/F (mL/min)
80
)
70
CL/F = 0.3832 * age + 8.1922
60
R2 = 0.3615
50
40
30
CL/F
(mL/min
20
10
0
0
20
2
40
60
6
Age (days)
Blum MR, et al. 13th CROI, 2006; #568.
80
8
100
Conclusions
• A dose of 3 mg/kg FTC QD in neonates < 3 months old
produced plasma FTC exposure (AUC) similar to those
shown to be safe and efficacious in HIV-infected adults
and children ≥ 3 months old
• Short (4-day) courses of FTC dosed at 3 mg/kg QD
were safe and well tolerated in neonates < 3 months
old
Blum MR, et al. 13th CROI, 2006; #568.