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The PACTG 1020A Protocol: Atazanavir with or without Ritonavir in HIV-infected Infants, Children, and Adolescents
Richard Rutstein*1, P Samson2, J Kiser3, C Fletcher3, B Graham4, S Schnittman5, M Smith6, L Mofenson6, T Fenton2, G Aldrovandi7, and the PACTG 1020A Study Team
1Children's Hosp of Philadelphia, PA, US; 2Harvard Sch of Publ Hlth, Boston, MA, US; 3Univ of Colorado Hlth Sci Ctr, Denver, US; 4Frontier Sci & Tech Res Fndn, Amherst, NY, US; 5Bristol-Myers Squibb, Wallingford, CT, US; 6NIH, Bethesda, MD, US; and 7Children's Hosp Los Angeles, CA, US
Background: The Pediatric AIDS Clinical Trial Group (PACTG)
1020A is a phase I/II study of atazanavir (ATV) ± ritonavir (r) with 2 nucleoside
reverse transcriptase inhibitors (NRTI) (excluding tenofovir DF) in
HIV-infected children (91 days to 21 years) from the United States and South Africa
to determine the safety, pharmacokinetics, and optimal dosage of ATV powder (p)
and capsules (c). Children are treatment naive or experienced with
pheno-susceptibility to ATV (IC50-fold change <10) and RNA ≥5000
copies/mL. Dosing levels for age/formulation
cohorts are determined by protocol-driven pharmacokinetics targets and safety
criteria.
Methods: Dosing was started at 310 mg/m2 for
each group and adjusted based on day 7 24-hour intensive pharmacokinetics and
safety results of the first 5 patients in each cohort. Cohort dose acceptance
criteria were: AUC ≥30 µg*hour/mL
and C24 ≥60 ng/mL in 4of 5 patients, no AUC <15 µg*hour/mL, and median
AUC for 5 patients ≤60 µg*hour/mL. Safety criteria were: no life-threatening toxicities, ≤1 grade
3 or 4 toxicity (not including bilirubin), ≤2 patients with total
bilirubin values >5.1xULN. If pharmacokinetics and safety criteria were not
met, the cohort starting dose was modified. If pharmacokinetics and safety
criteria were met, 5 additional patients were enrolled at that dose. Cohort
optimal dose was defined as ≥10 evaluable patients with acceptable pharmacokinetic
and safety results.
Results: We have enrolled 172 subjects, 69% from the United States of whom 109
remain on study; 6 dosing cohorts remain open with doses that passed pharmacokinetic
and safety targets: group 3, 2 to 13 years
on ATVc; group 4, >13 years on ATVc; group 5, <2 years on ATVp/r; group 6,
2 to 13 years on ATVp/r; group 7, 2 to 13 years on ATVc/r; group 8, >13 years
on ATVc/r. Pharmacokinetics, RNA response at 24 weeks, and selected safety
(bilirubin and electrocardiogram abnormalities) results on the first 10 patients
in each cohort are shown in the table.
Conclusions: Once daily ATV±r boosting can be dosed in
children to achieve target pharmacokinetic parameters with an acceptable safety
profile and viral load decrease. When administering powder formulation,
ritonavir boosting is required to obtain protocol-defined pharmacokinetic
parameters.
|
Group
|
Median
Age
|
Median
Dose mg/m2
|
Median
Dose
mg
|
Median
AUC
µg*hr/ mL
|
Median
Cmax
µg/mL
|
Median
C24hr ng/mL
|
Median
log
change viral load
|
# ≤400 copies/mL week24
|
# Tbili >5.1
ULN
|
#
Abm
PR
|
|
3c
|
10.2
|
511.0
|
600
|
42.3
|
7.2
|
317.6
|
–1.23*
|
5/9
|
1
|
6
|
|
4c
|
15.0
|
600.0
|
900
|
67.1
|
7.0
|
676.4
|
–0.58
|
1/6
|
2
|
2
|
|
5p/r
|
1.2
|
321.0
|
150
|
33.8
|
7.4
|
373.0
|
–2.40*
|
7/8
|
0
|
1
|
|
6p/r
|
4.8
|
306.5
|
200
|
51.2
|
4.5
|
1045.2
|
–1.88*
|
8/10
|
0
|
1
|
|
7c/r
|
9.7
|
212.0
|
250
|
43.7
|
4.9
|
634.0
|
–1.10*
|
5/8
|
2
|
2
|
|
8c/r
|
17.0
|
194.5
|
375
|
41.9
|
3.9
|
887.5
|
–1.48
|
3/5
|
3
|
1
|
*p = <0.05 (Wilcoxon signed rank test)
|
