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Pharmacokinetics of High-dose Lopinavir/Ritonavir with and without Saquinavir or NNRTI in HIV-infected Pediatric and Adolescent Patients Previously Treated with PI
Brian Robbins*1, P Havens2, E Capparelli3, E Chadwick4, R Yogev5, L Serchuck6, C Worrell7, C Alvero8, B Heckman9, J Rodman1, and PACTG 1038 Team
1St Jude Children's Res Hosp, Memphis, TN, US; 2Med Coll of Wisconsin, Children's Res Inst, Milwaukee, US; 3Univ of California, San Diego, US; 4Northwestern Univ, Chicago, IL, US; 5Children's Memorial Hosp, Northwestern Univ, Chicago, IL, US; 6Natl Inst of Child Hlth and Human Devt, NIH, Rockville, MD, US; 7Div of AIDS, NIAID, NIH, Bethesda, MD, US; 8Statistical & Data Analysis Ctr, Harvard Sch of Publ Hlth, Boston, MA, US; and 9Frontier Sci & Tech Res Fndn, Amherst, NY, US
Background: Successful protease inhibitor (PI) therapy
has been associated with the ratio of the Ctrough to the IC50
(inhibitory quotient) in individual subjects. Pediatric AIDS
Clinical Trials Group (PACTG) study P1038 used high-dose lopinavir
(LPV)/ritonavir (r), with or without saquinavir (SQV), to attain an inhibitory quotient
sufficient for viral suppression.
Methods: PACTG P1038
was an open-label, phase I/II study of high-dose LPV/r in HIV-infected children
and adolescents ages 2 to 18 failing >6 months of PI therapy with viral loads >5000 copies/mL
and LPV fold-change resistance ≥5 by phenotype resistance testing. Subjects
received LPV/r 400/100 mg/m2 every 12 hours (group 1, no concurrent non-nucleoside
reverse transcriptase inhibitor (NNRTI), maximum LPV dose 667 mg) or 480/120
mg/m2 by mouth every 12 hours (group 2, with concurrent NNRTI, maximum
LPV dose 800 mg). Intensive 12-hour pharmacokinetic sampling was performed at week
2 and SQV 750 mg/m2 every 12 hours (maximum dose 1600 mg) was added if
the week 2 LPV inhibitory quotient was <15. SQV pharmacokinetics was
determined at week 6. Pharmacokinetic
parameters were calculated using non-compartmental methods.
Results: Of 26 subjects enrolled, 19 completed initial pharmacokinetic
studies. Of 19 evaluable subjects (median age 14.2 years, range 7.7 to 17.6),
16 were in group 1, and 3 in group 2. Of the evaluable subjects, only 1 did not
require addition of SQV based on week 2 LPV inhibitory quotient.
Of the 20 patients scheduled for SQV, 4 were non-adherent, 2 of whom could not take the pills. The high doses of LPV/r with
or without SQV were well tolerated. Only 1 patient withdrew because of
hypersensitivity, but none because of drug toxicity,
and no increase in QTc was associated with these drug
exposures. The median inhibitory quotient was 1.3 with a range of 0.2 to 29.8. The
median (range) pharmacokinetic parameters are shown in the table. LPV exposure
showed high inter-subject variability, not correlated with age or gender.
Higher LPV doses plus concurrent NNRTI therapy compensated for induction
effects on LPV metabolism. Addition of SQV did not alter LPV pharmacokinetics.
Conclusions: A combination of high-dose LPV/r with SQV can
be safely used in children and adolescents with HIV infection.
|
Pharmacokinetics Parameters
|
LPV Pharmacokinetics
Group 1 (n = 16)
|
LPV Pharmacokinetics
Group 2 (n = 3)
|
LPV Pharmacokinetics
Overall (n = 19)
|
SQV Pharmacokinetics
Overall (n = 16)
|
|
AUC (µg*h/mL)
|
155.4
(62.8-305.5)
|
162.2
(63.8-185.7)
|
157.2
(62.8-305.5)
|
33.7 (4.4-76.5)
|
|
Cmax (µg/mL)
|
16.8
(6.7-29.8)
|
15.8
(8.28-7.2)
|
17.2
(6.7-29.8)
|
3.6 (0.6-8.3)
|
|
C0&C12
average (trough)(µg/mL)
|
10.5
(4.1-25.3)
|
10.8
(5.58-14.8)
|
10.8
(4.1-25.3)
|
2.1 (0.2-4.1)
|
|
CL (L/h/m2)
|
2.53 (
1.29-6.32)
|
3.01
(2.53-7.39)
|
2.58
(1.29-7.39)
|
23.1
(8.9-184.5)
|
|
