766a
Increased Lopinavir Concentrations on Once-daily Tablets as Compared with Capsules and Liquid Formulations
Brookie Best*1, G Rieg2, S Sun1, S Jain1, C Kemper3, C Diamond4, A Hermes5, R Haubrich1, E Daar2, and California Collaborative Treatment Group (CCTG) 585 Team
1Univ of California, San Diego, US; 2Los Angeles Biomed Res Inst at Harbor-UCLA Med Ctr and Univ of California, Los Angeles, US; 3Santa Clara Valley Med Ctr, San Jose, CA, US; 4Univ of California, Irvine, US; and 5Abbott Labs, Abbott Park, IL, US
Background: Lopinavir/ritonavir (LPV/r) is one of
the Department of Health and Human Services Guidelines' preferred protease
inhibitors (PI). The capsule formulation is effective when dosed once-daily in HIV-infected
antiretroviral (ARV) -naïve subjects; however, plasma LPV Cmin was
variable. The pharmacokinetics of the existing liquid and newer tablet
formulations dosed once-daily in HIV-infected subjects have not been reported.
Methods: CCTG 585 is an ongoing, phase IV,
prospective, randomized, open-label, multi-center switch study. Subjects on a
stable, well-tolerated regimen with plasma HIV-1 RNA <75 copies/mL sequentially
switched their PI to once-daily LPV/r 800/200 mg as the liquid, capsule, and
tablet formulations. This pharmacokinetic sub-study measured LPV and ritonavir
(RTV) concentrations at 3 study visits at least 2 weeks after starting each
formulation. Blood was drawn at pre-dose, 2, 4, 6, 8, 12, and 24 hours
post-dose, and assayed by validated reversed-phase high-performance liquid
chromatography (HPLC). Noncompartmental pharmacokinetic parameters were estimated
with WinNonlin version 5. Descriptive statistics and Paired Wilcoxon Rank Sum
tests were used to compare pharmacokinetic parameters among formulations.
Results: Of 17 subjects, 15 were male, age 41±10
years, weighed 78±13 kg**, and completed the pharmacokinetic
sub-study. LPV exposure for once-daily LPV/r taken as liquid and capsules were
similar, but increased when taken as the tablet formulation. RTV results were
similar to LPV results. Of the 3 samples that were below detection, 2 were in
the liquid arm, and 1 was in the tablet arm. The median Cmin/IC50
ratio (wild type IC50 = 0.08 µg/mL) for tablets is approximately
double that of capsules and liquid (46 vs 20 and 25).
|
LPV pharmacokinetic parameter; median (IQR)
|
Liquid
|
Capsule
|
Tablet
|
|
AUC0-24 (µg·h/mL)
|
150 (110 to 185)
|
199 (133 to 248)
|
236 (178 to 276)†
|
|
Cmax (µg/mL)
|
11.4 (9.2 to 14.2)
|
14 (10.1 to 16.2)
|
16.5 (15 to 18.8)*†
|
|
Cmin (µg/mL)
|
1.1 (0.3 to 3.6)
|
1.6 (0.7 to 4.2)
|
3.7 (1.2 to 7.4)*
|
|
Cl/F (L/h)
|
5.3 (4.3 to 7.3)
|
4 (3.2 to 6)
|
3.4 (2.9 to 4.5)†
|
**Mean±SD; * p <0.05 tablets
vs capsules; † p <0.05 tablets vs liquid; Cl/F = oral clearance.
Conclusions: This is the first report comparing the pharmacokinetics
of LPV/r liquid, capsules, and tablets taken once-daily in HIV-infected subjects.
Within-subject LPV exposures were generally higher with the tablet compared to
liquid and capsule formulations at the same dose. The Cmin/IC50
ratio of once-daily tablets is similar to that seen historically with
twice-daily capsule dosing, and may afford some clinical benefit.
|
