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The Steady-state Pharmacokinetics of Efavirenz and Lopinavir/Ritonavir in HIV-infected Persons Requiring Hemodialysis: AIDS Clinical Trials Group Study A5177
Samir Gupta*1, S Rosenkranz2, Y Segal2, S Koletar3, M Basar4, L Szczech5, V Amorosa6, S Hall1, and AIDS Clin Trials Group 5177 Protocol Team
1Indiana Univ Sch of Med, Indianapolis, US; 2Statistical and Data Analysis Ctr, Harvard Sch of Publ Hlth, Boston, MA, US; 3Ohio State Univ, Columbus, US; 4Frontier Sci & Tech Res Fndn, Amherst, NY, US; 5Duke Univ Med Ctr, Durham, NC, US; and 6Univ of Pennsylvania, Philadelphia, US
Background: Efavirenz (EFV) and lopinavir/ritonavir (LPV/RTV) primarily undergo hepatic
metabolism. It has been assumed that renal failure does not influence their pharmacokinetics.
However, renal failure has affected the disposition of other drugs undergoing
extensive hepatic metabolism. The objectives of this study were to estimate the
pharmacokinetics of these agents in renal failure and compare to those with
normal renal function.
Methods: A prospective, observational study of the
steady-state pharmacokinetics of HIV-infected subjects requiring hemodialysis and
receiving either 1 once-daily 600-mg tablet of EFV (n = 13) or 3 twice-daily 133.3/33.3-mg capsules of LPV/RTV (n = 12) was conducted. Subjects were
excluded if other CYP450 inhibitors or inducers were prescribed. Ctrough, Cmax,
and AUC (24 and 12 hours for EFV and LPV/RTV, respectively, on non-dialysis
days) were compared to HIV-infected historical controls with normal renal
function using the bioequivalence method of calculating the geometric mean
ratio (GMR) and associated 90% confidence interval (CI). Inhibitory quotients
(IQ) for LPV were estimated by dividing Ctrough
by 0.07 µg/mL (wild type IC50).
Results: Median age and percentage of men were 47 years
and 92%, respectively, in both groups. Blacks represented 100% and 92% of the
EFV and LPV/RTV groups, respectively. The median CD4 cell counts were 360 and
271 for the EFV and LPV/RTV groups, respectively. All results are presented as
geometric means (95%CI; %CV). Mean AUC for EFV, LPV, and RTV of 58.0, 92.6, and
4.6 µg·h/mL, respectively, were used as historical
controls. The AUC GMR (90%CI) for EFV, LPV, and RTV were 132.3% (88.9, 197.0),
76.8% (64.5, 91.4), and 91.3% (72.5, 115.0), respectively. The median (range) Ctrough and IQ for LPV were 3.80 µg/mL (0.86 to 6.70), and 54 (12 to 96), respectively.
|
|
Ctrough(µg/mL)
|
Cmax(µg/mL)
|
AUC(µg·h/mL)
|
|
EFV
|
2.23 (1.19, 4.18; 99%)
|
5.04 (3.48, 7.29; 72%)
|
71.4 (43.1, 118.3; 93%)
|
|
LPV
|
3.47† (2.29, 5.23; 45%)
|
7.76 (6.23, 9.66; 34%)
|
66.0 (53.3, 81.8; 34%)
|
|
RTV
|
0.15† (0.09,
0.24; 53%)
|
0.58 (0.44, 0.76; 39%)
|
3.73 (2.83, 4.91; 38%)
|
†Data from
11 subjects
Conclusions: Using no-effect boundaries of 50 to 200%, the
AUC of EFV and LPV/RTV appear bioequivalent between HIV-infected subjects
requiring hemodialysis and those with normal renal function. Despite lower PK, LPV
IQ remained high. Dose adjustments for EFV and LPV/RTV in HIV-infected patients
requiring hemodialysis may not be necessary. Further studies are needed to
explain the large variability in EFV pharmacokinetics in this population.
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