609 
Pharmacologic Management of the Drug-Drug Interaction between Lopinavir/Ritonavir and Amprenavir
H E Wynn Vezina*1, R C Brundage1, L Bushman2, and C V Fletcher2
1Univ. of Minnesota, Minneapolis, USA and 2Univ. of Colorado Hlth. Sci. Ctr., Denver, USA
Background:
Decreases in plasma concentrations of
lopinavir/ritonavir (LPV/r) or amprenavir (APV) have been described when these
protease inhibitors (PI) are co-administered. Appropriate management of this
drug-drug interaction is not known. We describe pharmacokinetic management of
this interaction in HIV+ subjects starting salvage therapy with
LPV/r/APV.
Methods:
This is a 24-week prospective study of LPV/r 400/100
mg and APV 600 mg taken every 12 hours with NRTI. HIV RNA, CD4 count, and
metabolic panel were checked at weeks 0, 4, 12, and 24. Lipids were measured at
weeks 0 and 12. After 2 weeks of therapy, LPV and APV plasma concentrations
were determined over 12 hours using HPLC. Noncompartmental methods (WINNONLIN)
were used to calculate LPV CL/F and AUC0-12h. Due to late peaks,
compartmental methods (ADAPT II) were used to predict APV AUC0-12h.
Doses of LPV/r and APV were adjusted if pharmacokinetic parameters were lower
than published values. Sparse PI levels were checked monthly.
Results:
The median (range) week 2 pharmacokinetics, and week
12 virologic and immunologic response data were available for 12 subjects. Baseline HIV RNA (copies/mL) and CD4 count (cells/mm3)
were 4.8log10 (4.0 to 5.0) and 137 (0 to 645), respectively. Pharmacokinetics
for LPV were C12h (ng/mL) = 1639 (833 to 9966), AUC0-12h (h*ng/mL)
= 42,206 (23,005 to 140,131) and CL/F (L/h) = 8.1 (1.4 to 12.9). LPV C12h
and AUC0-12h were 3- and 2-fold lower, respectively, than the
manufacturer’s reported average Ctrough (5500 ng/mL) and AUC0-12h
(82,800 h*ng/mL). Median CL/F was higher than the 6-7L/h reported in the
package insert. Pharmacokinetics for APV were C12h (ng/mL) = 1228
(195 to 3342) and AUC0-12h (h*ng/mL) = 22,435 (5996-36,990). Median
values were similar to those reported for APV/r 600/100mg. Of 12 subjects, 6
(50%) had LPV/r dose increases (533/133 mg, n
= 2; 666/166 mg, n = 4) and 3/12
(25%) had APV dose increases (750 mg, n
= 2; 900 mg, n = 1). One subject
decreased LPV/r to 267/67 mg secondary to diarrhea. At 12 weeks, HIV RNA
(copies/mL) decreased to 2.5log10 (1.3 to 5.0) and CD4 count
(cells/mm3) increased to 225 (10 to 710). In 6 subjects with LPV
dose increases, median C12h (ng/mL) went from 960 (833 to 2943) to
4465 (1752 to 7841). No adverse events resulted from PI dose increases.
Conclusions: Pharmacokinetic
parameters for LPV/r/APV were highly variable, indicating the magnitude of the
interaction was poorly predictable. LPV/r dose adjustments were more common
than APV. Optimal management of the complex interaction between LPV/r and APV
may require pharmacokinetically-guided dose individualization.
Keywords: drug interaction; lopinavir; amprenavir
