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Kaletra and Amprenavir Interaction
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Impact of ABT 378/r (Kaletra) on the amprenavir (APV) plasma concentrations
in HIV-experienced patients treated by the association APV-ABT 378/r
two reports are below
first report written by Scott Penzak, PharmD, NIH
Meynard et. al. reported an interesting interaction between
lopinavir-ritonavir (LPV-RTV) and amprenavir (APV).9 Plasma Cmin
concentrations were determined in consecutive patients receiving:
--LPV-RTV 400 mg-100 mg twice daily (n=11)
--APV 600 mg twice daily + RTV 100 mg twice daily (n=36)
--LPV-RTV 400 mg-100 mg twice daily + APV 600 mg twice daily (n=10)
--LPV-RTV 400 mg-100 mg twice daily + APV 750 mg twice daily (n=5)
All patients received concurrent NRTIs without NNRTI therapy. APV median
Cmins were:
--1,755 ng/mL (607-3066): APV 600 mg twice daily + RTV 100 mg twice daily
--778 ng/mL (190-2037): LPV-RTV 400 mg-100 mg twice daily + APV 600 mg twice
daily
--998 ng/mL (669-3066): LPV-RTV 400 mg-100 mg twice daily + APV 750 mg twice
daily
Median lopinavir Cmins were:
--3326 ng/mL (1316-6698): LPV-RTV 400 mg-100 mg twice daily
--2226 ng/mL (518-8722): LPV-RTV 400 mg-100 mg twice daily + APV 600 mg twice
daily
--1716 ng/mL (347-4810): LPV-RTV 400 mg-100 mg twice daily + APV 750 mg twice
daily
LPV-RTV appeared to markedly reduce APV exposure (by approximately 50%) in
this study (p < .001). Unfortunately, the wide interpatient variability in
APV concentrations and the small number of patients studied mandate that
results from this study be interpreted cautiously. Nonetheless, these results
support the use of a 750 mg twice daily dose of APV when given along with
LPV-RTV as recommended by the LPV-RTV product information (Abbott). Admin
istering APV 750 mg twice daily (with LPV-RTV) is expected to approximate
the systemic APV exposure achieved with conventional APV dosing (1200 mg
twice daily). When LPV-RTV is given concurrently with APV, it is probably
based on these data- not possible to achieve plasma APV concentrations
comparable to those achieved with APV 600 mg twice daily plus RTV 100 mg
twice daily. Also of note, is that fact that APV appeared to lower LPV-RTV
concentrations; but again, interpatient variability in LPV concentrations was
large. Future investigations assessing the interaction between LPV-RTV and
APV are being conducted in crossover fashion in order to reduce the impact of
interpatient variability (due to diet, concomitant drugs etc.) in the
disposition of these agents. Nonetheless, results from this study have
scientists speculating that lopinavir and amprenavir may induce the
CYP3A4-mediated metabolism of each other; further study is necessary to
confirm or refute such speculation.
APV + Kaletra: Is there an interaction here?
Written by Steve Piscatelli, PharmD, Tibotec-Virco
There has been much recent debate regarding the potential interaction between
Kaletra (lopinavir/ritonavir) and APV. Data from the recent HIV Clinical
Pharmacology meeting in Noordwijk, the Netherlands, earlier this year
suggested that there may be a detrimental interaction between these three
protease inhibitors.13 Investigators from France examined LPV and APV levels
in four groups of patients. Kaletra alone (n=11), APV/RTV 600/100 mg (n=36),
Kaletra + APV 600 mg (n=10), and Kaletra + APV 750 mg (n=5).14 Median trough
concentrations of APV 600 mg were decreased from 1755 ng/ml when given with
RTV alone to 778 ng/ml when given with Kaletra. Also, lopinavir troughs were
decreased from 3326 ng/ml alone to 2226 ng/ml with 600 mg APV and 1716 ng/ml
with 750 mg APV. These data are suggestive of a bi-directional drug
interaction lowering both PIs, however this study has limitations in both its
sample size and its design. A comparison of concentrations across different
patient groups is limited by a number of factors including immunologic
status, concomitant meds, diet, and demographics of the groups being
compared. The previous study also compared different patient groups or
compared the data from the combined Kaletra+ APV group to historical
controls. These two studies raise the question that there may be some
reduction in PI levels perhaps by induction of metabolism or other
mechanisms. Two studies with cross-over designs are currently underway and
may help to finally sort out this interesting interaction. From a clinical
standpoint, the concentrations of both APV and LPV in this study were still
adequate and well above the IC50 values, even for many resistant HIV strains.
The poster abstract reported APV Cmin remained >500ng/ml in all patients
except one; the impact of this interaction on the clinical efficacy of the
combination remains to be seen.
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