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Assessment of the Multiple Dose Pharmacokinetic Interaction of
Lopinavir/ritonavir with Nelfinavir
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Abbott researchers (R Bertz et al) presented this poster abstract at the 10th
Conference on Retroviruses and Opportunistic Infections, Boston, MA, February
2003.
Brief summary: Study examined drug blood levels in healthy volunteers of
standard Kaletra dose (400/100 mg twice daily) with lower dose of nelifinavir
than is usually administered. Standard dose of nelfinavir is 1250 mg twice
daily. Study found Kaletra levels decrease, but nelfinavir levels were the
same as if using 1250 mg of nelfinavir. Abbott researchers suggest
considering higher Kaletra dosing when combining it with nelfinavir,
particularly in patients with PI resistance or reduced Kaletra susceptibility.
Background: The HIV PIs nelfinavir (NFV) and lopinavir/ritonavir (LPV/r) are
substrates for and inhibitors of CYP3A, as well as metabolic inducers. The
purpose was to assess the effects of coadministration of LPV/r and NFV on
pharmacokinetic parameters of LPV, ritonavir (RTV), NFV and the
hydroxy-t-butylamide metabolite of NFV (M8). The multiple-dose
pharmacokinetic interaction between NFV and LPV/r has not previously been
assessed. At clinical concentrations, LPV/r and NFV inhibit CYP3A-mediated
metabolism and are also metabolic inducers.
The objective of this study is to assess:
- The effect of LPV/r on the pharmacokinetics of NFV after multiple dosing.
- The effect of NFV on the pharmacokinetics of LPV/r after multiple dosing.
This was a multiple-dose, sequential, open-label, single-center, non-fasting,
drug interaction study. Fourteen healthy subjects were enrolled and 13
subjects completed the study; one subject prematurely discontinued for
personal reasons. Each subject received LPV/r 400/100 mg BID for 21 days.
NFV, 1000 mg BID, was coadministered with LPV/r starting with the evening
dose of day 11 through the morning of day 21. NFV, 1250 mg BID, was
administered alone from the evening of day 21 to 35. Plasma samples were
collected pre-dose and up to 12 hours after the morning dose on days 11, 21
and 35. Concentrations of LPV, RTV, NFV and M8 were determined using LC/MS/MS
and analyzed by noncompartmental methods. Parameter estimates were compared
by paired t-test.
RESULTS
Safety results:
--The most frequently reported treatment-emergent adverse events during the
study were diarrhea, headache, nausea, abdominal pain and anorexia.
--No serious adverse events or discontinuations due to adverse events
occurred during the study.
--No new safety concerns were identified as a result of 10 days of concurrent
administration of NFV and LPV/r.
LPV C max , AUC 12 and C trough were significantly decreased during NFV
coadministration by 21, 27 and 33%, respectively. LPV median (range) ratio of
C trough to IC 50 for wt-HIV (IQ) was reduced from 105 (55 to 235) to 76 (30
to 136) during NFV; similar decreases in RTV concentrations were noted.
NFV 1000 mg BID in combination with LPV/r 400/100 mg BID produced a similar
AUC 12 and C max and higher C min compared to that produced by NFV 1250 mg
BID alone; the NFV median IQ was similar despite a 20% lower NFV dose.
LPV/r also substantially increased concentrations of the active M8 metabolite
of NFV; M8 C max , AUC 12 and C min were increased by 2.4-, 3.5- and
7.5-fold, respectively.Coadministration with LPV/r resulted in similar NFV IQ
of 2.3 (0.7 to 7.3) alone and 2.2 (1.2 to 15.9) during LPV/r.
Safety profiles were not altered with concomitant administration.
The authors concluded that NFV decreases the bioavailability of both LPV and
RTV, while LPV/r increases the dose-normalized bioavailability of NFV and M8.
The dose of LPV/r may need to be increased when coadministered with
nelfinavir, particularly in HIV patients with extensive protease inhibitor
experience or reduced viral susceptibility to LPV. Concentrations of
nelfinavir are similar when dosed at 1000 mg BID with LPV/r compared to NFV
1250 mg BID alone.
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