icon-folder.gif   Conference Reports for NATAP  
  10th Conference on Retroviruses and Opportunistic Infections
Boston, Mass, Feb 10-14, 2003
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Assessment of the Multiple Dose Pharmacokinetic Interaction of Lopinavir/ritonavir with Nelfinavir
  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.
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.