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 co-administration of LPV/r and NFV on pharmacokinetic parameters of LPV, ritonavir (RTV), NFV, and the hydroxy-t-butylamide metabolite of NFV (M8).

Methods: This was a multiple-dose, sequential, open-label, single-center, non-fasting, drug interaction study. Fourteen (14) healthy subjects were enrolled and 13 subjects completed the study; one subject prematurely discontinued for personal reasons. Each received LPV/r 400/100 mg BID for 21 days. NFV, 1000 mg BID, was co-administered 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 hrs 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: The effect of co-administration of NFV with LPV/r can be seen below:       

	Ctrough (mg/mL)+				AUC12 (mg*h/mL)+
Regimen	LPV	RTV	NFV	M8	LPV	RTV	NFV	M8
LPV/r or 1250 mg NFV alone	7.1	0.2	1.1	0.2	95.9	5.3	24.2	6.4
LPV/r with 1000 mg NFV	4.8*	0.2	1.3	1.2*	70.0*	4.1*	25.8	22.3*

*p<0.05 compared to LPV/r or NFV alone

+ Geometric mean

 

LPV C_max, AUC₁₂ and C_trough were significantly decreased during NFV co-administration by 21, 27 and 33%, respectively. LPV median (range) ratio of C₀ to IC₅₀ 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. Co-administration 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 and increased AUC of M8 by 3-fold despite a 20% reduction in the NFV dose. Safety profiles were not altered with concomitant administration.

Conclusions: NFV decreases the bioavailability of both LPV and RTV, while LPV/r increases dose-normalized bioavailability of NFV and M8. The dose of LPV/r may need to be increased when co-administered 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.