Saquinavir, nelfinavir and M8 pharmacokinetics following combined saquinavir, ritonavir and nelfinavir administration.
OBJECTIVE
This study evaluated the steady-state pharmacokinetic interaction between ritonavir-boosted saquinavir and nelfinavir.


METHODS
Open label, multiple-dose, two parallel-groups, single crossover study conducted in 24 HIV-infected patients (12 in each group). Patients in the nelfinavir group added saquinavir/ritonavir, 1000/100 mg twice daily to their ongoing stable treatment regimen consisting of nelfinavir, 1250 mg twice daily and two nucleoside reverse transcriptase inhibitors (NRTIs). Patients in the saquinavir group added nelfinavir, 1250 mg twice daily to their ongoing stable treatment regimen consisting of saquinavir/ritonavir, 1000/100 mg twice daily and two NRTIs. Pharmacokinetic assessments were performed before and 7 days after the start of combined treatment with nelfinavir/saquinavir/ritonavir. Blood samples were collected before and 1, 2, 3, 4, 6, 8, 10 and 12 h after dosing for measurement of nelfinavir, the nelfinavir metabolite M8 and saquinavir using liquid chromatography tandem mass spectrometry (LC-MS/MS).


RESULTS
The addition of saquinavir/ritonavir to the nelfinavir-containing regimen resulted in significant increases in the M8 pharmacokinetic parameters AUC(0-12), Cmax and C12; geometric mean ratios (90% confidence intervals) of 2.25 ng.h/mL (1.47-3.44), 1.74 ng/mL (1.25-2.40) and 4.21 ng/mL (2.10-8.47), respectively. The intra-individual changes in nelfinavir and saquinavir concentrations were highly variable. Statistical analysis could not discard a relevant interaction but includes the possibility that some parameters may be halved, others more than doubled. At the same time the analysis failed to show any directed change.


CONCLUSIONS
The co-administration of nelfinavir and saquinavir/ritonavir leads to unpredictable changes in concentrations of both drugs. It is unclear whether the increased concentrations of M8 are associated with a clinical benefit.
Stocker
Hartmut
H
Vivantes Auguste-Viktoria Klinikum, Rubensstrasse 125, 12157 Berlin, Germany. hartmut.stocker@vivantes.de
Herzmann
Christian
C
Breske
Antje
A
Kruse
Guido
G
Berger
Marcel
M
Schulbin
Hubert
H
Hill
Andrew
A
Steinmüller
Jutta
J
Becker
Mark
M
Arastéh
Keikawus
K
Kurowski
Michael
M
D000328:Adult; D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D019888:Nelfinavir / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000008:administration & dosage; D019258:Saquinavir / Q000008:administration & dosage / Q000493:pharmacokinetics*
D019380:Anti-HIV Agents; C495123:hydroxy-t-butylamidenelfinavir; D019888:Nelfinavir; D019258:Saquinavir; D019438:Ritonavir