Effect of ketoconazole on ritonavir and saquinavir concentrations in plasma and cerebrospinal fluid from patients infected with human immunodeficiency virus
Y. Khaliq et al., Effect of ketoconazole on ritonavir and saquinavir concentrations in plasma and cerebrospinal fluid from patients infected with human immunodeficiency virus, CLIN PHARM, 68(6), 2000, pp. 637-646
Aim: Our aim was to evaluate the effect of ketoconazole on ritonavir and sa
quinavir plasma and cerebrospinal fluid (CSP) concentrations.
Methods: Twelve patients who were human immunodeficiency virus-seropositive
and who were receiving 400 mg of ritonavir and 400 mg of saquinavir twice
daily completed a nonfasted, two-period, two-group, longitudinal pharmacoki
netic study. Blood samples were collected over the daytime 12-hour dosing i
nterval of the protease inhibitors at baseline (period I, day 0) and after
10 days of coadministration of 200 mg (n = 6) or 400 mg (n = 6) of ketocona
zole once daily (period 2, day 10). One set of paired CSF and blood samples
was collected between 4 and 5 hours after the dose on both days.
Results: Ketoconazole significantly increased area under the plasma concent
ration-time curve, plasma concentration at 12 hours after the dose, and hal
f-life of ritonavir by 29% (95% confidence interval (CI), 13%-46%), 62% (95
% CI, 37%-92%), and 31% (95% CI, 13%-51%), respectively. Similar increases
of 37% (95% CI, 4%-81%), 94% (95% CI, 41%-167%), and 38% (95% CI, 15%-66%),
respectively, were observed for these parameters for saquinavir. Ketoconaz
ole significantly elevated ritonavir CSP concentration by 178% (95% CI, 59%
-385%), from 2.4 to 6.6 ng/mL, with no change in paired unbound plasma leve
l (26 ng/mL); this led to a commensurate 181% increase (95% CI, 47%-437%) i
n CSF/plasma unbound ratio. All pharmacokinetic changes were unrelated to k
etoconazole dose or plasma exposures. Corresponding changes for saquinavir
CSF pharmacokinetics were insignificant (P > .06); saquinavir CSP levels we
re unmeasurable in 7 patients (<0.2 ng/mL).
Conclusions: The disproportionate increase in CSF compared with plasma conc
entrations of ritonavir is consistent with ketoconazole inhibiting both dru
g efflux from CSF and systemic clearance.