Effect of Omeprazole on the Pharmacokinetics of Saquinavir 500 mg Formulation
with Ritonavir
Recent
studies have described a reduced absorption of certain protease
inhibitors (PIs), including atazanavir
(Reyataz), indinavir
(Crixivan) and tipranavir
(Aptivus), when administered with agents known to reduce gastric
pH.
Not
all PIs are affected by changes in gastric pH. For example no significant interactions
between drug exposure and gastric pH have been shown for saquinavir/
SQV (Invirase).
However,
in view of these potential interactions and the recent development of the new
500 mg film-coated tablet (FCT) formulation of SQV, the aim of this study was
to evaluate the effect of the proton pump inhibitor omeprazole on the pharmacokinetics
(PK) of the new SQV
500 mg formulation co-administered with ritonavir (RTV) in healthy
volunteers.
This
was a prospective, open-label, two-treatment drug–drug interaction study of the
PK and tolerability profile of SQV 500 mg FCT co-administered with RTV and with
or without omeprazole in healthy adult volunteers at a single site in the UK.
Subjects
received the current licensed dosage of SQV/RTV (1000/100 mg bid) for 15 days.
On the morning of days 11 to 15, subjects also received omeprazole 40 mg qd.
On
days 10 and 15, after overnight admission to the unit, serial plasma samples were
collected for 12-hour PK profiles of SQV and RTV. Study drugs were administered
with a standardized meal and drug intake was directly observed by study staff
on the morning of and evening prior to the PK sampling, and on every third day
throughout the study.
Results
Nineteen healthy adult volunteers were screened, of which 18 successfully completed
the study (one subject was excluded due to a positive urine drug-of-abuse test).
SQV PK parameters (Ctrough, Cmax, and AUC0–12h) of SQV were
markedly increased when the new 500 mg film-coated formulation of SQV (boosted
with RTV) was co-administered with the proton pump inhibitor omeprazole,
including an 82% increase in total plasma exposure.
There were no significant changes in RTV PK parameters.
Discussion
While
the exact mechanism for the interaction observed in this study remains to be elucidated,
the changes observed in the PK profile of SQV 500 mg FCT are in keeping with a
process of increased absorption rather than reduced clearance, since t1/2 or time
to Cmax were not affected.
Despite
the increase in plasma SQV exposure, no increase in clinical or laboratory adverse
events occurred during the 5-day period when omeprazole was co-administered.
The
pharmacokinetics and safety of concomitant SQV/RTV and omeprazole therapy have
not been evaluated in HIV-infected subjects. Based on the data currently available,
relatively high SQV exposure levels do not appear to be associated with any unusual
or significant adverse effects in HIV-infected patients.
For
example, a mean SQV AUC0-24h of 53,950 ng.h/ml was reported for a subset of Thai
patients receiving SQV/RTV 1600/100 mg qd (+ 2 NRTIs) in the Staccato trial, in
which there were no grade 3/4 adverse events and no study withdrawals observed
over 24 weeks.
In
conclusion, the study authors write, “When omeprazole was coadministered with
SQV/RTV in healthy volunteers, RTV exposure did not seem to be affected but total
SQV plasma exposure was significantly increased. However, no short-term toxicities
were observed.”
“The
mechanism of this interaction has yet to be determined.
12/02/05
Reference
A
Winston and others. EFFECT OF OMEPRAZOLE ON THE PHARMACOKINETICS OF SAQUINAVIR
500 MG FORMULATION WITH RITONAVIR IN HEALTHY MALE AND FEMALE VOLUNTEERS. Poster
LBPE4.3/16. 10th European AIDS Conference/EACS. November 17-20, 2005. Dublin, Ireland.
