Biology Reference
In-Depth Information
2002
). The metabolites are inactive (Giembycz
2002
) with the main metabolite
(SB 217493) being tenfold less potent than cilomilast as a PDE4 inhibitor
(Giembycz
2002
).
The plasma elimination half-life (
t
m1/2
) is short with approximately 7 h (Table
1
)
(Zussman et al.
2001b
) and the drug must be administered twice daily.
Total and maximum exposure increase proportionally with the dose. Cilomilast
shows similar pharmacokinetics following both single and repeated oral adminis-
trations though some accumulation (range: 1.04-1.18 with 4-20 mg) was observed
(Zussman et al.
2001a
). A pharmacokinetic steady state is reached after 3 days of
continuous treatment.
Food significantly decreases the rate, but not the extent, of absorption, and
administration with meals may reduce gastrointestinal adverse effects by reducing
maximum exposure (Martina et al.
2006
). Cilomilast plasma levels are not signifi-
cantly affected by cigarette smoking (Kelly et al.
1999
). Cilomilast has a low
potential for pharmacokinetic or pharmacodynamic drug-drug interactions with
commonly prescribed drugs including warfarin, digoxin, antacids, theophylline, pre-
dnisolone, and salbutamol (Giembycz
2001
; Kelly et al.
2001
; Murdoch et al.
1998
,
2002
,
2004
; Zussman et al.
2001a
,
c
). Drug-drug interaction studies of cilomilast
with competitive CYP 2C8 substrates such as rosiglitazone have not been reported.
A small reduction in plasma half-life was noted following evening dosing com-
pared to morning dosing in healthy adults taking cilomilast after eating a fat-rich
meal (Zussman et al.
1999
).
In renally impaired patients, the half-life and total plasma exposure (AUC) to free
cilomilast increased progressively with severity of renal impairment (Zussman et al.
2002
). This increase in cilomilast plasma exposure was paralleled by an increased
incidence of adverse events.
Though cilomilast had a slightly higher peak plasma concentration in elderly
patients and a prolonged elimination half-life compared with healthy young adults,
these differences are not clinically significant (Zussman et al.
2001a
).
4.5 Oglemilast
Oglemilast is well absorbed and has favorable pharmacokinetics permitting once-
daily dosing. The highest doses tested in human single and multiple ascending dose
studies were 24 mg. The pharmacokinetics was less than dose proportional at lower
doses and higher doses. A single active metabolite, oglemilast N-oxide, was
observed to have an exposure of nearly 25% of the parent compound and the
same half-life as the parent compound. In vitro, the metabolite was found to be
equipotent to the parent as inhibitor of PDE4. The half-life of oglemilast was
14-30 h. A shorter half-life of approximately 3 h and moderate bioavailability
(
50%) was found in animal pharmacokinetic studies in mice, cynomolgus, and
beagle but not in rats (9 h).
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