Biology Reference
In-Depth Information
4.6 Roflumilast
Roflumilast is rapidly absorbed after oral administration with an absolute bioavail-
ability of approximately 80% (Bethke and Lahu
2011
). Roflumilast is metabolized
in the liver to its major active metabolite, roflumilast N-oxide, mainly by the
cytochrome P450 isozymes 3A4 and 1A2 (Fig.
3
) (Bethke et al.
2007
).
F
F
CYP3A4, CYP1A2
OCl
OCl
F
F
O
O
N
+
- O
-
N
H
N
H
N
O
O
Cl
Cl
Roflumilast
Roflumilast N-oxide
Fig. 3 Metabolism of roflumilast into its active metabolite, roflumilast N-oxide
The systemic exposure to roflumilast and roflumilast N-oxide increased propor-
tionally with the administered dose (Bethke et al.
2002a
,
2007
). The maximum
plasma concentration of roflumilast is reached after approximately 1 h and of
roflumilast N-oxide after about 4 h (Table
1
). Protein binding of both roflumilast
and roflumilast N-oxide to human plasma is high (99 and 97%, respectively)
(Bethke et al.
2007
).
As a lipophilic substance, roflumilast exhibits a high volume of distribution,
a property that makes roflumilast readily available to the peripheral tissue
(Bethke and Lahu
2011
). Other metabolites have also been observed in plasma
as glucuronides.
Both roflumilast and roflumilast N-oxide are extensively metabolized and are
excreted into urine with less than 1% unchanged parent drug (Bethke et al.
2002b
).
The median half-lives of 22.8 and 24.7 h for roflumilast and roflumilast N-oxide
are long and support once-daily oral dosing. Because of its long half-life and its
systemic exposure, the active metabolite substantially contributes to the overall
clinical efficacy of roflumilast. In fact, roflumilast N-oxide accounts for about
90% of the PDE4 inhibitor effect (Bethke et al.
2007
).
Comparing the pharmacokinetics of morning and evening dosing, the maximum
plasma concentration of roflumilast was marginally lower and the time to reach the
peak concentration was slightly longer with evening dosing, while total exposures
to parent drug and metabolite were unaffected (Bethke et al.
2010
).
As roflumilast exhibits the unique property that both parent drug and metabolite
considerably contribute to the overall pharmacologic effect, a measure was required
to assess the total pharmacodynamic effect in conditions where their relative ratio
might change and a potential rational for dose adjustment would be needed.
Considering that the intrinsic potency of roflumilast N-oxide is threefold lower
compared to roflumilast, but the total plasma exposure of the metabolite is 10- to
12-fold higher with a threefold higher free fraction, the concept of total PDE4
