Biology Reference
In-Depth Information
inhibition (tPDE4i) (Fig.
4
) has been developed (Hermann et al.
2006b
). It permits
relative quantitative comparisons of the pharmacodynamic effect on the basis
of plasma concentrations, if extrinsic and intrinsic factors (e.g., drug-drug interac-
tions, smoking, food or age, sex, and hepatic injury) might influence the CYP-
dependent metabolism of roflumilast to the N-oxide (Hermann et al.
2006a
,
2007b
;
von Richter et al.
2007
; Lahu et al.
2011
).
The tPDE4i concept was developed (Hermann et al.
2006b
; Lahu et al.
2011
)as
an empirical construct to simplify the complex enzyme kinetics underlying the
pharmacodynamic effect of roflumilast. Variables and fixed parameters that deter-
mine tPDE4i and are meaningful in a clinical pharmacology setting were included
in this model. It was assumed that the contributions of roflumilast and roflumilast
N-oxide are independent of each other and additive, which is true only for low
concentrations. The inhibition may then be described as linear. The substrate
(cAMP) concentration available for the enzyme PDE4 is assumed to be constant
and sufficiently higher than the inhibitor concentrations. Consequently, the sub-
strate concentration was not included in the model.
Roflumilast and roflumilast N-oxide have different affinities for the enzyme
(potencies for PDE4 inhibition) as measured by the IC
50
(inhibitory concentration
50%). The degree of PDE4 inhibition is indirectly proportional to the IC
50
at a given
inhibitor concentration and the model includes a correction term for IC
50
.
The effective inhibitor concentrations
c
i
of roflumilast and roflumilast N-oxide,
which may interact with PDE4, are determined by the fraction
F
u
of the total plasma
concentration
c
p
, which is not bound to plasma proteins (
c
i
¼
c
p
*
F
u
). As the time to
achieve the maximum plasma concentration (
t
max
) is different for roflumilast and
roflumilast N-oxide, no single-point measurement is possible to investigate poten-
tial alterations of tPDE4i. The amount of drug in plasma, which is available for
inhibition in the dosing interval, is described by plasma concentration (
c
p
)-time (
t
)
curve. A quantitative measure is the area under the curve AUC
0
t
calculated as
the integral
R
c
p
d
t
. An alignment of the fluctuating effective inhibitor concentration
in time is possible by calculating moments such as 1/
t
*AUC
0
t
in the proposed
model. Using the dosing interval
*(AUC
0
t
)
will describe the aligned inhibitor concentrations of roflumilast or roflumilast
N-oxide.
In summary, the tPDE4i by both active compounds was defined in (1) as the sum
of the roflumilast (rof) and roflumilast N-oxide (rofNO) inhibitory effects given by
the total in vivo exposure (AUC
0
t
) at steady state during the dosing interval (
t
as the time scale (
t
¼
t
), the term 1/
t
),
after accounting for substance differences in protein unbound fraction (
F
u
) and
intrinsic activity (IC
50
):
t
AUC
rof
Fu
;
rof
AUC
rofNO
;
rofNO
IC
50
;
rofNO
t
Fu
t
PDE4
i
¼
þ
:
(1)
IC
50
;
rof
t
The AUC
0
t
was assessed as the experimental variable (calculated from
R
c
p
d
t
)
in several clinical studies that compared normal with altered metabolic conditions.
