Single dose pharmacokinetics
All available mesdopetam concentration values for all subjects in all
dose groups were included in the PK calculations. Following oral single
dose administration of mesdopetam the plasma concentration increased
rapidly to reach a maximum 0.7 to 3 hours after dosing, with a
subsequent log-linear decline (Figure 1). The single dose PK parameter
results are presented in Table 8. In brief, for dose levels 5‑120 mg
fasted, the following ranges were obtained for mesdopetam:
- Mean t1/2 from 6.4 ± 1.9 hours to 7.1 ± 1.0 hours with
the highest mean value after 80 mg mesdopetam.
- Median tmax from 1.0 hour (range 0.7-3.0) to 2.0 hours
(range 1.0-4.0) with the highest median value after 15 mg mesdopetam.
- Mean Cmax from 73.6 ± 18.4 nmol/L to 1940 ± 326 nmol/L
with the highest mean value after 120 mg mesdopetam.
- Mean AUC0-∞ from 786 ± 298 nmol∙h/L to 17300 ± 4620
nmol∙/L with the highest mean value after 120 mg mesdopetam.
- Mean CL/F from 23.8 ± 4.3 L/h to 32.5 ± 6.2 L/h with the highest mean
value after 80 mg mesdopetam.
- Mean Vz/F from 223 ± 41.7 L to 328 ± 59.0 L with the
highest mean value after 80 mg mesdopetam.
For dose levels 5-120 mg, the t1/2 of IRL902 ranged from
6.3 ± 0.6 hours to 7.3 ± 1.1 hours and the plasma concentration-time
profile was parallel to the profile for the parent compound.
For IRL872, the plasma concentration profiles were markedly different
from those of the parent compound with median tmaxvalues of 9.0 hours (range 8-24) to 12 hours (range 12‑12) and a mean
t1/2 of more than 20 hours. The estimate of the
t1/2 is uncertain both due to the short observation
period and the flat shape of the plasma profile.
Relative bioavailability
after fed and fasting conditions. For the four subjects receiving
mesdopetam both under fasting and fed conditions, a small food
interaction was observed. The geometric mean ratio (fed/fasted) was
110.7% for AUC0-8h and 109.0% for
Cmax. Tmax was also delayed after food intake compared
to fasting.
For the metabolites IRL902 and
IRL872 the geometric mean ratio (fed/fasting) was 82.5% and 84.5% for
AUC0-8h and 95.9% and 117.8% for Cmaxessentially reflecting the results for mesdopetam.
Dose proportionality
after single dose. The analysis of dose linearity for AUCt, AUC0-∞, and
Cmax showed a linear relationship with a proportionality constant (b)
close to 1, indicating dose proportionality for the parent compound
mesdopetam and the metabolite IRL902.
For the metabolite IRL872 dose linearity could only be calculated for
Cmax. since there were
too many likelihood evaluations detected for AUC0-∞ and convergence
criteria was not met for AUCt. The analysis of dose linearity for Cmax
showed a linear relationship with a proportional constant (b) close to
1, indicating dose proportionality.
Multiple dose
pharmacokinetics. Mean plasma concentration-time profiles for
mesdopetam after multiple dosing of 40 mg and 80 mg once daily are shown
in Figure 2. The individual concentration-time profiles for the first
and last dose of 40 mg mesdopetam show rapid absorption for the parent
compound with median tmax at 2.0 hours (range 0.3-3.0)
and 2.0 hours (range 0.7-8.0) and a mean Cmax of
631 ± 54.0 nmol/L and 567 ± 95.7 nmol/L for the first and last dose,
respectively. The t1/2 was 6.8 ± 1.3 hours and 7.0 ± 1.4
hours for the first and last dose, respectively. Mean
AUC0-24h after the first dose was 5580 ± 1650 nmol∙h/L
and mean AUCss was 6000 ± 1970 nmol∙/L (Table 9).
After the first and last dose of 80 mg mesdopetam a mean
Cmax of 1490 ± 410 nmol/L and 1430 ± 393 nmol/L was
reached at a median tmax of 0.8 hours (range 0.3-2.0)
and 2.0 hours (range 0.4-3.0), respectively. The t1/2was 7.1 ± 1.1 hours for the first dose and 7.2 ± 0.6 hours for the last
dose. Mean AUC0-24h after the first dose was 11500 ±
2410 nmol∙h/L and mean AUCss was 12200 ± 3150 nmol∙h/L.
Plasma profiles for the major metabolites are shown in Figure 3. The
time course of mesdopetam and IRL902 showed similar t1/2with lower concentrations for IRL902. IRL872 showed a longer
t1/2 as compared to the parent compound and IRL902; 46 ±
43 hours and 40 ± 14 hours after the first and last 40 mg dose and 73 ±
70 hours after the last 80 mg dose. The variations in IRL872 levels
between subjects were approximately 10-fold.
Dose proportionality
after multiple doses. The proportionality constant for
AUCss and Cmax of mesdopetam, for the last MAD dose,
indicated dose proportionality for AUCss (1.06) and
supra proportional increases of Cmax (1.3). The proportionality
constants for AUCss and Cmax of IRL902 for the last MAD
dose were AUCss (1.4) and Cmax (1.5), respectively. For
metabolite IRL872 the proportionality constant was below 1 for both
AUCss and Cmax indicating a less than dose proportional increase in
exposure.
Accumulation ratio (AR)
after multiple doses. The mean AR for mesdopetam and IRL902 was close
to 1 for both the 40 mg and 80 mg dose level indicating virtually no
accumulation from the first to the last dose which is in good agreement
with degree of accumulation calculated from the estimated half-lives and
the dose interval. IRL872 showed accumulation at both dose levels,
around 2‑fold, in line with its longer half-life.