Abstract Figure 2 · Ahmed A. Kousba1, Alexander Ivachtchenko2, Vasily Kazey2 and Yan Lavrovsky2...
1
Abstract Purpose: AVN-205, a potent multi-target small molecule, is being developed by Avineuro Pharmaceuticals for the treatment of neurological disorders. The objective of this study was to determine the pharmacokinetics (PK) of AVN-205 and its main metabolites, M1 and M2, in healthy volunteers following escalating single oral doses of AVN-205. Methods: This was an open-label, single-escalating dose, tolerability and PK Study. Four groups (n = 8 subjects/dose) were dosed orally with 2, 4, 10 or 20 mg AVN-205, respectively. Plasma samples were analyzed for AVN-205, M1 and M2 using an HPLC-MS/MS assay and the PK was determined by standard model independent methods based on individual subjects plasma concentrations. Results: AVN-205 demonstrated rapid absorption with median T max of 1 hour. AVN-205 exposure (C max and AUC (0-inf) ) was dose proportional with mean C max values of 5.79, 22.9, 53.7 and 84.1 pg/mL and mean AUC (0-inf) of 94.6, 211, 462 and 843 pg·h/mL for AVN-205 doses of 2, 4, 10 and 20 mg, respectively. AVN-205 harmonic mean half-life (T 1/2 ) ranged from 8.15 to 14.1 hours. The metabolites, M1 and M2, were observed immediately in plasma and had T max similar to the parent compound. The exposure of M1 metabolite was higher than parent compound (C max 5-10x and AUC 2-4x) while M2 exposure was markedly low. M1 T 1/2 ranged from 2.48 to 3.85 hours. The dose-normalized C max and AUC (0-inf) for AVN-205 and M1 also supported PK linearity. Conclusions: AVN-205 and M1 exhibited favorable PK in humans while M2 concentrations were markedly low. AVN-205 was rapidly absorbed and its T 1/2 supports either QD or BID dosing. The metabolite M1 appeared rapidly in plasma and had higher concentration than AVN-205. The PK of AVN-205 and M1 in human were proportional to AVN-205 dose. The Pharmacokinetics of AVN-205 and its Metabolites, M1 and M2, in Humans Following Escalating Single Oral Doses Ahmed A. Kousba 1 , Alexander Ivachtchenko 2 , Vasily Kazey 2 and Yan Lavrovsky 2 1 MicroConstants, Inc., San Diego, CA 92121, 2 Avineuro Pharmaceuticals, San Diego, CA 92122 Objective To determine the pharmacokinetics of AVN-205 and its main metabolites, M1 and M2, in healthy volunteers following escalating single oral doses of AVN-205. Introduction AVN-205, a potent multi-target small molecule, is being developed by Avineuro Pharmaceuticals for the treatment of neurological disorders. Neurological disorders are a group of quite diverse, chronic and often disabling disorders that involve the central nervous system, the peripheral nervous system and the autonomic nervous system. This work presents the PK of AVN-205 and its main metabolites, M1 and M2, in healthy volunteers following escalating single oral doses of AVN-205. Materials and Methods A. Study A healthy volunteer, open-label, single-escalating oral dose, tolerability and pharmacokinetic study of AVN-205. B. Dose Four groups of eight subjects each were dosed orally with either 2, 4, 10 or 20 mg AVN-205. C. Analytical Method The plasma was analyzed for AVN-205, M1 and M2 by validated HPLC-MS/MS assay. The assay measures concentrations for the three analytes ranging from 10.0 to 2,500 pg/mL using 50.0 µL of plasma for extraction. Chromatograms for the LLOQ standards of AVN-205, M1, M2 and I.S. are displayed in Figure 1. D. PK Analysis C max , T max , terminal half-life (T 1/2 ) and AUC (0-inf) were determined by standard model independent methods (Gibaldi and Perrier, 1982) from the concentration-time data of each subject using WinNonlin Professional 5.2.1 (Pharsight Corp., Mountain View, CA). Results and Discussion AVN-205 Following single oral doses of AVN-205, AVN-205 was absorbed rapidly with median T max ranged from 0.625 to 1.00 hour (Table 1 Figure 2). AVN-205 exposure (C max and AUC (0-inf) ) increased linearly as a function of the administered dose (Table 1 and Figures 3 and 4). The harmonic mean half-life (T 1/2 ) of AVN-01 ranged from 8.15 to 14.1 hours. AVN-205 T max and T 1/2 did not change as the dose increased (Table 1 and Figure 1). M1 and M2 Both metabolites, M1 and M2, were rapidly produced in plasma and their C max and AUC (0-inf) . The exposure of metabolite M1 was higher than that of the parent compound AVN-205 (C max 5-10x and AUC 2-4x). M1 exposure increased linearly as a function of AVN-205 doses. M1 harmonic mean T 1/2 ranged from 2.48 to 3.85 hours. M1 T max and T 1/2 did not change as AVN-205 dose increased (Table 1 and Figure 1). M2 exposure was markedly lower than M1 or the parent compound. AVN-205 Pharmacokinetic AVN-205 M1 M2 Dose, mg Parameters Mean SD Mean SD Mean SD 2 C max , pg/mL 5.79 2.90 56.1 18.2 2.10 3.16 T max , h a 1.00 0.5 - 4 1.00 0.5 - 1.5 1.00 1 - 1.5 T 1/2 , h b 14.1 10.2 2.49 1.20 ND c - AUC (0-inf) , pg•h/mL 94.6 26.8 220 116 ND d - 4 C max , pg/mL 22.9 16.4 112 38.1 1.70 2.17 T max , h a 1.00 0.5 - 1.5 1.00 0.5 - 1.5 1.50 1 - 4 T 1/2 , h b 8.15 2.23 2.48 1.27 ND c - AUC (0-inf) , pg•h/mL 211 86.2 555 297 ND d - 10 C max , pg/mL 53.7 31.8 292 176 5.08 6.96 T max , h a 0.625 0.25 - 4 1.00 1 - 2 2.00 1 - 4 T 1/2 , h b 10.2 2.55 2.80 1.71 ND c - AUC (0-inf) , pg•h/mL 462 207 1,410 688 ND d - 20 C max , pg/mL 84.1 46.2 635 311 4.67 1.90 T max , h a 1.00 0.25 - 2 1.00 1 - 2 2.00 0.25 - 4 T 1/2 , h b 8.18 2.09 3.85 0.557 4.74 1.36 AUC (0-inf) , pg•h/mL 843 333 3,100 870 35.2 0.442 a Expressed as median and range c ND - Not determined; requires 3 data points in the elimination phase to calculate the T 1/2 b Expressed as harmonic mean and pseudo SD d ND - Not determined since the T 1/2 was not calculated References Gibaldi, M. and Perrier, D. (1982). Pharmacokinetics, Second Edition, Marcel Dekker, Inc., New York. Conclusions AVN-205 and M1 exhibited favorable PK in humans while M2 concentrations were markedly low. AVN-205 was rapidly absorbed and its T 1/2 supports either QD or BID dosing. The metabolite M1 appeared rapidly in plasma and had higher concentration than AVN-205. The PK of AVN-205 and M1 in human were proportional to AVN-205 dose. Figure 1 Chromatograms of a LLOQ Standard (10.0 pg/mL) for AVN-205, M1, M2 and I.S. in Human Plasma Table 1 Summary Pharmacokinetic Parameters of AVN-205, M1 and M2 in Humans Following Single Oral Doses of AVN-205 at 2, 4, 10 or 20 mg Figure 2 Mean Plasma Concentrations (pg/mL) of AVN-205, M1 and M2 in Humans Following Single Oral Doses of AVN-205 at 2, 4, 10 or 20 mg Figure 3 Mean C max (pg/mL) of AVN-205, M1 and M2 in Humans Following Single Oral Doses of AVN-205 at 2, 4, 10 or 20 mg Figure 4 Mean AUC (0-inf) (pg·h/mL) of AVN-205, M1 and M2 in Humans Following Single Oral Doses of AVN-205 at 2, 4, 10 or 20 mg 2.20 2.40 2.60 2.80 3.00 3.20 3.40 3.60 3.80 min 100 % 0 AVN-205 2.56 3.16 3.89 MRM of 4 channels,ES+ 305.20 > 262.25 3.005e+003 AR05039 Smooth(Mn,2x2) Std. 10.0 pg/mL 2.20 2.40 2.60 2.80 3.00 3.20 3.40 3.60 3.80 min 100 % 0 MRM of 4 channels,ES+ 321.25 > 158.4 9.100e+002 AR05039 Smooth(Mn,2x2) Std. 10.0 pg/mL 2.20 2.40 2.60 2.80 3.00 3.20 3.40 3.60 3.80 min 100 % 0 MRM of 4 channels,ES+ 321.25 > 278.25 1.918e+004 AR05039 Smooth(Mn,2x2) Std. 10.0 pg/mL 2.20 2.40 2.60 2.80 3.00 3.20 3.40 3.60 3.80 min 100 % 0 MRM of 4 channels,ES+ 319.25 > 119.5 3.481e+005 AR05039 Smooth(Mn,2x2) Std. 10.0 pg/mL M1 2.75 2.21 2.49 3.05 3.48 2.47 2.73 M2 3.24 I.S. 2.47 Analyte Concentration, pg/mL Analyte Concentration, pg/mL 800 600 400 200 0 10 3 10 2 10 1 10 0 10 -1 30 0 6 12 24 18 30 0 6 12 24 18 30 0 6 12 24 18 30 0 6 12 24 18 30 0 6 12 24 18 30 0 6 12 24 18 30 0 6 12 24 18 30 0 6 12 24 18 Time, h Time, h Analyte C max , pg/mL Analyte C max , pg/mL 1000 800 600 400 200 0 800 600 400 200 0 0 5 10 15 20 2 4 10 20 AVN-205 Dose, mg AVN-205 Dose, mg AVN-205 Dose, mg AVN-205 Dose, mg Analyte AUC (0-inf) , pg•h/mL Analyte AUC (0-inf) , pg•h/mL 5000 4000 3000 2000 1000 0 2 4 10 20 4000 3000 2000 1000 0 0 5 10 15 20 AVN-205, 2mg AVN-205, 4mg AVN-205, 10mg AVN-205, 20mg AVN-205, 2mg AVN-205, 4mg AVN-205, 10mg AVN-205, 20mg AVN-205 M1 M2 AVN-205 M1 M2 AVN-205 M1 M2 AVN-205 M1 M2 AVN-205 AVN-205 Regression Line M1 M1 Regression Line M2 M2 Regression Line AVN-205 AVN-205 Regression Line M1 M1 Regression Line M2 FIP Pharmaceutical Sciences 2010 World Congress in Association with the AAPS Annual Meeting & Exposition | Nov. 14-18, 2010 | New Orleans, LA | Poster #M1495
Transcript of Abstract Figure 2 · Ahmed A. Kousba1, Alexander Ivachtchenko2, Vasily Kazey2 and Yan Lavrovsky2...
AbstractPurpose: AVN-205, a potent multi-target small molecule, is being developed by Avineuro Pharmaceuticals for the treatment of
neurological disorders. The objective of this study was to determine the pharmacokinetics (PK) of AVN-205 and its main metabolites, M1 and M2, in healthy volunteers following escalating single oral doses of AVN-205.
Methods: This was an open-label, single-escalating dose, tolerability and PK Study. Four groups (n = 8 subjects/dose) were dosed orally with 2, 4, 10 or 20 mg AVN-205, respectively. Plasma samples were analyzed for AVN-205, M1 and M2 using an HPLC-MS/MS assay and the PK was determined by standard model independent methods based on individual subjects plasma concentrations.
Results: AVN-205 demonstrated rapid absorption with median Tmax
of 1 hour. AVN-205 exposure (Cmax
and AUC(0-inf)
) was dose proportional with mean C
max values of 5.79, 22.9, 53.7 and 84.1 pg/mL and mean AUC
(0-inf) of 94.6, 211, 462
and 843 pg·h/mL for AVN-205 doses of 2, 4, 10 and 20 mg, respectively. AVN-205 harmonic mean half-life (T1/2
) ranged from 8.15 to 14.1 hours.
The metabolites, M1 and M2, were observed immediately in plasma and had Tmax
similar to the parent compound. The exposure of M1 metabolite was higher than parent compound (C
max 5-10x and AUC 2-4x) while M2 exposure
was markedly low. M1 T1/2
ranged from 2.48 to 3.85 hours. The dose-normalized Cmax
and AUC(0-inf)
for AVN-205 and M1 also supported PK linearity.
Conclusions: AVN-205 and M1 exhibited favorable PK in humans while M2 concentrations were markedly low. AVN-205 was rapidly absorbed and its T
1/2 supports either QD or BID dosing. The metabolite M1 appeared rapidly in plasma and
had higher concentration than AVN-205. The PK of AVN-205 and M1 in human were proportional to AVN-205 dose.
The Pharmacokinetics of AVN-205 and its Metabolites, M1 and M2, in Humans Following Escalating Single Oral Doses Ahmed A. Kousba1, Alexander Ivachtchenko2, Vasily Kazey2 and Yan Lavrovsky2
1MicroConstants, Inc., San Diego, CA 92121, 2Avineuro Pharmaceuticals, San Diego, CA 92122
ObjectiveTo determine the pharmacokinetics of AVN-205 and its main metabolites, M1 and M2, in healthy volunteers following escalating single oral doses of AVN-205.
IntroductionAVN-205, a potent multi-target small molecule, is being developed by Avineuro Pharmaceuticals for the treatment of neurological disorders.
Neurological disorders are a group of quite diverse, chronic and often disabling disorders that involve the central nervous system, the peripheral nervous system and the autonomic nervous system.
This work presents the PK of AVN-205 and its main metabolites, M1 and M2, in healthy volunteers following escalating single oral
doses of AVN-205.
Materials and MethodsA. Study A healthy volunteer, open-label, single-escalating oral dose, tolerability and pharmacokinetic study of
AVN-205.
B. Dose Four groups of eight subjects each were dosed orally with either 2, 4, 10 or 20 mg AVN-205.
C. Analytical Method The plasma was analyzed for AVN-205, M1 and M2 by validated HPLC-MS/MS assay. The assay measures concentrations for the three analytes ranging from 10.0 to 2,500 pg/mL using 50.0 µL of plasma for extraction. Chromatograms for the LLOQ standards of AVN-205, M1, M2 and I.S. are displayed in Figure 1.
D. PK Analysis Cmax
, Tmax
, terminal half-life (T1/2
) and AUC(0-inf)
were determined by standard model independent methods (Gibaldi and Perrier, 1982) from the concentration-time data of each subject using WinNonlin Professional 5.2.1 (Pharsight Corp., Mountain View, CA).
Results and DiscussionAVN-205Following single oral doses of AVN-205, AVN-205 was absorbed rapidly with median T
max ranged
from 0.625 to 1.00 hour (Table 1 Figure 2).
AVN-205 exposure (Cmax
and AUC(0-inf)
) increased linearly as a function of the administered dose (Table 1 and Figures 3 and 4).
The harmonic mean half-life (T1/2
) of AVN-01 ranged from 8.15 to 14.1 hours. AVN-205 Tmax
and T
1/2 did not change as the dose increased (Table 1 and Figure 1).
M1 and M2Both metabolites, M1 and M2, were rapidly produced in plasma and their C
max and AUC
(0-inf).
The exposure of metabolite M1 was higher than that of the parent compound AVN-205 (Cmax
5-10x and AUC 2-4x). M1 exposure increased linearly as a function of AVN-205 doses.
M1 harmonic mean T1/2
ranged from 2.48 to 3.85 hours. M1 Tmax
and T1/2
did not change as AVN-205 dose increased (Table 1 and Figure 1).
M2 exposure was markedly lower than M1 or the parent compound.
AVN-205 Pharmacokinetic AVN-205 M1 M2Dose, mg Parameters Mean SD Mean SD Mean SD
2 Cmax
, pg/mL 5.79 2.90 56.1 18.2 2.10 3.16
Tmax
, ha 1.00 0.5 - 4 1.00 0.5 - 1.5 1.00 1 - 1.5
T1/2
, hb 14.1 10.2 2.49 1.20 NDc -
AUC(0-inf)
, pg•h/mL 94.6 26.8 220 116 NDd -
4 Cmax
, pg/mL 22.9 16.4 112 38.1 1.70 2.17
Tmax
, ha 1.00 0.5 - 1.5 1.00 0.5 - 1.5 1.50 1 - 4
T1/2
, hb 8.15 2.23 2.48 1.27 NDc -
AUC(0-inf)
, pg•h/mL 211 86.2 555 297 NDd -
10 Cmax
, pg/mL 53.7 31.8 292 176 5.08 6.96
Tmax
, ha 0.625 0.25 - 4 1.00 1 - 2 2.00 1 - 4
T1/2
, hb 10.2 2.55 2.80 1.71 NDc -
AUC(0-inf)
, pg•h/mL 462 207 1,410 688 NDd -
20 Cmax
, pg/mL 84.1 46.2 635 311 4.67 1.90
Tmax
, ha 1.00 0.25 - 2 1.00 1 - 2 2.00 0.25 - 4
T1/2
, hb 8.18 2.09 3.85 0.557 4.74 1.36
AUC(0-inf)
, pg•h/mL 843 333 3,100 870 35.2 0.442
a Expressed as median and range c ND - Not determined; requires 3 data points in the elimination phase to calculate the T1/2
b Expressed as harmonic mean and pseudo SD d ND - Not determined since the T1/2
was not calculated
ReferencesGibaldi, M. and Perrier, D. (1982). Pharmacokinetics, Second Edition, Marcel Dekker, Inc., New York.
ConclusionsAVN-205 and M1 exhibited favorable PK in humans while M2 concentrations were markedly low. AVN-205 was rapidly absorbed and its T
1/2 supports either QD or BID dosing. The metabolite M1
appeared rapidly in plasma and had higher concentration than AVN-205. The PK of AVN-205 and M1 in human were proportional to AVN-205 dose.
Figure 1Chromatograms of a LLOQ Standard (10.0 pg/mL) for AVN-205, M1, M2 and I.S.
in Human Plasma
Table 1Summary Pharmacokinetic Parameters of AVN-205, M1 and M2 in Humans Following Single
Oral Doses of AVN-205 at 2, 4, 10 or 20 mg
Figure 2Mean Plasma Concentrations (pg/mL) of AVN-205, M1 and M2 in Humans Following Single
Oral Doses of AVN-205 at 2, 4, 10 or 20 mg
Figure 3Mean C
max (pg/mL) of AVN-205, M1 and M2 in Humans Following Single Oral Doses of
AVN-205 at 2, 4, 10 or 20 mg
Figure 4Mean AUC
(0-inf) (pg·h/mL) of AVN-205, M1 and M2 in Humans Following Single Oral Doses of
AVN-205 at 2, 4, 10 or 20 mg
2.20 2.40 2.60 2.80 3.00 3.20 3.40 3.60 3.80min
100
%
0
AVN-2052.56
3.16 3.89
MRM of 4 channels,ES+305.20 > 262.25
3.005e+003
AR05039 Smooth(Mn,2x2)Std. 10.0 pg/mL
2.20 2.40 2.60 2.80 3.00 3.20 3.40 3.60 3.80min
100
%
0
MRM of 4 channels,ES+321.25 > 158.4
9.100e+002
AR05039 Smooth(Mn,2x2)Std. 10.0 pg/mL
2.20 2.40 2.60 2.80 3.00 3.20 3.40 3.60 3.80min
100
%
0
MRM of 4 channels,ES+321.25 > 278.25
1.918e+004
AR05039 Smooth(Mn,2x2)Std. 10.0 pg/mL
2.20 2.40 2.60 2.80 3.00 3.20 3.40 3.60 3.80min
100
%
0
MRM of 4 channels,ES+319.25 > 119.5
3.481e+005
AR05039 Smooth(Mn,2x2)Std. 10.0 pg/mL
M12.75
2.212.49 3.05 3.48
2.47
2.73M2
3.24
I.S.2.47
Ana
lyte
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ratio
n, p
g/m
L
Ana
lyte
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ratio
n, p
g/m
L
800
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102
101
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10-1
300 6 12 2418 300 6 12 2418 300 6 12 2418 300 6 12 2418 300 6 12 2418 300 6 12 2418 300 6 12 2418 300 6 12 2418
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AVN-205 Dose, mg AVN-205 Dose, mg
AVN-205 Dose, mg AVN-205 Dose, mg
Ana
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M1
M2
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M1
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AVN-205
M1
M2
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M1
M2
AVN-205
AVN-205 Regression Line
M1
M1 Regression LineM2M2 Regression Line
AVN-205
AVN-205 Regression Line
M1
M1 Regression LineM2
FIP Pharmaceutical Sciences 2010 World Congress in Association with the AAPS Annual Meeting & Exposition | Nov. 14-18, 2010 | New Orleans, LA | Poster #M1495
