- Email: [email protected]
1124 Multiple-dose pharmacokinetics, safety, and tolerance of desloratadine in healthy volunteers
Abstracts
J ALLERGY CLIN IMMUNOL VOLUME 104. NUMBER 1, PART 2
relief
1124
and improvement
Multiple-Dose Desloratadine
in signs
and symptoms
Pharmacokinetics, in Healthy Volunteers
of SAR.
have characterized various antihistamines, including the new nonsedating antihistamine DL, in a Ca2+ flux assay at the human H, receptor that has been cloned and expressed in CHO cells and in a primary culture of human bronchial smooth muscle (HBSM)
Safety, and Tolerance of D Pudbi*. C Bar~field*, S
Gupro*. JM He~~ti. P Glue*. ME A@imc* Research Institute. Kenilworth, NJ tArkansas Testing Center, Little Rock. AR
*Schering-Plough Research Medical
cells.
which endogenously express the H, receptor. Histamine is the most potent agonist of Ca2+ flux in both CHO and the HBSM cells with an EC,, of 98 and 164 nM, respective-
Desloratadine (DL) is currently in development for the treatment of seasonal allergic rhinitis and other allergic conditions. It has selective peripheral histamine H,-receptor antagonist activity with additional antiallergic activity. This study was conducted to
ly. The rank order of agonist potency in this assay is histamine >imetit >R->>methyl-histamine tiimaprit, suggesting the effect is primarily related to H, receptors. Various classes of antihistamines inhibit this effect with similar potencies in both the CHO and the HBSM cells. The potency of certain antagonists is dependent on the time of pretreatment. The rank order of antagonist
evaluate the pharmacokinetics (PK), safety, and tolerability of DL after both single and multiple dosing. This single-center, randomized. double-blind (within-group),
potency in the CHO cells in this assay is clemastine = cyproheptadine = desloratadine = promethazine > astemizole = epinastine = pyrilamine > chlorpheniramine = terfenadine > loratadine = cet-
placebo-controlled. parallel-group. rising single/multiple-dose study of DL was conducted in 49 healthy male subjects (24-45 years old). Single oral doses of DL (5. 7.5. IO, or 20 mg; n=lO/dose) or placebo (n=2/dose) were followed 3 days later by the same doses given once daily for I4 days. Plasma concentrations of DL were determined up to 72 hours after single doses and
irizine = diphenhydramine = fexofenadine. These results in the Ca2+ flux assay are similar to values obtained in smooth muscle preparations from various animal species. These results demonstrate that measuring Ca2+ flux in the
up to I68 hours after the final dose in each dose group. Additional blood samples were obtained before dosing on Days l4- I7 for steady-state assessment. Vital signs, EC&. and clinical laborato-
CHO cells and the HBSM to evaluate antihistamines also indicate that among
ry tests were performed at pre-specified times throughout the study. Single-dose PK were characterized by dose-related increases in C,,;,, (I .83-7.08 ng/mL) and AUClo.i,fi,,,yl (32.5-169
desloratadine fexofenadine,
ng.h/mL). Dose-normalized C,,, and AUC were similar across groups. The apparent total body clearance ranged from I I4 to 20 I L/h; mean T!, was I9 to 34.6 hours. Steady-state PK parameters
1126
Tr, and the dosing frequency of DL. The apparent total body clearance and TN,: were not significantly different after single and multiple dosing. Headache was the most frequently reported adverse
administration
AuG,,
1125
5 mg
(n9WmL)
78.0
. (lq/mL)
2.18
DL
(127) (33)
7.5
(%
mg DL
104 (93) 3.03
(31)
20 mg OL
126 (99)
290
3.80
(29)
8.08
M Billah
Schering-Plough
Research
Institute.
(25)
slope for AUCIu.,l ginal deviation (P=O.O49) was of treatment-related
Kenilworth,
contraction
assays.
(PK)
profile
single-dose,
4-
vs dose deviate from linearity @‘X).05). A from linearity in the slope for C,,, vs no PK significance. Mild headache was the adverse event reported, and its incidence
mardose only was
not related to dose. The results of this study showed that desloratadine was safe and well tolerated and exhibited linear PK over the dose range 5 to 20 mg. Linearity implies predictability in the PK of DL.
of histamine and other inflammatory and allergic mediators. Identification and functional characterization of compounds that bind the histamine H, receptor have classically been performed in rat muscle
MB
malized (to 5 mg) C,,,, or AUClo.rl values (fiO.05). Neither the slope for C,,, vs dose (0.9645) nor the slope for AUCFo.,, vs dose (I .0197) were significantly different than I (p>O.O5), nor did the
Desloratadine (DL) relieves symptoms of seasonal allergic rhinitis and other allergic conditions. DL has selective peripheral histamine H,-receptor antagonist activity and inhibits the release
pig smooth
of
D Padhit.
mean (% coefficient of variation [CV]) PK parameters used in the assessment of dose-proportionality/linearity are provided below. There were no significant differences between the dose-nor-
NJ
and guinea
Pharmacokinetics
JM Hermn+.
least I4 days. Plasma concentrations of DL (O-168 h) were determined by gas liquid chromatography with nitrogen phosphorous detection, and PK parameters derived by standard methods. The
(92)
Functional Characterization of Desloratadine and Other Antihistamines in a Chinese Hamster Ovary (CHO) Cell Line That Expresses the Cloned Human Histamine H, Receptor and in Human Bronchial Smooth Muscle Cells (HBSMC) JCAnthes. C Riclmrd, RE West. S Willicrms. S Greenfedec H Gilchresf, RW &WI.
and
astemizole.
way crossover study, 20 healthy male volunteers (19-43 years old) received DL 5, 7.5, IO. and 20 mg orally under fasted conditions. Each subject received each dose on 4 occasions, separated by at
C”) 10 mg DL
Dose-Proportionality, Linearity, Desloratadine in Healthy Adults
dose-proportionality. linearity, and pharmacokinetic of DL. In this single-center, randomized, open-label,
of doses up to 20 mg.
MBrn mrans(er
has greater potency than terfenadine, cetirizine, and loratadine.
selective peripheral histamine H,-receptor antagonist activity and inhibits the release of histamine and other inflammatory and allergic mediators. The present study was conducted to assess the
event, regardless of association to study drug or placebo. There were no ECG changes or any dose-related adverse events. Desloratadine was found to be safe and well tolerated after I4 days of once-daily
cells are similar and represent systems at the human H, receptor. These data the newer generation antihistamines,
Affrimef. P Gluet. S Guprat, C Banjeldt *Arkansas Research Medical Testing Center. Little Rock, AR Wchering-Plough Research Institute, Kenilworth, NJ Desloratadine (DL) 5 mg is in development for the treatment of seasonal allergic rhinitis and other allergic conditions. DL has
(following once-daily dosing for I4 days) are presented below: Accumulation (ratio of multiple-dose AUCl,,.?,l single-dose AUC,o.illnnily,) ranged from I. I to I .6 and was consistent with the
c.
S385
In this study we
AUG. I (ngwrm)
77.5 (71.5)
73.82 (59.4)
99.696 (93.1074b)
en,. (“g/FL)
3.30 (1.20)
3.83 (1.17)
lOB.19b(99-11mt.)
‘“=I7
J ALLERGY CLIN IMMUNOL VOLUME 104. NUMBER 1, PART 2
relief
1124
and improvement
Multiple-Dose Desloratadine
in signs
and symptoms
Pharmacokinetics, in Healthy Volunteers
of SAR.
have characterized various antihistamines, including the new nonsedating antihistamine DL, in a Ca2+ flux assay at the human H, receptor that has been cloned and expressed in CHO cells and in a primary culture of human bronchial smooth muscle (HBSM)
Safety, and Tolerance of D Pudbi*. C Bar~field*, S
Gupro*. JM He~~ti. P Glue*. ME A@imc* Research Institute. Kenilworth, NJ tArkansas Testing Center, Little Rock. AR
*Schering-Plough Research Medical
cells.
which endogenously express the H, receptor. Histamine is the most potent agonist of Ca2+ flux in both CHO and the HBSM cells with an EC,, of 98 and 164 nM, respective-
Desloratadine (DL) is currently in development for the treatment of seasonal allergic rhinitis and other allergic conditions. It has selective peripheral histamine H,-receptor antagonist activity with additional antiallergic activity. This study was conducted to
ly. The rank order of agonist potency in this assay is histamine >imetit >R->>methyl-histamine tiimaprit, suggesting the effect is primarily related to H, receptors. Various classes of antihistamines inhibit this effect with similar potencies in both the CHO and the HBSM cells. The potency of certain antagonists is dependent on the time of pretreatment. The rank order of antagonist
evaluate the pharmacokinetics (PK), safety, and tolerability of DL after both single and multiple dosing. This single-center, randomized. double-blind (within-group),
potency in the CHO cells in this assay is clemastine = cyproheptadine = desloratadine = promethazine > astemizole = epinastine = pyrilamine > chlorpheniramine = terfenadine > loratadine = cet-
placebo-controlled. parallel-group. rising single/multiple-dose study of DL was conducted in 49 healthy male subjects (24-45 years old). Single oral doses of DL (5. 7.5. IO, or 20 mg; n=lO/dose) or placebo (n=2/dose) were followed 3 days later by the same doses given once daily for I4 days. Plasma concentrations of DL were determined up to 72 hours after single doses and
irizine = diphenhydramine = fexofenadine. These results in the Ca2+ flux assay are similar to values obtained in smooth muscle preparations from various animal species. These results demonstrate that measuring Ca2+ flux in the
up to I68 hours after the final dose in each dose group. Additional blood samples were obtained before dosing on Days l4- I7 for steady-state assessment. Vital signs, EC&. and clinical laborato-
CHO cells and the HBSM to evaluate antihistamines also indicate that among
ry tests were performed at pre-specified times throughout the study. Single-dose PK were characterized by dose-related increases in C,,;,, (I .83-7.08 ng/mL) and AUClo.i,fi,,,yl (32.5-169
desloratadine fexofenadine,
ng.h/mL). Dose-normalized C,,, and AUC were similar across groups. The apparent total body clearance ranged from I I4 to 20 I L/h; mean T!, was I9 to 34.6 hours. Steady-state PK parameters
1126
Tr, and the dosing frequency of DL. The apparent total body clearance and TN,: were not significantly different after single and multiple dosing. Headache was the most frequently reported adverse
administration
AuG,,
1125
5 mg
(n9WmL)
78.0
. (lq/mL)
2.18
DL
(127) (33)
7.5
(%
mg DL
104 (93) 3.03
(31)
20 mg OL
126 (99)
290
3.80
(29)
8.08
M Billah
Schering-Plough
Research
Institute.
(25)
slope for AUCIu.,l ginal deviation (P=O.O49) was of treatment-related
Kenilworth,
contraction
assays.
(PK)
profile
single-dose,
4-
vs dose deviate from linearity @‘X).05). A from linearity in the slope for C,,, vs no PK significance. Mild headache was the adverse event reported, and its incidence
mardose only was
not related to dose. The results of this study showed that desloratadine was safe and well tolerated and exhibited linear PK over the dose range 5 to 20 mg. Linearity implies predictability in the PK of DL.
of histamine and other inflammatory and allergic mediators. Identification and functional characterization of compounds that bind the histamine H, receptor have classically been performed in rat muscle
MB
malized (to 5 mg) C,,,, or AUClo.rl values (fiO.05). Neither the slope for C,,, vs dose (0.9645) nor the slope for AUCFo.,, vs dose (I .0197) were significantly different than I (p>O.O5), nor did the
Desloratadine (DL) relieves symptoms of seasonal allergic rhinitis and other allergic conditions. DL has selective peripheral histamine H,-receptor antagonist activity and inhibits the release
pig smooth
of
D Padhit.
mean (% coefficient of variation [CV]) PK parameters used in the assessment of dose-proportionality/linearity are provided below. There were no significant differences between the dose-nor-
NJ
and guinea
Pharmacokinetics
JM Hermn+.
least I4 days. Plasma concentrations of DL (O-168 h) were determined by gas liquid chromatography with nitrogen phosphorous detection, and PK parameters derived by standard methods. The
(92)
Functional Characterization of Desloratadine and Other Antihistamines in a Chinese Hamster Ovary (CHO) Cell Line That Expresses the Cloned Human Histamine H, Receptor and in Human Bronchial Smooth Muscle Cells (HBSMC) JCAnthes. C Riclmrd, RE West. S Willicrms. S Greenfedec H Gilchresf, RW &WI.
and
astemizole.
way crossover study, 20 healthy male volunteers (19-43 years old) received DL 5, 7.5, IO. and 20 mg orally under fasted conditions. Each subject received each dose on 4 occasions, separated by at
C”) 10 mg DL
Dose-Proportionality, Linearity, Desloratadine in Healthy Adults
dose-proportionality. linearity, and pharmacokinetic of DL. In this single-center, randomized, open-label,
of doses up to 20 mg.
MBrn mrans(er
has greater potency than terfenadine, cetirizine, and loratadine.
selective peripheral histamine H,-receptor antagonist activity and inhibits the release of histamine and other inflammatory and allergic mediators. The present study was conducted to assess the
event, regardless of association to study drug or placebo. There were no ECG changes or any dose-related adverse events. Desloratadine was found to be safe and well tolerated after I4 days of once-daily
cells are similar and represent systems at the human H, receptor. These data the newer generation antihistamines,
Affrimef. P Gluet. S Guprat, C Banjeldt *Arkansas Research Medical Testing Center. Little Rock, AR Wchering-Plough Research Institute, Kenilworth, NJ Desloratadine (DL) 5 mg is in development for the treatment of seasonal allergic rhinitis and other allergic conditions. DL has
(following once-daily dosing for I4 days) are presented below: Accumulation (ratio of multiple-dose AUCl,,.?,l single-dose AUC,o.illnnily,) ranged from I. I to I .6 and was consistent with the
c.
S385
In this study we
AUG. I (ngwrm)
77.5 (71.5)
73.82 (59.4)
99.696 (93.1074b)
en,. (“g/FL)
3.30 (1.20)
3.83 (1.17)
lOB.19b(99-11mt.)
‘“=I7