Antihypertensive efficacy of Omapatrilat, a vasopeptidase inhibitor, compared with lisinopril.

124A

ASH XIV ABSTRACTS

AJH-APRIL

2999-VOL.

12, NO. 4, PART 2

DO53

DO54

LACK OF PHARMACOKINETIC INTERACTION BETWEEN VALSARTAN, AN ANGIOTENSIN II RECEPTOR BLOCKER, AND DIGOXIN. A CARDIOTONIC AGENT. P Prasad, S Mangat, CM Yeh. and R Glazer. Novartis Pharmaceuticals Corporation, East Hanover, NJ. Valsartan (VAL) is an angiotensin II receptor blocker used as an antihypertensive agent. Dig&n (DIG) is a frequently prescribed drug to patients with congestive heart failure. Currently VAL is being evaluated clinically in CHF patients. It is likely that both VAL and DIG may be wadministered in clinical practice. It is, therefore. important to examine the potential for a drug-drug interaction. especially for DIG. which has a narrow therapeutic range (0.52 ng/ml). The present trill examined a pharmacokinetic (PK) interaction between VAL and DIG in healthy volunteers following single doses of one 160 mg VAL capsule, one 0.25 mg DIG tablet and a combination of the two. The subjects received the three treatments in a randomized. three-way crossover fashion with a two week washout between doses. Seventeen subjects completed the trial. Following the dose administration. serial blood samples were obtained up to 40 h and 168 h for VAL and DIG, respectively for PK assessment. Plasma concentrations of VAL and DIG were determined by validated HPLC and RIA methods, respectively. Area under the plasma concentration curve (AUC), maximum concentration (Cm& and time to Cmax (Tmax) were determined. AUC and Cmax parameters were evaluated statistically based on 90% confidence intervals (Cl) for the ratios of the means using the log transformed parameter values. The mean * SD of PK parameters are listed below:

ANTIHYPERTENSIVE EFFICACY OF OMAPATRILAT, A VASOPEPTIDASE INHIBITOR, COMPARED WITH LISINOPRIL. ,!&!&#, A. Shepherd’, J. Pool’, E. Levy, R. Saini’, and P.I. Chang. Orange County Research Ctr.. Orange, CA, University of Texas, San Antonio, TX, Baylor University, Houston, TX, Bristol-

AUC(O-1) (ng*h/ml)

Cmax ,tnglml)

MedianTmax (h)

17949 * 7748 15472f7573

2632*1115 2297 * 1022

3.0 3.0

Treatment

SAFETY

AND

EFFICACY

NICARDIPINE

WE, Bunchmsn

calcium

channel

emergencies

To date, there

(HTN).

greater than

the 99th

of intravenous

percentile

for age. All

continuous

infusion

indwelling

arterial line or Dinamap

initiationofNC as primary

monitor.

aversged7.4+5.4 treatment

NC CH

HTN.

Oma

Lis

Smg

1Omg

20 mg

40 mg

20 mg (99) -10.5

(101)

-2.8

-11.1

(103) -10.5

(118) -14.3’

(110) -16.0*

-9.1

-8.8

-10.1

-11.1

ADBP

-3.5

In African-American

oatients.

the A in SBPlDBP

>65 yr. the A in SBPlDBP

-9.7

was

1.4 mm Hg wkh Oma 40 mg vs -OS/-5.1

omapatrilat, vasopeptidase antihypertensive efficacy,

(age

NC

between

NC provided

effective

BP control

without

1SBP (mmHg) 1 144237

NC treatment

1

mm Hg with Lis

was

inhibitor, dose ranging, safety, African-American

(

IZqC_lS

0.003

1

NS

to NC &tment:

and one child complained on Holter

for

NC

emergencies antihypertensive

yesrs)

with

HTN.

vs. 0.17+0.13

dosing to achieve sustained control

with AM

required

two additional

pressure

(BP)

fell

(P=O.O4). For the entire 123.4*14.9

mmHg

from

BP fell

treatment,

pts) and leg edema (1 pt). All

with no evidence

of

any

agent, CH treated with

children,

calcium

for

NC should

channel

blockers

131.6+12.4

to

79.hk13.4

systolic

be

bpm

dizziness

that AM

dosing in order

m&$day

HTN

KeY Words:

appear to require

amlodipine,

children,

BP

AM

(80%

alone, systolic

123.5+12.9

mmHg

to 68.2i6.6

mmHg

130.8*12.1

to

77.Z9.8

to

bpmbefore

treatment

(P=NS).

Side (2

with dose reduction. effective

BP control

higher

without

and secondary

in a significant

sustained

agents to achieve optimal

BID

were more likely

BP fell from

with primary

may be required

additional

in

required

with sHTN

BP fell from

during

improved

secondary

(32

group required

(3 pts), fatigue (2 pts). flushing

provides

to achieve

20,

dose for

agent, and 14%

with pHTN

that received

side effects in children

Twice-daily children

intravenously

included

We conclude significant

with

AM

36% of patients achieved

(P=O.O3), and diastolic

and 90.7A24.1

HTN

transplant

67.7+10.7mmHg(P~O0.001).Hesrirateaveraged89.4+22.3 AM

We

in tablet form

one additional

from

group,

agents.

3). Average given

of

of action

had primary organ

alone than children

For the group

(CCB)

in 36 children

47% ofpatients

agents. Children

and diastolic

CCB

ofAM

group (O.OwO.03

BP control.

with AM

other

in the sHTN

P=O.Ol).

alone, 50% required

to achieve BP control

blocker

children

m&g/day,

in sHTN,

(BP)

TE Bunchman.

longer duration

(sHTN;

(4 pts). Children

intravenous

As

Five HTN

was 0.16*0.12

that was treated with

CH.

than

a higher dose than those in the pHTN pHTN

channel

has a

renal disease 8, renovsscular

pts), or as a suspension

(P=NS),

were two

treatment

WE Smoyer,

and tolerability

and 31 had secondary

PRESSURE

OR SECONDARY

MI.

of side effects

effects reported

of palpitations,

Arbor,

studied the efficacy

hypotension

to avoid adverse effects. nicardipine,

JT Flvnn’,

one child~developed

is a safe and effective in

(pHTN),

BLOOD

PRIMARY

is a newer calcium

incidence

(age 11.5i4.8

blood

monitoring. that

lower

WITH

class that reportedly

vs. 29%, P=O.O47).

70.4k7.2

as a single agent in all but 3 patients.There overdose

dose

to slowly

112215

adverse reactions

caused by an accidental

NC

HR (bpm)

NC was effective

and

EFFECTIVE

Ann

(AM)

the entire group

(range 0.6 _ 4.0).

) DBP (mmHg) 1 91.3+12.7 1

0.02

Amlodipine the dihydropyridine

by

to 16h). 60% ofCH

(HTN).

of Michigan,

psrenchymal

causing tachycsrdia:

119+18.7

P

HYPERTENSION

by

prior to

the 90th and 95th percentiles

dose was 2.2~1.3 mcgikglmin

Before NC treatment

of HTN

PROVIDES IN CHILDREN

prospectively

as BP

NC was started at an initial

effective

Key Words:

on its

defined

0.4 - 3.0), and was titrated

age. Average

monitored

by

in 17 CH received

Duration

hours (rsnge0.5

(range

achieve target BP, usually

We conclude

of

with other agents, and 40% received

of their

of 1.2kO.9 mcg!kg/min

administered

Oma

(108)

CONTROL

in an ICU setting with constant BP monitoring

received NC after treatment

closely

,

Oma

ASBP

AMLODIPINE

We prospectively

the safety

hypertensive

I

I

Oma

dose N

is an effective

are few data available

severe hypertension

and efficacy

blocker,

yrs, range 3 days to 16.4 yrs) with severe HTN,

arrhythmia

Pbo

FOR

in adults when administered

studied

calcium,

I

Target

JT,*

TE. University

9825.5

During

(DBP) 95-l 10 mm Hg. All Oma doses produced significant (P
University

for hypertensive infusion.

(CH)Flvnn

MI

a dihydropyridine

in CH with

(NC)

IN CHILDREN

DB, Smoyer

Ann Arbor,

intravenous

OF

EMERGENCIES

TA, Kershaw

efticacy

NJ for

is (NEP)

DO56

HYPERTENSIVE

NC,

Princeton.

and angiotensin converting enzyme. Inhibition of NEP protects endogenous vasodilators, including natriuretic peptides, bradykinin. and adrenomedullin, from degradation. The effects of Oma 5-40 mg once daily vs lisinopril (Lis) 20 mg once daily and placebo (Pbo) were studied in a g-week trial in patients with diastolic BP

Keywords:

DO55

treatment

Institute,

-17.11-10.6 mm Hg with Oma 40 mg vs -8.5/-10.6 mm Hg with Lis 20 mg. Discontinuation due to adverse events was similar in Oma, Lis. and Pbo groups. Oma in doses up to 40 mg once daily is well tolerated and produces substantial dose-related reductions in SBP and DBP. BP reduction with Oma is similar regardless of age or race/ethnicity. Doses up to 80 mg once daily are being evaluated for the treatment of hypertension and heart failure.

w

Michigan,

Research

(Oma). a novel vasopeptidase inhibitor, that inhibits both neutral endopeptidase

20 mg. In patients

1.0 DIG alone 0.93 * 0 28 8.5 k3.3 0.94 * 0.29 1.0 DIG with VAL 8.6 f3.l 1 = 48 hours‘or VAL and 168 hoursfor DIG All subjects tolerated VAL. DIG, and the combination treatments well. Statistical analysis showed the Cls were within 0.7-l .25 for the PK parameters of VAL and 0.9-1.25 for that of DIG. Based on the study results and statistical analysis, it was concluded that there wss no PK interaction between VAL and DIG and these drugs can be safely administered together. Key Words: v alsartan. Digoxin. Pharmacokinetics, drug interaction

Mattes

Omapatrilat a single molecule

-16.81-l

VALSARTAN VAL alone VAL with DIG

Myers Squibb Pharmaceutical Omapatrilat Investigators.

BP control.

HT’N.

percentage Children

doses of AM

of with

as well

as

BP control.

calcium channelblockers