A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Remodulin Pharmacology, Pharmacokinetics, Studies, Metabolism - Treprostinil sodium
Remodulin Pharmacology, Pharmacokinetics, Studies, Metabolism - Treprostinil sodium
CLINICAL PHARMACOLOGY
General: The major pharmacological actions of treprostinil
are direct vasodilation of pulmonary and systemic arterial vascular beds and
inhibition of platelet aggregation. In animals, the vasodilatory effects reduce
right and left ventricular afterload and increase cardiac output and stroke
volume. Other studies have shown that treprostinil causes a dose-related negative
inotropic and lusitropic effect. No major effects on cardiac conduction have
been observed.
Pharmacokinetics
The pharmacokinetics of continuous subcutaneous Remodulin are
linear over the dose range of 1.25 to 22.5 ng/kg/min (corresponding to plasma
concentrations of about 0.03 to 8 mg/L) and can be
described by a two-compartment model. Dose proportionality at infusion rates
greater than 22.5 ng/kg/min has not been studied.
Absorption: Remodulin is relatively rapidly and completely
absorbed after subcutaneous infusion, with an absolute bioavailability approximating
100%. Steady-state concentrations occurred in approximately 10 hours. Concentrations
in patients treated with an average dose of 9.3 ng/kg/min were approximately
2 mg/L.
Distribution: The volume of distribution of the drug in the
central compartment is approximately 14L/70 kg ideal body weight. Remodulin
at in vitro concentrations ranging from 330-10,000 mg/L
was 91% bound to human plasma protein.
Metabolism: Remodulin is substantially metabolized by the liver,
but the precise enzymes responsible are unknown. Five metabolites have been
described (HU1 through HU5). The biological activity and metabolic fate of these
metabolites are unknown. The chemical structure of HU1 is unknown. HU5 is the
glucuronide conjugate of treprostinil. The other metabolites are formed by oxidation
of the 3-hydroxyoctyl side chain (HU2) and subsequent additional oxidation (HU3)
or dehydration (HU4). Based on the results of in vitro human hepatic cytochrome
P450 studies, Remodulin does not inhibit CYP-1A2, 2C9, 2C19, 2D6, 2E1, or 3A.
Whether Remodulin induces these enzymes has not been studied.
Excretion: The elimination of Remodulin is biphasic, with a
terminal half-life of approximately 2-4 hours. Approximately 79% of an administered
dose is excreted in the urine as unchanged drug (4%) and as the identified metabolites
(64%). Approximately 13% of a dose is excreted in the feces. Systemic clearance
is approximately 30 liters/hr for a 70 kg ideal body weight person.
Special Populations
Hepatic Insufficiency: In patients with portopulmonary hypertension
and mild (n=4) or moderate (n=5) hepatic insufficiency, Remodulin at a subcutaneous
dose of 10 ng/kg/min for 150 minutes had a Cmax that was increased
2-fold and 4-fold, respectively, and AUC 0-¥ was
increased 3-fold and 5-fold, respectively, compared to healthy subjects. Clearance
in patients with hepatic insufficiency was reduced by up to 80% compared to
healthy adults.
In patients with mild or moderate hepatic insufficiency, the
initial dose of Remodulin should be decreased to 0.625 ng/kg/min ideal body
weight and should be increased cautiously. Remodulin has not been studied in
patients with severe hepatic insufficiency.
Renal Insufficiency: No studies have been performed in patients
with renal insufficiency, so no specific advice about dosing in such patients
can be given. Although only 4% of the administered dose is excreted unchanged
in the urine, the five identified metabolites are all excreted in the urine.
Effect of Other Drugs on Remodulin: In vitro studies: Remodulin
did not significantly affect the plasma protein binding of normally observed
concentrations of digoxin or warfarin.
In vivo studies: Acetaminophen - Analgesic doses of acetaminophen,
1000 mg every 6 hours for seven doses, did not affect the pharmacokinetics of
Remodulin, at a subcutaneous infusion rate of 15 ng/kg/min.
Clinical Trials in Pulmonary Arterial Hypertension (PAH)
Two 12-week, multicenter, randomized, double-blind studies
compared Remodulin to placebo in a total of 470 patients with NYHA Class II-IV
pulmonary arterial hypertension (PAH). PAH was primary in 58% of patients, associated
with collagen vascular disease in 19%, and the result of congenital left to
right shunts in 23%. The mean age was 45 (range 9 to 75 years). About 81% were
female and 84% were Caucasian. Pulmonary hypertension had been diagnosed for
a mean of 3.8 years. The primary endpoint of the studies was change in 6-minute
walking distance, a standard measure of exercise capacity. There were many assessments
of symptoms related to heart failure, but local discomfort and pain associated
with Remodulin may have substantially unblinded those assessments. The 6-minute
walking distance and an associated subjective measurement of shortness of breath
during the walk (Borg dyspnea score) were administered by a person not participating
in other aspects of the study. Remodulin was administered as a subcutaneous
infusion, described in DOSAGE AND ADMINSTRATION,
and the dose averaged 9.3 ng/kg/min at Week 12. Few subjects received doses
> 40 ng/kg/min. Background therapy, determined by the investigators, could
include anticoagulants, oral vasodilators, diuretics, digoxin, and oxygen but
not an endothelin receptor antagonist or epoprostenol. The two studies were
identical in design and conducted simultaneously, and the results were analyzed
both pooled and individually.
Hemodynamic Effects
As shown in Table 1, chronic therapy with Remodulin resulted
in small hemodynamic changes consistent with pulmonary and systemic vasodilation.
Table 1: Hemodynamics During Chronic Administration of Remodulin
in Patients with PAH
|
Hemodynamic
Parameter
|
Baseline
|
Mean change from baseline at Week 12
|
|
Remodulin (N=204-231)
|
Placebo (N=215-235)
|
Remodulin (N=163-199)
|
Placebo (N=182-215)
|
|
CI (L/min/m2)
|
2.4 ± 0.88
|
2.2 ± 0.74
|
+0.12 ± 0.58*
|
-0.06 ± 0.55
|
|
PAPm (mmHg)
|
62 ± 17.6
|
60 ± 14.8
|
-2.3 ± 7.3*
|
+0.7 ± 8.5
|
|
RAPm (mmHg)
|
10 ± 5.7
|
10 ± 5.9
|
-0.5 ± 5.0*
|
+1.4 ± 4.8
|
|
PVRI (mmHg/L/min/m2)
|
26 ± 13
|
25 ± 13
|
-3.5 ± 8.2*
|
+1.2 ± 7.9
|
|
SVRI (mmHg/L/min/m2)
|
38 ± 15
|
39 ± 15
|
-3.5 ± 12*
|
-0.80 ± 12
|
|
SvO2 (%)
|
62 ± 100
|
60 ± 11
|
+2.0 ± 10*
|
-1.4 ± 8.8
|
|
SAPm (mmHg)
|
90 ± 14
|
91 ± 14
|
-1.7 ± 12
|
-1.0 ± 13
|
|
HR (bpm)
|
82 ± 13
|
82 ± 15
|
-0.5 ± 11
|
-0.8 ± 11
|
*Denotes statistically significant difference between Remodulin
and placebo, p<0.05.
CI = cardiac index; PAPm = mean pulmonary arterial pressure;
PVRI = pulmonary vascular resistance indexed;
RAPm = mean right atrial pressure; SAPm = mean systemic arterial
pressure; SVRI = systemic vascular resistance indexed;
SvO2 = mixed venous oxygen saturation;
HR = heart rate.
Clinical Effects
The effect of Remodulin on 6-minute walk, the primary end point
of the studies, was small and did not achieve conventional levels of statistical
significance. For the combined populations, the median change from baseline
on Remodulin was 10 meters and the median change from baseline on placebo was
0 meters. Although it was not the primary endpoint of the study, the Borg dyspnea
score was significantly improved by Remodulin during the 6-minute walk, and
Remodulin also had a significant effect, compared with placebo, on an assessment
that combined walking distance with the Borg dyspnea score. Remodulin also consistently
improved indices of dyspnea, fatigue and signs and symptoms of pulmonary hypertension,
but these indices were difficult to interpret in the context of incomplete blinding
to treatment assignment resulting from infusion site symptoms.
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