CLINICAL PHARMACOLOGY
in vitro plasma protein binding of dronedarone
and its N-debutyl metabolite is >98 % and not saturable. Both compounds bind
mainly to albumin. After intravenous (IV) administration the volume of
distribution at steady state is about 1400 L.
Gender
Dronedarone exposures are on average 30% higher in females than in
males.
Race
Pharmacokinetic differences related to race were not formally assessed.
However, based on a cross study comparison, following single dose administration
(400 mg), Asian males (Japanese) have about a 2-fold higher exposure than
Caucasian males. The pharmacokinetics of dronedarone in other races has not been
assessed.
Elderly
Of the total number of subjects in clinical studies of dronedarone, 73% were
65 years of age and over and 34% were 75 and over. In patients aged 65 years old
and above, dronedarone exposures are 23% higher than in patients less than 65
years old [see Use in Specific Populations ].
Hepatic impairment
In subjects with moderate hepatic impairment, the mean dronedarone exposure
increased by 1.3-fold relative to subjects with normal hepatic function and the
mean exposure of the N-debutyl metabolite decreased by about 50%.
Pharmacokinetic data were significantly more variable in subjects with moderate
hepatic impairment.
The effect of severe hepatic impairment on the pharmacokinetics of
dronedarone was not assessed [see Contraindications (4) ].
Renal impairment
Consistent with the low renal excretion of dronedarone, no pharmacokinetic
difference was observed in subjects with mild or moderate renal impairment
compared to subjects with normal renal function [see Use in Specific Populations ]. No pharmacokinetic
difference was observed in patients with mild to severe renal impairment in
comparison with patients with normal renal function.
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of
Fertility
In studies in which dronedarone was administered to rats and mice
for up to 2 years at doses of up to 70 mg/kg/day and 300 mg/kg/day,
respectively, there was an increased incidence of histiocytic sarcomas in
dronedarone-treated male mice (300 mg/kg/day or 5— the maximum recommended human
dose based on AUC comparisons), mammary adenocarcinomas in dronedarone-treated
female mice (300 mg/kg/day or 8— MRHD based on AUC comparisons) and hemangiomas
in dronedarone-treated male rats (70 mg/kg/day or 5— MRHD based on AUC
comparisons).
Dronedarone did not demonstrate genotoxic potential in the in vivo mouse
micronucleus test, the Ames bacterial mutation assay, the unscheduled DNA
synthesis assay, or an in vitro chromosomal aberration assay in human
lymphocytes. S-9 processed dronedarone, however, was positive in a V79
transfected Chinese hamster V79 assay.
In fertility studies conducted with female rats, dronedarone given prior to
breeding and implantation caused an increase in irregular estrus cycles and
cessation of cycling at doses ≥10mg/kg (equivalent to 0.12— the MRHD on a
mg/m2 basis).
Corpora lutea, implantations and live fetuses were decreased at 100 mg/kg
(equivalent to 1.2— the MRHD on a mg/m2 basis). There
were no reported effects on mating behavior or fertility of male rats at doses
of up to 100 mg/kg/day.
13.3 Developmental Toxicity
Dronedarone was teratogenic in rats given oral doses ≥80
mg/kg/day (a dose equivalent to the maximum recommended human dose [MHRD] on a
mg/m2 basis), with fetuses showing external, visceral and
skeletal malformations (cranioschisis, cleft palate, incomplete evagination of
pineal body, brachygnathia, partially fused carotid arteries, truncus
arteriosus, abnormal lobation of the liver, partially duplicated inferior vena
cava, brachydactyly, ectrodactylia, syndactylia, and anterior and/or posterior
club feet). In rabbits, dronedarone caused an increase in skeletal abnormalities
(anomalous ribcage and vertebrae, pelvic asymmetry) at doses ≥20 mg/kg (the
lowest dose tested and approximately half the MRHD on a mg/m2 basis).
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