Administration and Dosage
It has been suggested that a 90 – 99 % reduction of viral replication
is required for effective therapy of quickly progressing acute viral
infections; the general standard for chronic viral infections being 50
% [19]. The dose for a ~ 90 % reduction of
SARS-CoV-2 pseudovirus replication in vitro was shown to be
approximately 3 µg/ml [7].
Tetrandrine has been reported to be poorly soluble (saturation is
0.015 mg/ml in phosphate buffered saline at pH 7.4), and to have low and
variable oral bioavailability (cited in [20], and references
therein). Pharmaceutical methods have thus been investigated to improve
the bioavailability; including lipid nanocapsules, nanoparticles,
ethosomes, and microspheres [20]. Tetrandrine has also been
administered by inhalation in humans with a metered dose inhaler for the
treatment of asthma (reviewed in [21], original not available).
Administration in mice of 30 mg/kg tetrandrine intraperitoneally, a
frequently-used dose in animal studies, was shown to give a peak plasma
concentration of 2 µM (1.2 µg/ml) [22], whilst 10 mg/kg of oral
tetrandrine resulted in a peak plasma concentration of 500 ng/ml in rats
[20]. If the drug was emulsified, the same dose gave a peak
concentration of 1.2 µg/ml [20]. Pharmacodynamic studies in human
subjects [23] showed that a single oral dose of 100 mg tetrandrine
produced an average maximal serum concentration of 67.26 ng/ml (n = 6).
However, these data require confirmation, as there seems to be a
discrepancy between this value and a graph in the same publication.
In rats, the average maximal serum concentration obtained after
inhalation of 8 mg/kg of tetrandrine was 140 ng/ml. While this serum
concentration was moderate, average maximal wet lung tissue
concentration obtained at post mortem examination following inhalation
of the same dose of tetrandrine was over 90 µg/g. Lung concentrations
following intravenous administration of 7.5 mg/kg were also relatively
high with an average maximal concentration of ~ 20 µg/g
[24]. In another study investigating the spatiotemporal distribution
of tetrandrine in rats using mass spectrometry imaging, 30 mg/kg
intravenous administration also resulted in high drug concentrations
specifically in the lungs with a peak of ~ 120 µg/g
[25].
The above data suggest that tetrandrine may reach therapeutic
concentrations in lung tissue even when serum concentrations remain
relatively low. This is in keeping with its two compartment kinetic
profile and high apparent volume of distribution (though up to 90 % of
the drug can be plasma protein bound; [2], and references therein).
Toxic doses have been reported in an MRC-5 human lung cell line study
with cytotoxic concentration (CC50) > 10 µM
[18]. Similar results were reported in WI-38 human lung fibroblast
and NL-20 human bronchial epithelial cell lines [26] In animal
experiments, the reported median lethal dose (LD50) for
oral administration was 3700 mg/kg in mice and 2230 mg/kg in rats (cited
in [6]). Acute lung injury was demonstrated in mice at a dose of 150
mg/kg intraperitoneally [26]. Toxic effects of tetrandrine in humans
have been reported with 10 mg/kg intravenous administration (cited in
[2] and [6]).
According to the above-mentioned Chinese patent (WO2004009106A1, 2002),
dosage in humans is usually in the range of 0.02 - 1.5 g/day depending
on the weight and symptoms of the patient. Tetrandrine has been used at
an oral dose of 60 – 100 mg three times a day in recent studies on
silicosis ([27], [28]), and at 60 mg four times a day in an
ongoing clinical trial (see below). In intravenous administration in
humans, doses between 240 mg and 300 mg have been described as a ‘safe
range’ (cited in [6] , original not available). The maximum utilised
doses in human studies that could be found were 200 mg orally three
times a day (cited in [2]), and 400 mg three times a day with the
route of administration not stated (cited in [6]).
It is difficult to conduct relevant animal to human dose conversions
given the lack of in vivo studies of tetrandrine in SARS-CoV-2
infection and the lack of lung concentration data for oral
administration of tetrandrine. The following human equivalent dose (HED)
calculation serves only to illustrate that established clinical doses of
tetrandrine in humans are likely to lead to potentially effective doses
for viral inhibition in lung, as based on animal/cell line studies. The
HED of a 7.5 mg/kg intravenous dose in rat (shown to give rise to lung
concentrations of tetrandrine many times that required for a
~ 90 % reduction of SARS-CoV-2 pseudovirus replicationin vitro ) is ~ 1.21 mg/kg [29], i.e.
~ 72.6 mg for a standard 60 kg human. This is well below
reported toxic doses in humans, and even with low bioavailability should
be achievable with oral equivalent doses in the range of the above
mentioned clinical trial (240 mg/day in divided doses).