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Lamson MJ, et al. Show all
Clin Drug Investig. 2011;31(8):585-97. doi:
10.2165/11590250-000000000-00000.
Pfizer Inc, Cary, NC, USA.
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BACKGROUND AND OBJECTIVE: Acute repetitive seizures (ARS) are
a
debilitating part of episodic seizure activity that can
sometimes progress to
status epilepticus. Currently approved treatment that can be
administered by
non-medical personnel to patients with ARS is a diazepam rectal
gel. While
effective, rectal administration can be difficult, inconvenient
and objectionable. A
diazepam autoinjector has been developed to deliver diazepam via
an
intramuscular (IM) injection. This study evaluated the dose
proportionality of the
diazepam autoinjector and the consequent diazepam
bioavailability relative to
an equivalent dose of diazepam administered rectally as a
commercial gel.
METHODS: This was a phase I, randomized, open-label, two-part,
single-dose,
crossover, single-centre pharmacokinetic study in 48 healthy
young adult (aged
18-40 years) male and female subjects. Part I of the study (n =
24) evaluated the
dose proportionality of three strengths of the diazepam
autoinjector (5, 10 and
15 mg) administered into the mid-outer thigh via a deep IM
injection. Part II (n =
24) assessed the relative bioavailability of the diazepam 10 mg
autoinjector
versus the diazepam 10 mg rectal gel. Parts I and II were run
concurrently. Each
subject completed screening up to 30 days prior to three (Part
I) or two (Part II)
dosing periods. Serial blood sampling for plasma diazepam
and
desmethyldiazepam (metabolite) concentrations, vital signs and
adverse event(AE) assessments were performed at prespecified times.
Treatments were
separated by a 14-day washout period.
RESULTS: In Part I, dose proportionality was demonstrated for
the diazepam
autoinjector at 5, 10 and 15 mg doses by increases in mean
maximum plasma
concentration (C(max)), mean area under the plasma
concentration-time curve
(AUC) from time zero to infinity (AUC()), and mean AUC from time
zero to time
of last measurable concentration (AUC(last)). The median time to
reach C(max)
(t(max)) was consistent at 1 hour for each dose. In Part II of
the study, IM
Search term
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administration via diazepam autoinjector (10 mg) resulted in
plasma
concentrations of both diazepam and desmethyldiazepam that were
slightly
higher and less variable than those observed following
administration of
diazepam rectal gel (10 mg). The geometric mean ratio
(diazepam
autoinjector/diazepam rectal gel) and 90% confidence intervals
for diazepam
C(max) and AUC(last) were 0.94 (0.84, 1.05) and 1.14 (1.08,
1.21), respectively,
indicating that the overall bioavailability of the diazepam
autoinjector was
approximately 14% higher than that of diazepam rectal gel. Both
treatments were
generally well tolerated. Although the incidence of
treatment-emergent AEs was
higher with diazepam autoinjector compared with diazepam rectal
gel (21.7% vs
13.6%), the difference can be attributed to injection site pain.
Injection site pain
also correlated with the diazepam autoinjector dose administered
in Part I: 5 mg
(4.3%), 10 mg (21.7%) and 15 mg (27.3%). However, no patients
discontinued the
trial due to injection site pain. No other AEs correlated with
dose, and there was
no evidence of respiratory depression with either
administration.
CONCLUSION: Results of the present study indicated that diazepam
can be
safely and reliably administered IM using a diazepam
autoinjector.
PMID 21721594 [PubMed - indexed for MEDLINE]
Full text: Springer
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Bioavailability and dose proportionality of intramuscular
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