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CYCLOSET: A UNIQUE
APPROACH TO TREATING
DIABETES

Michael Meldrum, Pharm.D. Candidate


Diabetes Mellitus (DM) has become more preva-
lent in the United States. The CDC estimates
that 23.6 million people had a diagnosis of DM
in 2007, including 1.6 million incident cases. The esti-
mated cost of DM in 2007 was $174 billion.'
Current therapy for DM relies on medications that
either supplement the bodies ability to produce insu-
lin or improve the bodies response to insulin. Cyc-
loset is an immediate-release formulation of bro-
mocriptine mesylate (IR-Brom) intended to release
the dose quickly at a certain time of day. The new drug
application was submitted by Veroscience, a small
drug development and research company, which has
subsequently partnered with S2 Therapeutics to mar-
ket and manufacture the drug.2
Cycloset was approved by the FDA on May 5,
2009 after more than ten years of study. The initial
application was filed on August 22, 1997, but required
multiple supplemental submissions to satisfy the
FDA.3 As part of the approval process, IR-Brom was
subject to the new higher standards for DM medica-
tions to prove cardiovascular safety.
IR-Brom has been approved for use as an adjunct
to diet and exercise for the treatment of adults with
Type II DM. Combination therapy with thiazoladin-
ediones and/or insulin has not been adequately stud-
ied.4 The labels of DM medications have been changed
recently to reflect a more generic statement of use of
addition to diet and exercise. This article will review


the unique mechanism of IR-Brom, its pharmacokinet-
ics, adverse effects, and results of the most recent
clinical studies.


PHARMACOLOGY


The exact mechanism of IR-Brom in the treatment
of DM is unknown; however, bromocriptine decreases
Alc and fasting plasma glucose. Bromocriptine may
work by resetting the neuroendocrine rhythms in the
hypothalamus of DM patients.5 Research with bro-
mocriptine for the treatment of DM began after the
discovery that neuroendocrine levels are altered sea-
sonally in migrating vertebrates, affecting fat stores
and glucose utilization. This seasonal variation creates
an obese, insulin-resistant and hyperinsulinemic state
in these animals.6 Circadian rhythm alteration is re-
lated to the activity of dopaminergic (DA) and seroton-
ergic neurons. Bromocriptine may cause the neuroen-
docrine activity to be reset by adjusting DA and sero-
tonin activity resulting in increased insulin sensitiv-
ity.7
The circadian rhythm alteration occurs via a
change in the activity of the suprachiasmatic nucleus
(SCN). Regulation of the SCN then alters the activity of
the ventromedial hypothalamus (VMH) which is re-
sponsible for the seasonal insulin resistant state in




INSIDE THIS ISSUE:

CYCLOSET: A UNIQUE APPROACH TO
TREATING DIABETES

ONCE DAILY AMINOGLYCOSIDES:
A REVIEW AND UPDATE


mm
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Table 1. Pharmacokinetic properties of immediate-release bromocriptine.4


CHARACTERISTIC


EFFECT


Absorption/Bioavailability 7% bioavailable; peak concentration 53 min
Food 55-65% increase in bioavailability; peak concentration 90-120 min
Distribution 61 L; 90-96% protein binding
Metabolism CYP 450 3A4
Excretion Mostly biliary; 2-6% in urine
Renal/Hepatic Adjustment None/caution in impairment
Age Not indicated for pediatric use; no studies in geriatric population
Gender 18-30% increased plasma exposure in females


mammals. The dopamine activity of bromocriptine
reduces the activity of noradrenaline and serotonin at
the VMH.6


PHARMACOKINETICS


IR-Brom is 65-95% absorbed and reaches peak
concentration in 53 minutes following oral dosing.4
The rapid absorption creates the proper peak activity
on DA receptors which then resets the circadian
rhythm. Bromocriptine is metabolized by the CYP 450
system, specifically 3A4. A high first pass metabolism
results in only 7% of absorbed drug reaching circula-
tion. Approximately 2-6% of bromocriptine is excreted
in the urine, while the remainder undergoes biliary
excretion.
Food increases the percent absorbed and delays
the time to peak concentration of IR-Brom, thus ad-
ministration with food is recommended. IR-Brom is
bound by plasma proteins (90-96%) with a half life of
approximately 6 hours. Currently, no studies have
been performed in patients with renal or hepatic fail-
ure. Based on the route of elimination, renal impair-
ment should have little effect on the concentration of
bromocriptine, but hepatic impairment may lead to
increased concentrations. Therefore, caution should be
used in patients with hepatic impairment when taking
this medication. A summary of the pharmacokinetic
properties of IR-Brom can be found in Table 1.4

CLINICAL TRIALS

Six phase II efficacy trials have evaluated quick re-
lease bromocriptine formulations (Table 2). These
trials demonstrated that IR-Brom was effective in re-
ducing glucose levels in obese Type II DM patients.6
Multiple phase III trials have also demonstrated that
IR-Brom is safe and effective for reducing Aic in DM


patients (Table 3). Two larger studies were used to
obtain final approval of IR-Brom. Gaziano, et al. evalu-
ated IR-Brom in a double-blind, placebo-controlled,
non-inferiority trial designed to determine safety, de-
fined as time to first major adverse event, and efficacy,
defined as the change in Aic after 24 weeks of therapy,
as the primary outcomes. Enrolled patients were on
usual DM therapy (defined as diet alone, 2 oral agents,
or insulin plus 1 oral agent) and were randomly as-
signed to IR-Brom or placebo. Treatment lasted for 52
weeks and patients were assigned in a 2:1 ratio to IR-
Brom or placebo (N=3095). A lower risk of the cardio-
vascular endpoint was found in the IR-Brom treatment
group compared to the placebo arm. In addition, no
significant difference occurred between groups for the
composite of serious adverse events. The authors ob-
served a 0.69 difference in Aic between groups (P=
0.0002) with 52.9% of IR-Brom patients achieving a
0.7 drop in Aic versus 23.5% in the placebo arm (P=
0.0004).8
Scranton, et al., in a double blind, placebo-
controlled, 52 week trial, evaluated the cardiovascular
safety of IR-Brom. Three thousand and seventy partici-
pants were randomly assigned in a 2:1 ratio to IR-
Brom or placebo in this non-inferiority trial. The pri-
mary outcomes of the trial were overall safety and car-
diovascular safety. Secondary analysis was planned to
look at subgroups in regards to Aic control. Patients
were allowed to be on other DM medications but had
to be on a stable dose for the first 3 months and then
adjustments could be made to the drug regimen as
needed. IR-Brom was titrated weekly to the maximum
tolerated dose of 4.8 mg/d. IR-Brom was non-inferior
to placebo for the adverse effects profile, and showed a
42% macrovascular risk reduction. Aic was reduced to
a greater extent with IR-Brom than placebo in all sub-
sets analyzed.9


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Table 2: Summary of Phase II trials of immediate-release bromocriptine.
DESIGN POPULATION TREATMENT FINDINGS
Open label Obese nondiabetic with hyperin- 1.6 mg/day for 2 weeks Decreased elevated fasting and post-prandial
sulinemia (n=12) insulin
SDecreased post-prandial glucose
Open label Obese nondiabetic postmeno- 1.6 mg/d for 8 weeks Decreased post-prandial glucose
pausal with hyperinsulinemia
(n=13)
Double blind, placebo- Obese DM II 1.6 mg/d for 16 weeks Reduced Alc by 1.8%
controlled
Dose response study Obese DM II 1.6 mg/d to 15 mg/d for. Linear relation between increasing IR-Brom
35 days dose and 24-hour glucose AUC
Increased side effects above 7.2 mg/d
Optimal dose = 4.8 mg/d
Double blind placebo- Obese DM II (n=22) 4.8 mg/d for 16 weeks Decreased Alc by 1.2% compared to placebo
controlled Decreased FPG by 54 mg/dl compared to pla-
cebo
Placebo-controlled DM II currently using insulin 4.8 mg/d for 12 weeks Decreased Alc by 0.7% compared to placebo
(n=11 placebo; 21 treatment) Decreased insulin requirement by 8% over pla-
cebo




Adverse effects from clinical trials are summarized food to increase the absorption of the drug. Titration is
in Table 4 stopped either when 6 tablets per day are reached or
side effects limit any further increase in dose.4
DOSING & ADMINISTRATION
COST
The approved dose of IR-Brom is 0.8 mg daily and
is intended to be titrated up weekly. The target dose is Cycloset is currently not available as Veroscience
between 2 and 6 tablets daily (1.6-4.8 mg daily). Since is in the process of finding a distributor. The company
IR-Brom is designed to affect circadian rhythms, it has not released any timeline for when the drug will
should be taken within the first two hours of waking. actually make it to the market.1
Furthermore, IR-Brom should be administered with


Table 3. Summary of Phase III trials of immediate-release bromocriptine.

STUDY DESIGN TREATMENT FINDINGS
Cincotta et al.6 Placebo-controlled Sulfonylurea plus placebo or IR. IR-Brom decreased Alc 0.21% (P<0.0001)
(1999) Obese DM II -Brom Alc difference 0.55% IR-Brom vs placebo
N=494 IR-Brom titrated weekly to 4.8 (P<0.0001)
mg/d for 24 week Reduced FPG 23 mg/dl vs placebo
(P<0.0001)
Cincotta et al.6 Placebo-controlled IR-Brom monotherapy IR-Brom reduced Alc by 0.17% and Alc
(1999) Obese DM II IR-Brom titrated weekly to 4.8 between group difference 0.56% (P<0.02)
N=159 mg/d for 24 week IR-Brom reduced FPG by 31 mg/dl
(P<0.001)
Pijl et al.5 Double blind, placebo- IR-Brom titrated weekly to 4.8 Reduced FPG by 22 mg/dl (P=0.02)
(2000) controlled mg/d for 16 weeks Reduced Alc by 0.6% compared with 0.6%
Obese DM II increase for placebo (P=0.009)
SN = 22
Aminorroaya et al.10 Double blind, placebo- IR-Brom 2.5 mg/d for 12 weeks. Reduced FPG by 27.54 mg/dL (P<0.01)
(2004) controlled IR-Brom reduced Alc by 0.4% (P=0.06)
Obese DM II Alc difference of 1.5% between groups
SN = 40 with -0.4% in IR-Brom and 1.1% in placebo
(P<0.01)

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Table 4. Adverse events in trials with immediate-release bromocriptine.4
ADVERSE EFFECT IR-BROM (%)
Monotherapy n =80
Nausea 26 (32.5)
Rhinitis 11 (13.8)
Headache 10 (12.5)
Asthenia 10 (12.5)
Dizziness 10 (12.5)
Constipation 9 (11.3)
Sinusitis 8 (10.0)
Diarrhea 7 (8.8)
Amblyopia 6 (7.5)
Dyspepsia 6 (7.5)
Vomiting 5 (6.3)
Infection 5 (6.3)
Anorexia 4 (5.0)
Adjunct to Sulfonylurea n = 244
Nausea 62 (25.4)
Asthenia 46 (18.9)
Headache 41 (16.8)
Flu syndrome 23 (9.4)
Constipation 24 (9.8)
Cold 20 (8.2)
Dizziness 29 (11.9)
Rhinitis 26 (10.7)
Sinusitis 18 (7.4)
Somnolence 16 (6.6)
Vomiting 13 (5.3)
Amblyopia 13 (5.3)
52- Week Safety Trial n = 2054
Nausea 661(32.2)
Dizziness 303 (14.8)
Fatigue 285 (13.9)
Vomiting 167(8.1)
Diarrhea 167(8.1)
Constipation 119 (5.8)


SUMMARY

Cycloset was approved on May 5, 2009 for the
treatment of Type II DM. The addition of IR-Brom to
current therapy is expected to provide a minor addi-
tional reduction in A1c. However, this option is cur-
rently unavailable in the United States.


REFERENCES


1. National Diabetes Fact Sheet, 2007. http://
www.cdc.gov/diabetes/pubs/pdf/ndfs_2007.pdf
2. Cycloset. http://www.Cycloset.com Accessed Oct 12,
2009.
3. FDA Approval Letter. Available at http://
www.accessdata.fda.gov/drugsatfda_docs/
appletter/2009/020866s0001tr.pdf
4. Cycloset Package Insert. Last Revised April 2009.


Pha rma Note Volume 25, Issue 6 I March 2010


PLACEBO (%)
n=79
6(7.6)
3 (3.8)
7 (8.9)
5(6.3)
6(7.6)
3 (3.8)
2(2.5)
4(5.1)
1(1.3)
2(2.5)
1(1.3)
4(5.1)
1(1.3)
n = 250
12 (4.8)
20 (8.0)
40 (16.0)
19 (7.6)
11 (4.4)
20 (8.0)
14 (5.6)
12 (4.8)
16 (6.4)
5 (2.0)
8(3.2)
6 (2.4)
n = 1016
77 (7.6)
93 (9.2)
68 (6.7)
32 (3.1)
81 (8.0)
52 (5.1)


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http://www.accessdata.fda.gov/drugsatfda_docs/
label/2009/0208661bl.pdf
5. Pijl H, Pipek R, Ohashi S, lozzo P, Matsuda M, Lancaster
JL, et al. Bromocriptine: A novel approach to the treat-
ment of type 2 diabetes. Diabetes Care 2000;23(8):1154
-1161.
6. Cincotta AH, Meier AH, Cincotta Jr, M. Bromocriptine
improves glycaemic control and serum lipid profile in
obese Type 2 diabetic subjects: a new approach in the
treatment of diabetes. Exp Opin Invest Drugs 1999; 8
(10):1683-1707.
7. Cincotta AH, Meier AH. Bromocriptine Inhibits In Vivo
Free Fatty Acid Oxidation and Hepatic Glucose Output
in Seasonally Obese hamsters (Mesocricetus auratus).
Metabolism 1995;44(10):1349-1355.
8. Gaziano JM, Ezrokhi M, Cincotta AH, Scranton RE. Ef-
fects of Timed CyclosetTM (a Quick Release Formula-
tion of Bromocriptine Mesylate) Administration on
Safety, Cardiovascular Event Rate, and Glycemic Control
in Subjects with Type 2 Diabetes Receiving Diet, Oral
Hypoglycemic, and/or Insulin Treatment Regimens
[poster]. 67th Scientific Sessions of the American Diabe-
tes Association; 2007 Jun 22-26; Chicago (IL).
9. Scranton RE, Cincotta AH, Ezrokhi M, Gaziano JM. Cyc-
loset (Quick-Release Bromocriptine Mesylate), a
Novel Centrally Acting Treatment for Type 2 Diabetes
[abstract no. 80 plus poster]. Canadian Diabetes Asso-
ciation; 2008 Oct 15-18; Montreal (QU).
10. Aminorroaya A, Janghorbani M, Ramezani M, Haghighi
S, Animi M. Does Bromocriptine Improve Glycemic Con-
trol of Obese Type-2 Diabetics? Horm Res 2004;62:55-
59.
11. Johnson CY. A drug's journey from idea to reality. May
7, 2009. www.boston.com/business/healthcare/
ar ti cl e s / 2 0 0 9 / 0 5 / 0 7 /
a_drugsjourney_from_idea_to_reality/


ONCE DAILY
AMINOGLYCOSIDES:
A REVIEW AND UPDATE

David Joeckel, Pharm.D. Candidate


Aminoglycosides (AGs) were first introduced in
1944 with the discovery of streptomycin. Over
the next 15 years, neomycin, kanamycin and
paromycin were developed. Although these AGs are
still available today, they are rarely used due to their


increased risk of toxicity. Currently the most com-
monly used AGs are gentamicin, approved by the FDA
in 1966, and tobramycin, and amikacin, which were
introduced in 1975 and 1976, respectively.1,2
AGs are an effective treatment option in patients
with susceptible gram negative bacterial infections
and cover many serious organisms including Acineto-
bacter, Citrobacter, Enterobacter, Pseudomonas, and
Serratia spp. AGs are used for treatment of septicemia,
osteomyelitis, meningitis, respiratory tract infections,
and febrile neutropenia. AGs also treat gram positive
organisms including staphylococcus and streptococcus
species when used synergistically with beta-lactams.2
This article will discuss the properties of AGs that
allow them to be effective when dosed once daily
(ODD), as well as compare the use of multiple daily
dosing with ODD, and summarize relevant studies sug-
gesting ODD is superior to multiple daily dose regi-
mens.

TOXICITY

Although effective bactericidal agents, caution is
required with AGs due to nephrotoxicity and ototoxic-
ity. Nephrotoxicity typically occurs several days after
administration when drug begins to accumulate in the
renal tubules. AG accumulation occurs when trough
concentrations remain elevated for an extended dura-
tion, generally above 2 mcg/ml. AGs are really elimi-
nated and accumulate in the tubules following glome-
rular filtration.3,4 Although nephrotoxicity is a concern,
it is reversible upon drug discontinuation as trough
levels fall.
Ototoxicity is the other major adverse effect asso-
ciated with AGs. This process is irreversible and pre-
sents with permanent hearing loss and vestibular
damage. Ototoxicity is a result of drug accumulation
and consistently elevated peak concentrations, gener-
ally greater than 12 to 15 mcg/ml for gentamicin and
tobramycin.3,5 Despite the possibility of toxicity, and
the development of new antibiotics, AGs remain im-
portant agents in the treatment of many infectious dis-
eases.

MULTIPLE DAILY DOSING

Traditional recommendations suggest AGs be ad-
ministered in multiple daily infusions, usually every 8
to 12 hours. Multiple daily dosing assumes drug con-
centrations remain above the minimum inhibitory
concentration (MIC) for the entire duration of therapy.
Early data suggested that when concentrations fell
below the MIC, AGs were not effectively killing the in-
fecting organisms, and the risk of resistance increased.


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However, when concentrations are elevated for ex-
tended durations and continually remain above the
MIC, the risk of toxicity increases.6,7
Other disadvantages of multiple daily dosing in-
clude frequent serum creatinine and lab monitoring.
Labs must be drawn at the appropriate time or results
will be misleading and lead to unnecessary dosage ad-
justments and further increase the risk of toxicity.6,7
Overall, this process increases costs and the likelihood
of errors. An effective alternative to multiple daily dos-
ing is ODD of AGs. The rationale for ODD is based on
two characteristics of these drugs: concentration de-
pendent killing and the post-antibiotic effect (PAE).

Concentration-Dependent Killing
AGs exhibit concentration dependent killing,
meaning the extent of killing is increased when the
bacteria are exposed to increasing drug concentra-
tions. They are most effective when peak concentra-
tions are at least ten times greater than the MIC. Tradi-
tional dosing usually does not produce peak concen-
trations at this level. Although ODD results in in-
creased peaks, these peaks do not result in increased
toxicity because concentrations do not remain ele-
vated long enough for accumulation to occur. This
method results in decreased toxicity and increased
efficacy.8,27,28

Post-Antibiotic Effect
The PAE means AGs will continue to be bacteri-
cidal despite drug concentrations falling below the
MIC. This effect may last up to 8 hours after serum
concentrations fall below the MIC and decreases expo-
sure to AGs and potentially toxic levels, making drug
accumulation less likely. This characteristic allows for
continued killing at low levels and significantly de-
creases the occurrence of nephrotoxicity.9,10,26,28


CLINICAL STUDIES


Several meta-analyses have compared once daily
dosing with traditional dosing. AGs used in these trials
included netilmicin, amikacin, gentamicin, sisomicin,
and tobramycin. A majority of patients had severe in-
fections including pneumonia, bacteremia, urinary
tract infections, and intra-abdominal infections.
Barza M, et al. evaluated 21 clinical trials per-
formed between 1966 and 1995 involving a total of
3091 adult and pediatric patients." ODD of AGs was
compared with either two or three times daily dosing.
No significant decrease in antibiotic failures was ob-
served with ODD (RR 0.83, 95% CI: 0.57-1.21, p=0.32)
although significance was reached with the fixed effect
model (p=0.02). A nonsignificant reduction was also
observed in favor of a single daily dose in patients
with febrile neutropenia (RR 0.52, 95% CI: 0.11-2.46).
Nephrotoxicity was significantly decreased with ODD
(RR 0.74, 95% CI: 0.54-1, p=0.05), although there was
no difference in observed ototoxicity (RR 1.09, 95% CI
0.68-1.75). The authors concluded that ODD is at least
as effective as MDD, has a trend toward decreased fail-
ures, and significantly decreases nephrotoxicity.
Ferriols-Lisart, et al. compared ODD with MDD
regimens in 18 clinical trials involving 2317 immuno-
competent adult patients performed between 1988
and 1995.12 ODD was significantly more effective than
the MDD (odds ratio 1.47, 95% CI: 1.13-1.94), defined
as the resolution of signs and symptoms of infection.
ODD showed a significant reduction in nephrotoxicity
(odds ratio 0.60, 95% CI: 0.04-0.86), although ototox-
icity was not significantly reduced (odds ratio 0.56, CI:
0.26-1.16). The authors concluded that ODD is an ef-
fective alternative to multiple daily dosing.
Hatala, et al. performed a meta-analysis of 17 ran-
domized, controlled trials performed between 1966
and 1995 including immunocompetent adults.13 Trials


Table 1. Comparison of once-daily versus multiple-daily dosing of aminoglycosides.
STUDY STUDIES N EFFICACY NEPHROTOXICITY OTOTOXICITY
Barza, et al.11 21 3091 Trend favored ODD ODD < MDD No difference
(1996) RR 0.83 RR 0.74 RR 1.09
(95% Cl: 0.57-1.21) (95% Cl: 0.54-1) (95% Cl 0.68-1.75)
Hatala, et al.13 17 811 Trend favored ODD Trend favored ODD Trend favored ODD
(1996) RR 0.91 RR 0.87 RR 0.67
(95% CI: 0.63-1.31) (95% CI: 0.60-1.26) (95% CI: 0.35-1.28)
Ferriols-Lisart, et al.12 18 2317 ODD > MDD ODD < MDD ODD < MDD
(1996) OR 1.47 OR 0.60 OR 0.56
(95% CI: 1.13-1.94) (95% CI: 0.04-0.86) (95% Cl:0.26-1.16)
ODD = once-daily dosing; MDD = multiple daily dosing; RR = relative risk (risk ratio); OR = odds ratio; 95% Cl = 95% confidence interval.

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Table 2. Once daily dosing in specific patient populations.
AUTHOR STUDY DESIGN CONDITION ONCE DAILY DOSE CONTROL ARM
Del Priore et al.s1 (1996) Randomized Postpartum Gentamicin 5mg/kg + clinda- 1.75mg/kg 3x/day +


endometriosis


Livingston et al.16 (2003)





Locksmith et al.17 (2005)


Contopoulos-loannidis,
et al.18 (2004)


Riethmueller et al.19
(2001)


Smyth et al.20
(2005)


Vic et al.21
(1998)


Whitehead et al.22(2002)




Conil et al.24
(2006)


Randomized





Ranomized


Meta-analysis


Randomized cross-
over


Ranomized



Ranomized


Ranomized




Pharmacokinetic


Postpartum
endometriosis




Chorioamnionitis


Nonspecific
infections


Cystic fibrosis
(Pseudomonas
aeruginosa)

Cystic fibrosis



Cystic fibrosis


Cystic fibrosis




Burn patients


mycin


Gentamicin 5mg/kg + clinda-
mycin 2700 mg x 1




Gentamicin 5.1mg/kg


Gentamicin 4-5mg/kg


Tobramycin 10mg/kg/day


Tobramycin 10mg/kg/day



Tobramycin 15/mg/kg/day


Tobramycin 10mg/kg/day




Amikacin 20mg/kg/day


clindamycin


Gentamicin 120 mg
Q8H + clindamycin 900
mg Q8H


Gentamicin 120mg LD,
80mg Q8H


Gentamicin BID orTID


Tobramycin lOmg/kg/
day (3 divided doses)


Tobramycin lOmg/kg/
day (3 divided doses)


Tobramycin 15mg/kd/
day (3 divided doses)


Tobramycin lOmg/kg/
day (3 divided doses)


N/A


RESULTS


. No efficacy difference.
. Dose adj to reach desired peak: 0%
ODD vs 37% MDD
. Cost analysis (per pt) ODD = $16.12
vs MDD = $41.75 (P=<0.001)


. Success rate: 82% ODD vs 69% MDD
(P=0.12)
. Decreased administration cost (no
values given)

. No difference in outcomes or toxic-
ity. Maternal vs cord peak conc.:
18.2mcg/ml vs 7.1mcg/ml (P
<0.001).


SEfficacy trends favored ODD: RR
0.71 (95% Cl 0.45 to 1.11).
SNephrotoxicity: ODD RR 0.33 (95% Cl 0.12-0.89).


SNo efficacy difference between
groups (14 days of tx).


. ODD as effective as MDD. Nephro-
toxicity: Favored ODD (95% Cl -15.7
to -0)

. ODD: Significant improvements in
FEV and FVC (P<0.05)


. ODD: significant improvements in
FVC (P=0.013)
. Renal function: No change

. Burns > 15% of the body: 15-20 mg/
kg dose not sufficient to reach de-
sired peak.







were excluded if more than 50% of patients had a
lower UTI as AGs concentrate in the urine regardless
of dosing regimen. Results demonstrated no signifi-
cant difference in bacteriologic cure between dosing
regimens (RR 1.02, 95% CI: 0.99-1.05). However, a
nonsignificant reduction was observed in mortality
(RR 0.91 95% CI: 0.63-1.31), nephrotoxicity, RR 0.87
(95% CI: 0.60-1.26) and ototoxicity, RR 0.67 (95% CI:
0.35-1.28) with ODD. Based on these relative risks, the
authors concluded that ODD is at least as effective as
MDD and has a trend toward reduced toxicity and
mortality.
Overall, these meta-analyses demonstrate that
ODD is at least as effective as traditional dosing and
has significantly fewer cases of toxicity. This regimen
provides a simplified dosing schedule, decreases the
need for monitoring, and decreases drug exposure for
patients.

ONCE-DAILY DOSING IN SPECIFIC POPULATIONS

ODD of AGs has been widely accepted as the pre-
ferred dosing regimen. The multiple benefits of ODD
have lead to studies conducted on patient populations
that have been historically excluded from ODD recom-
mendations.
Several studies have found ODD effective in both
pregnant and postpartum women for infections in-
cluding postpartum endometriosis, choriamnionitis,
and pelvic inflammatory disease.15,16,17 Gentamicin 5
mg/kg once daily, based on actual body weight, was
the most common dose in these studies (Table 2).
Contopoulos-Ioannidis, et al. performed a meta-
analysis of 24 randomized, controlled trials between
1991 and 2003 including children and neonates.18 No
significant difference was observed with microbiologi-
cal failures, but trends favored ODD with a risk ratio of
0.71 (95% CI 0.45 to 1.11, p=0.13). ODD was signifi-
cantly superior with a risk ratio of 0.33 (95% CI 0.12-
0.89, p=0.03) in nephrotoxicity outcomes. No signifi-
cant difference in ototoxicity was observed (RR 1.06
(95% CI 0.51-2.19, p=0.92). The authors concluded
that ODD has the potential for increased safety and
efficacy compared to MDD when used for children and
neonates.
ODD has also been evaluated in patients with cys-
tic fibrosis (Table 2).19-23 Four clinical trials have com-
pared ODD to TID dosing and found it an effective al-
ternative with decreased nephrotoxicity. Although
cystic fibrosis remains an exclusion criteria for ODD,
these trials suggest ODD may be an effective treatment
option following further studies (Table 2).
Lam, et al. used pharmacokinetic modeling to de-
termine an effective dose for tobramycin when given


Table 3. Exclusion criteria for ODD of AGs.

SElderly (Age 3 70) .Dialysis
. Endocarditis CrCL< 20 ml/min
SSynergy (Gram(+) organisms) Cystic Fibrosis
. General surgery prophylaxis Ascites
SLiver disease Hearing impaired
. Burns .Fluid retention



once daily for cystic fibrosis.23 These authors con-
cluded that female patients < 14 years old would re-
quire a dose of 7 mg/kg/day, with all other patients
requiring a dose of 9 mg/kg/day. Although these
doses may be effective, they are solely based on phar-
macokinetic modeling and still require safety and effi-
cacy evaluation.
Conil, et al. studied once daily amikacin in burn
patients.24 Burns cause altered pharmacokinetics and
changes in volume of distribution. ODD has generally
been considered inappropriate for this patient popula-
tion. The authors found patients with significant burns
to > 15% of the body did not reach the desired peak
concentration with the standard 15-20 mg/kg dose,
which was attributed to altered pharmacokinetics and
an increase in drug clearance in burn patients. Signifi-
cant burns remains an exclusion criteria for ODD until
further studies are performed (Table 3).

DETERMINING ONCE-DAILY DOSE

Step 1: Determine Dosing Weight (DW)
AGs are distributed into the extracellular fluids,
have poor distribution into tissues, and have difficulty
crossing cell membranes. Ideal body weight (IBW) is
the preferred dosing weight Actual body weight is
used when less than the calculated IBW and in preg-
nant patients. Adjusted body weight (ABW) is used
when total body weight is 30% greater than IBW.

IBW (males): 50 kg + (2.3 x height in inches > 60 in)

IBW (females): 45 kg + (2.3 x height in inches > 60 in)

ABW (obese) = IBW + 0.4 x (total body weight IBW)

Step 2: Determine AG Dose
The AG dose is calculated by multiplying the ap-
propriate body weight calculation (above) by specified
mg/kg doses of AGs (Table 4).


Pha rma Note Volume 25, Issue 6 I March 2010


Volume 25, Issue 6 1 March 2010


PharmaNote







Table 4. Once-daily dosing by weight.

DRUG DOSE

Gentamicin* 5-7 mg/kg x DW

Tobramycin* 5-7 mg/kg x DW

Amikacin 15-20 mg/kg x DW
*IDSA recommends 7 mg/kg plus an additional antipseudomonal
beta lactam when Pseudomonas is suspected.



Step 3: Determine Dosing Interval
The dosing interval is based on the patient's calcu-
lated creatinine clearance (CrC1) (Table 5). CrCl is
tested at baseline, then weekly. ODD is recommended
if CrCl > 60 ml/min. The dosing interval is extended
beyond 24 hours when CrCl < 60 ml/min.

MONITORING

ODD does not require peak concentration monitor-
ing. Trough concentrations are checked 24 hours after
administration or within one hour of the next infusion.
The desired trough for gentamicin and tobramycin is <
1 mcg/ml and < 5 mcg/ml for amikacin. If trough is at
desired level, no future monitoring is necessary.29,30
Nomograms are commonly used to monitor
troughs and determine if an interval adjustment is
necessary. A random trough level is drawn 6-16 hours
after the infusion, and based on concentration results
the interval can be expanded to every 36 hours or
every 48 hours.

COST COMPARISON

ODD provides an economic benefit with reductions
in the cost of drug, supply, preparation, administra-
tion, and monitoring. Hitt, et al. retrospectively ana-
lyzed the cost of once daily gentamicin and found a
58% decrease in cost of therapy including treatment
of nephrotoxicity. With an average of 4.5 days of treat-
ment, total blood samples drawn per patient was re-


duced from 1.7 to 0.65 with once daily dosing with a
62% reduction in monitoring costs. Nephrotoxicity
costs were reduced from $182 to $55 per patient25

SUMMARY

ODD of AGs provides an effective alternative to
multiple daily dosing. ODD is at least as effective as
traditional dosing, reduces toxicity, decreases moni-
toring, and results in an overall cost reduction. In the
appropriate patient, ODD of AGs has become widely
accepted as the preferred dosing regimen.




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Table 5. Dosing intervals for aminoglycosides.

Drug CrCI3 60 ml/min CrCI 40-59 ml/min CrCI 20-39 ml/min

Gentamicin Dose every 24 hrs Dose every 36 hrs Dose every 48 hrs

Tobramycin Dose every 24 hrs Dose every 36 hrs Dose every 48 hrs

Amikacin Dose every 24 hrs Dose every 36 hrs Dose every 48 hrs
* Once daily dosing is not recommended if CrCI < 20 ml/min.

Phri N V l I &I IRA 2010


I OVIaltc I .


rii l ii;i i u L


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5.


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