This invention relates to coadministration of tigecycline and digoxin
FIELD OF THE INVENTION
The invention relates to treatment of bacterial infections with tigecycline and
cardiac insufficiency with digoxin by coadministration to a human in need thereof.
BACKGROUND OF THE INVENTION
Tigecycline (GAR-936) is a glycylcycline antibiotic and an analog of the
semisynthetic tetracycline, minocycline. Tigecycline has broad-spectrum antibacterial
activity both in vitro and in vivo. Further, tigecycline was developed in response to the
worldwide threat of emerging resistance to antibiotics. Glycylcycline antibiotics, like
tetracycline antibiotics, act by inhibiting protein translation in bacteria.
Glycylcyclines, including tigecycline, are active against many antibiotic-resistant
gram-positive pathogenic bacteria, such as methicillin-resistant Staphylococcus aureus,
penicillin-resistant Streptococcus pneumoniae, and vancomycin-resistant enterococci
(Weiss et al., 1995; Fraise et al., 1995). Of great significance is the activity of
tigecycline against bacterial strains carrying the two major forms of tetracycline
resistance, efflux and ribosomal protection (Schnappinger and Hillen, 1995).
Digoxin is a digitalis glycoside inotropic drug used extensively to treat cardiac
insufficiency. However, it is likely that individuals in the critical care setting who require
intravenous antiinfective therapy could also already be receiving or begin receiving
digoxin for a coexisting cardiac condition. A major clinical concern surrounding
coadministration of other drugs, in particular antiinfectives with digoxin is one of cardiac
toxicity resulting from increased plasma levels of digoxin in a patient with preexisting
cardiac insufficiency. This is of grave concern since digoxin has a very narrow
therapeutic index. For example, Clarithromycin in particular has been shown to increase
plasma levels of digoxin, sometimes to toxic levels, (Xu H, Rashkow A. Clarithromycininduced
digoxin toxicity: a case report and a review of the literature. Connecticut
Medicine 2001;65:527-9; and Gooderham MJ, Bolli P, Fernandez PG. Concomitant
digoxin toxicity and warfarin interaction in a patient receiving Clarithromycin. Annals of
Pharmacotherapy 1999;33:796-9); this interaction has been linked to reduced renal
clearance of digoxin (Rengelshausen J, Goggelmann C, Burhenne J, Riedel KD,
Ludwig J, Weiss J, et al. Contribution of increased oral bioavailability and reduced
nonglomerular renal clearance of digoxin to the digoxin-clarithromycin interaction.
British Journal of Clinical Pharmacology 2003;56:32; Baron JM, Goh LB, Yao D, Wolf
CR, Friedberg T. Modulation of P450 CYP3A4-dependent metabolism by Pglycoprotein:
implications for P450 phenotyping. Journal of Pharmacology &
Experimental Therapeutics 2001;296:351-8; Nordt SP, Williams SR, Manoguerra AS,
Clark RF, Clarithromycin induced digoxin toxicity, Journal of Accident & Emergency
Medicine 1998; 15:194-5; Tanaka H, Matsumoto K, Ueno K, Kodama M, Yoneda K,
Katayama Y, et al. Effect of Clarithromycin on steady-state digoxin concentrations.
Annals of Pharmacotherapy 2003;37:178-81; and Wakasugi H, Yano I, Ito T, Hashida T,
Futami T, Nohara R, et al. Effect of Clarithromycin on renal excretion of digoxin:
interaction with P-glycoprotein.Clinical Pharmacology & Therapeutics 1998;64:123-8,
which, in turn, may be linked to P-gp transport (Rengelshausen J, Goggelmann C,
Burhenne J, Riedel KD, Ludwig J, Weiss J, et al. Contribution of increased oral
bioavailability and reduced nonglomerular renal clearance of digoxin to the digoxinclarithromycin
interaction. British Journal of Clinical Pharmacology 2003;56:32-8).
Tetracycline and minocycline interaction with digoxin has been described in the
reference Roos T C and Merk H F, Drugs, (2000) 59/2 (181-192). Interactions of
tetracyclines are also described by Gregg C R, Am.J.Med. (106, No. 2, 227-37, 1999).
The interaction of digoxin with quinidine, verapamil, & of p.o. digoxin with broadspectrum
antibiotics such as erythromycin or tetracycline HCI is discussed in the
reference Roffman D S, Postgraduate Medicine, (1997).
There is therefore a need for a combination of an antibiotic and digoxin that
addresses the problems noted above especially increased plasma digoxin levels and
the toxicity as a result of the same since digoxin is a drug with a very narrow therapeutic
index
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. I Mean (SE) Plasma Digoxin Concentrations, hours 0 through 24. Period 2
(Digoxin alone, 0.25 mg/day + tigecycline 50 mg/12h) Versus Period 3 (tigecycline 50
mg/12h + digoxin 0.25 mg/day)
FIG. 2 Mean (SE) Serum Tigecycline Concentrations: Hours 0 through 12 Period 1
(Tigecycline alone, 100 mg Single Dose) Versus Period 3 and 3 (Tigecycline 50 mg/12h
+ Digoxin 0.25 mg/day)
FIG. 3 Mean (SE) Serum Tigecycline Concentrations, Hours 0 through 96, Period 1
(Tigecycline Alone, 100 mg Single Dose) Versus Period 3 (Tigecycline 50/12h + Digoxin
0.25 mg/day)
FIG. 4 Distribution of EGG changes for predose values in QT interval in healthy
subjects, Tigecycline alone, digoxin alone, digoxin + Tigecycline concomitantly
BRIEF SUMMARY OF THE INVENTION
The invention relates to the coadministration of tigecycline and digoxin to a
human patient without the condition of cardiac compromise resulting from increased
plasma levels of digoxin and potential toxicity in said patient with preexisting cardiac
insufficiency.
The invention further relates to a method of treating, controlling or reducing the
risk of a bacterial infection and a cardiac insufficiency condition in a human which
comprises administering to said human in need thereof an effective amount of
tigecycline and an effective amount of digoxin.
The invention further relates to a method for improving steady state digoxin
plasma levels in a human experiencing cardiac insufficiency condition and a bacterial
infection, the method comprising administering to said human in need thereof an
effective amount of digoxin and tigecycline.
The invention relates to a method of treating, controlling or reducing the risk of a
bacterial infection and a cardiac insufficiency condition in a human which comprises
administering to said human in need thereof an effective amount of tigecycline and an
effective amount of digoxin.
The invention relates to a method of treating, controlling or reducing the risk of a
bacterial infection with tigecycline in a patient having preexisting cardiac insufficiency
and being treated with digoxin said method having the advantage of controlling and
stabilizing from increasing plasma digoxin levels in said patient.
The invention relates to a method of treating, controlling or reducing the risk of a cardiac
insufficiency condition and a bacterial infection in a human which comprises
administering to said human in need thereof an effective amount of digoxin and an
effective amount of tigecycline.
Following intravenous administration of tigecycline and oral administration of
digoxin to healthy, male volunteers, an analysis was performed to determine by
pharmacokinetic (PK) and pharmacodynamic (PD) assessments the absence of any
clinically significant interaction.
It was determined that by treating humans by intravenous (IV) infusion of
tigecycline in 0.09% sterile normal saline over 30 minutes and administering digoxin
orally with 240 ml of room-temperature water that digoxin and tigecycline may be
coadministered.
The overriding clinical concern surrounding coadministration of tigecycline and
digoxin is one of cardiac compromise resulting from increased plasma levels of digoxin
in a patient with preexisting cardiac insufficiency. From pharmacokinetic and
bioequivalence viewpoints, the following described clinical results suggest that the
coadministration of tigecycline would not effect such a compromise. Specifically,
tigecycline did not affect the steady-state plasma digoxin AUCO-24h, CL/F, or digoxin
concentrations during the 12- to 24-hour period after dose administration (therapeutic
drug monitoring times), although the 90% CIs for Cmax and tmax fell outside of the
equivalence window. Tigecycline also did not affect the steady-state digoxin urinary PK
as shown by measurement of digoxin Ae,% and digoxin CLr. Another concern with
coadministering these 2 drugs is a potential compromise in therapeutic serum
tigecycline concentrations in a patient being treated for a complicated infection in the
critical care setting. Although digoxin increased both tigecycline t1/2 and Vss, these
increases did not affect tigecycline AUC or CL; hence, tigecycline exposure during the
concomitant administration of digoxin would probably be unchanged, necessitating no
tigecycline dosage adjustment in a patient receiving a therapeutic dosage of digoxin.
The present invention provides to the art a new method useful for the treatment
or control of bacterial infections by parenteral administration, and oral coadministered
with
digoxin which avoids adverse interactions.
Other advantages and aspects of the present invention will become apparent
upon
reading the following detailed description of the invention.
DESCRIPTION OF PREFERRED EMBODIMENTS
The following definitions are used throughout the application.
"Cardiac insufficiency condition" or "cardiac insufficiency" means slow failure of
the heart and occurs when the heart loses its ability to pump enough blood through the
body. Further is also any condition which calls for the use of digoxin which includes
preexisting cardiac insufficiency.
"Treating" refers to reversing, alleviation of symptoms or inhibiting the progress
of a bacterial infection. Further, treating also means reducing and alleviation of
symptoms and conditions associated with cardiac insufficiency with digoxin.
"Administering" means a treatment process wherein an effective amount of
tigecycline is delivered to a human patient. Further, administering means a treatment
process wherein an effective amount of digoxin is delivered to a human patient.
"Bacterial infection" is the proliferation of a bacteria pathogen caused by Grampositive
and Gram-negative bacteria.
"Effective amount" is an amount of tigecycline, where upon administration, is
capable of reducing or preventing the proliferation of bacteria or reducing the symptoms
of the bacterial infection. Further, effective amount means an amount of digoxin
capable of reducing or preventing cardiac insufficiency condition. Additionally, the
effective amount means an amount of tigecycline which will not increase the Cmax of
digoxin.
"Coadministration" is simultaneous or sequential coadministration of tigecycline
and, digoxin. When administration is sequential, either the tigecycline or the digoxin
may be administered first.
EXPERIMENTAL METHODS
MATERIALS AND METHODS
Study subjects
Healthy men aged 27 to 45 years who were in good health on the basis of
medical history, physical examination, electrocardiograms (ECGs), and laboratory
evaluations, and had a body mass index in the range of 18 to 30 kg/m2 and body weight
50 kg, were enrolled. Subjects were nonsmokers or smoker of fewer than 10 cigarettes
(half a pack) per day as determined by history and able to abstain from smoking during
the inpatient stay.
Tobacco use or the consumption of any caffeine-containing products (eg, coffee,
tea, chocolate, or cola), grapefruit, grapefruit-containing products, or alcoholic
beverages was prohibited from at least 48 hours before study day 1 until the end of the
inpatient confinement period.
Subjects were excluded if they had a history or presence of any significant
cardiovascular (including Wolf-Parkinson-White syndrome), hepatic, renal, respiratory,
gastrointestinal, endocrine, immunologic, dermatologic, hematologic, neurologic, or
neuropsychiatric disease, surgical or other medical condition that may have interfered
with the absorption, distribution, metabolism, or excretion of either study drug, acute
disease state (eg, nausea, vomiting, fever, diarrhea) within 7 days of study day 1,
admitted alcohol abuse or consumption of more than 2 standard units per day, any
clinically important deviation from normal limits in physical examination, vital signs, or
clinical laboratory test results, positive serologic findings for HIV antibodies, hepatitis B
or C surface antigen and/or antibodies, positive drug screen (eg, amphetamines,
barbiturates, benzodiazepines, cannabinoids, cocaine, opiates), or had a PR interval
>200 msec; resting heart rate <50 bpm at screening or on day-1.
The study was conducted at the Wyeth Clinical Pharmacology Unit,
Philadelphia, PA, USA, and was approved by the Institutional Review Board of The
Methodist Hospital in Philadelphia, PA, USA, and was conducted according to the
Declaration of Helsinki and its amendments. All subjects gave written informed consent
before enrollment.
Study medications
Tigecycline (Wyeth Pharmaceuticals, Collegeville, PA, USA) was supplied as
lyophilized powder in 5-mL, flint-glass vials, each containing lyophilized free base
equivalent to 50 mg of tigecycline without additives or preservatives. This powder was
reconstituted with sterile normal saline (0.9% NaCI for Injection, USP) to the correct
volume before administration. Digoxin was supplied as Lanoxin® (Glaxo SmithKline,
Collegeville, PA, USA) 0.25 mg tablets for oral administration.
Study design and treatment
The purpose of this open-label, single-sequence, 3-period, multiple-dose
crossover drug interaction study was to determine the effects of steady-state tigecycline
concentrations on steady-state levels of digoxin. The coadministration of multiple doses
of digoxin and tigecycline maximized the potential to detect an interaction. Because this
was a single-sequence crossover study, multiple washout periods were not necessary;
this was an important consideration because both digoxin and tigecycline have long
half-lives (ti/2).
A 20% or greater difference in the area under the plasma concentration-time
curve during a dose interval (AUC0.T) of digoxin could be considered a clinically
significant interaction. With a sample size of 16, the statistical power for detecting a
20% difference in AUC0.Tat a 0.05 level of significance was expected to exceed 80%.
On each day before the start of study periods 1 and 2 (day -1 and day 6), all
subjects underwent physical examinations, laboratory tests, vital sign assessments, and
a standard 12-lead electrocardiogram (EGG), which included measurements of rhythm,
heart rate, PR, QRS, QT, and QTc intervals. Adverse event monitoring was continuous,
and blood samples for PK analysis was completed at the designated times throughout
all study periods. Before dose administration on days 1, 7 and 15, 3 complete ECGs
were performed for each subject, and the mean value used as the subject's baseline for
each corresponding period.
Both study medications were always administered 1 hour after a medium-fat
meal. Tigecycline was administered intravenously (IV) in 0.09% sterile normal saline
over 30 minutes for all doses. Digoxin was administered orally with 240 mL of roomtemperature
water for all doses.
Period 1
One (1) hour after a medium-fat meal, and after a predose 7-mL blood sample
for a baseline tigecycline PK analysis, each subject received a single 100-mg dose of
tigecycline.
Subjects received no study medication on days 2 through 5.
Period 2
On day 6, after a predose 3-mL blood sample and urine samples for baseline
digoxin PK analyses, each subject received 0.5 mg of digoxin. On days 8 through 14,
each subject received 0.25 mg of digoxin.
Period 3
On day 15, predose blood samples (5 ml) for determination of digoxin trough
levels and blood samples (3 ml) for PK analysis were collected. In addition, a 24-hour
urine collection (day 14 to day 15) for PK analysis was completed for each subject. The
volume and pH of urine collected during each interval were recorded and an aliquot
stored for digoxin analysis.
At approximately 8 AM, each subject received 100 mg of tigecycline. At the
same time, each subject received 0.25 mg of digoxin. At approximately 8 PM, each
subject received 50 mg of tigecycline.
On days 16 through 18, blood samples for digoxin plasma trough level
determination were collected 2 hours before administration of digoxin. Then, at
approximately 8 AM, each subject received 0.25 mg of digoxin. In addition, on days 16
through 18, each subject received 50 mg of tigecycline every 12 hours (at approximately
8 AM and 8 PM).
On study day 19 at 8 AM, 1 hour after a medium-fat meal, each subject received
50 mg of tigecycline plus 0.25 mg of digoxin.
Serum tigecycline determinations
Venous blood samples (7 mL each) for determination of tigecycline
concentrations in serum were collected at the following times: on day 1, predose (within
2 hours before the start of the tigecycline infusion), and at 0.5 (end of infusion), 1, 1.5,
2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours after tigecycline administration; and on
day 19, predose, and at 0.5 (end of infusion), 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72,
and 96 hours after tigecycline administration.
All samples were collected from an indwelling catheter or by direct venipuncture
into blood collection tubes that did not contain any anticoagulant.
Serum tigecycline samples were analyzed by a validated liquid chromatography/tandem
mass spectroscopy (LC/MS/MS) method. The standard curve used for serum
tigecycline had lower
and upper limits of quantitation of 10 and 2000 ng/mL, respectively.
Serum digoxin determinations
Venous blood samples (3 ml each) for determination of digoxin concentrations
in plasma were collected at the following times: on day 7, predose, on day 14 at 0.5, 1,
2, 4, 6, 8, 10, 12, 16, and 24 hours after digoxin administration, and on day 19 at 0.5, 1,
2, 4, 6, 8, 10, 12, 16, and 24 hours after digoxin administration. A serum digoxin sample
was collected at hour 0 of day 15. All samples were collected from an indwelling
catheter or by direct venipuncture into blood collection tubes containing
ethylenediaminetetraacetic acid.
Validated radioimmunoassay (RIA) methods were used for the analysis of
digoxin in plasma and urine samples. During validation, the serum RIA assay had a
range of 0.150 ng/mL to 8.0 ng/mL and a sensitivity of 0.150 ng/mL.
In addition, digoxin trough samples (5 mL) for determination of digoxin levels (for
safety purposes) were routinely collected within 2 hours before digoxin administration
on days 10 through 19. This assessment used a commercial microparticle enzyme
immunoassay (MEIA, AxSYM Digoxin II assay, Abbott Laboratories, Abbott Park, IL,
USA). The reagents for the assay consisted of 6 calibrators (0.0, 0.50, 1.0, 2.0, 3.0, and
4.0 ng/mL) and 3 controls (0.9 [range = 0.6 to 1.2], 1.9 [1.5 to 2.30], and 3.2 [2.60 to 3.8]
ng/mL, respectively).
Urine digoxin determinations
Urine samples for determination of digoxin concentrations were obtained on day
7 within 2 hours before digoxin administration, and on days 14 and 19 before study drug
administration, at 0 to 4 hours, 4 to 8 hours, 8 to 12 hours, and 12 to 24 hours after
morning digoxin administration. Subjects were required to void completely at the end of
the predose period and at the end of each time interval after dose administration to
ensure a complete interval collection.
Urine tigecycline was not measured in this study.
Pharmacokinetic analyses
Pharmacokinetic (PK) parameters for serum tigecycline, plasma digoxin, and
urine digoxin were estimated by noncompartmental analysis.( Gibaldi M, Perrier D.
Pharmacokinetics. Marcel Dekker, Inc., 1982) Multiple sequential sampling for
tigecycline and digoxin over a 96-hour interval during all 3 study periods allowed
accurate estimates of PK
parameters for both drugs.
Tigecycline peak serum concentration (Cmax) and time to peak concentration
(tmax) were reported from the observed data. Concentrations that were judged to be in
the terminal phase were used to obtain the terminal-phase disposition rate constant (A^)
by log-linear regression. The half-life (ti/2) was calculated as 0.693A*. Tigecycline
concentrations over the time period from hours 24 to 96 were used to estimate the tt/2.
Tigecycline area under the serum concentration-time curve over the 12-hour
multiple-dose dose interval (AUC0.i2h), total area under the concentration-time curve
(AUC), peak concentration (Cmax), intravenous clearance (CL), mean residence time
(MRT), and apparent steady-state volume of distribution (Vss), were determined.
Similarly, plasma digoxin Cmax, tmax, AUC over the 24-hour dose interval (AUC0.24h), and
oral-dose clearance (CL/F), together with the percentage of digoxin excreted in urine
(Ae,%) and digoxin renal clearance (CLr), were also determined.
Single-dose Tigecycline PK
After a single dose (period 1 , days 1 to 5), the area under the concentration-time
curve (AUCt) and area under the first moment concentration-time curve (AUMCt)
truncated at the last observable concentration (Ct) at time t, were calculated by applying
the linear trapezoidal rule to Cmax and the log-linear trapezoidal rule thereafter. Total
AUC0.& and AUMC were estimated as follows: AUC = (AUCt) + Ct/X^, and AUMC =
(AUMC,) + t|ast • Ctfl,
The single-dose systemic mean residence time (MRT) was calculated as: MRT =
(AUMC/AUC) - Tmf/2, where Tinf is the infusion time (0.5 hours). The IV clearance (CL)
was calculated and normalized by body weight (WT) as follows: CL = Dose/(AUC»WT).
The apparent Vss was estimated by Vss = CL-MRT.
Multiple-dose Tigecycline PK
After multiple doses (period 2, day 19), the steady-state ADC (AUC0.t) and
AUMC (AUMCo-t) over the dose interval (t = 12 hours) were also calculated by applying
the linear trapezoidal rule to Cmax and the log-linear trapezoidal rule thereafter. For this
period of the
study, the MRT was calculated as: MRT = (AUMC0.t +
Tigecycline concentrations in individual patients without coadministration of
digoxin during period 1 were based on a single 100-mg tigecycline dose, whereas
concentrations with coadministration of digoxin during period 2 were based on a 50-
mg/12h multiple-dose regimen. According to linear PK theory,( Gibaldi M, Perrier D.
Pharmacokinetics. Marcel Dekker, Inc., 1982) the total AUC after a single dose (AUC0-»)
is equal to AUC over the dose interval T at steady state (AUC0 T)- Therefore, it was
possible to determine the effect of digoxin on serum tigecycline exposure by comparing
tigecycline AUCo-» after a single tigecycline dose alone (dose-normalized to 50 mg) with
tigecycline AUC0.T after the concomitant multiple-dose administration of tigecycline and
digoxin.
Digoxin steady-state concentrations
Plasma digoxin steady-state profiles were obtained on study days 1 4 (period 2,
digoxin alone) and 19 (period 3, digoxin with tigecycline). The Cmax and W values were
taken directly from the observed data. The ^ and t1/2 values were not estimable
because blood samples were not collected during the terminal disposition phase.
Estimates of the plasma steady-state AUC (AUC0.t) on days 14 (period 2) and 19
(period 3) were obtained over 24-hour (AUC0-24) intervals.
Digoxin oral-dose clearance and renal clearance
The digoxin oral-dose clearance (CL/F) was calculated and normalized by body
weight (WT) as follows: CL/F = Dose/(AUC-WT). VSS/F and MRT could not be
calculated because X? could not be estimated.
The amount of digoxin excreted in urine over the intervals of 0 to 4, 4 to 8, 8 to
12, and 12 to 24 hours on study days 14 (period 1) and 19 (period 2) were determined
in order to estimate the total amount of digoxin excreted in urine (Ae,0-24h). The
percentage of the dose of digoxin excreted unchanged in urine (Ae,%) was calculated
using the formula: Ae,% = (Ae.O 24h/Dose) • 100. The renal clearance of digoxin (CLr)
normalized by body weight (WT) was calculated from the formula: CLr = Ae,0-24h/AUC0-
Pharmacodynamic assessments
The pharmacodynamic (PD) analysis was based on changes from baseline in
12-lead EGG parameters (PR, QRS, QT, and QTc intervals, performed at 25 mm/s) at
24 hours after digoxin administration, when serum digoxin concentrations would be
expected to be in equilibrium with tissue concentrations. Baseline values for tigecycline
alone (period 1) were taken on day 1 just before tigecycline administration, while the
baseline values for digoxin alone (period 2) and digoxin + tigecycline (period 3) were
taken on day 7 just before the start of digoxin multiple-dose administration.
Twelve (12)-lead ECGs were performed at screening, on day -1, on days 1, 7,
14, 15, and 19 within 2 hours before study drug administration, on days 2 through 6, 8
through 13,16 through 18, 20, 21, and 22, and at the final evaluation at approximately 8
AM. Distribution of EGG changes from predose values in QT interval in healthy
subjects. Tigecycline alone, digoxin alone and digoxin + tigecycline concomitantly are
shown in Figure 4.
Statistical analysis
Descriptive statistics were obtained for all demographic characteristics, drug
concentrations, PK parameters, and changes from baseline in EGG parameters.
Analysis of variance (ANOVA) was performed on the natural logarithm-transformed PK
parameters to evaluate treatment and subject effects. An analysis of the change from
baseline in EGG parameters with and without multiple-dose tigecycline administration
was conducted by using ANOVA, which included terms for subject and treatment
effects.
For statistical comparisons, AUC, MRT, and Vss on day 1 (period 1) were based
on concentrations normalized to the 50-mg tigecycline dose given during period 3.
All statistical comparisons for individual PK parameters were performed on logtransformed
data. Calculation of statistical power between 2 treatments was based on
detecting a 20% difference in log-transformed parameters at the 0.05 significance level.
Bioequivalence testing
Further comparisons between treatments were performed by using the "two 1-
sided tests" bioequivalence procedure for log-transformed data on PK parameters, to
determine the equivalence of serum tigecycline PK when tigecycline was given alone
and concomitantly with digoxin. Identical equivalence testing was conducted for plasma
and urine digoxin.
Geometric least-squares (GLS) mean ratios of tigecycline PK parameters were
computed, and their associated 90% confidence intervals (CIs) calculated based on
least squares means and the mean square error obtained from the 2-way ANOVA. The
test procedure for log-transformed data is equivalent to requiring the ordinary 90% CIs
of the geometric least squares (GLS) mean ratio to be in the range of 80% to 120%.(
Schuirmann DJ. A comparison of the two one-sided tests procedure and the power
approach for assessing the equivalence of average bioavailability. J Pharmacokinet
Biopharm 1987; 15:657-80) After the log-transformation, these equivalence limits were
revised to the customary range of 80% to 125% to allow for symmetry. The SAS
statistical software package was used for all statistical analyses.
Safety evaluations
Safety was evaluated from spontaneously reported signs and symptoms and
from the results of physical examinations including weight and height, vital sign
measurements, 12-lead ECGs, clinical laboratory evaluations (trough digoxin
concentrations, hematology and blood chemistry tests), and routine urinalyses.
Adverse events (AEs) were recorded throughout the study.
Digoxin trough samples (5 mL) were collected within 2 hours before
administration of digoxin on days 10 through 19.
RESULTS
Thirty (30) healthy men aged 27-45 years were enrolled. The subjects'
demographic characteristics are presented in Table 1.
(Table Removed)
a: Ten (10) subjects discontinued prematurely from the study and were excluded from all
statistical analyses
In the present study, different tigecycline IV dose regimens were used during
periods 1 (single dose) and 3 (multiple dose); which prevented a direct comparison of
PK parameters obtained from periods 1 and 3. However, since tigecycline exhibits
linear pharmacokinetics, based on linear PK theory, (Gibaldi M, Perrier D.
Pharmacokinetics. Marcel Dekker, Inc., 1982), it was determined that the following
parameters could be compared: (a) total tigecycline exposure (ADC) as reflected by
dose-normalized AUC0.« (period 1) and actual AUCO-12h (period 2), (b) t1/2, CL, and
actual AUC0-i2hfor the 2 periods, and (c), MRT and Vss for the 2 periods, with estimates
for period 1 based on concentrations normalized to a 50-mg dose.
Digoxin Plasma PK2
Tigecycline did not affect the steady-state plasma digoxin AUC0-24h, oral-dose
CL/F, or digoxin concentrations during the 12- to 24-hour period after dose
administration (therapeutic drug monitoring times), although the 90% CIs for Cmax and
tmax fell outside of the equivalence window.
Based on the bioequivalence analysis, 90% CIs for the plasma digoxin AUC0-24h
and CL/F were both within the 80% to 125% equivalence window, but the 90% CIs for
Cmax (Cl = 77%-98%) and tmax (Cl = 91%-135%) were not. Thus, tigecycline did not
affect digoxin total exposure (AUC) or oral-dose clearance (CL/F); but the digoxin
absorption rate was slightly decreased.
The descriptive statistics for mean pharmacokinetic parameters for plasma digoxin are
presented in Table 2. There were no statistically significant treatment effects for the
digoxin PK parameters, although the statistical power was low for Cmax (p = 0.067,
power = 74%) and tmax (p = 0.379, power = 18%).
(Table Removed)
The results of the bioequivalence analysis therefore indicate that tigecycline did
not affect the AUC or CL/F of digoxin. Although coadministration of tigecycline
decreased the absorption rate of digoxin, as reflected by a concurrent decrease in Cmax
(13%) and increase in tmax(11%), these changes were small and would not be expected
to alter the PD effect of the digoxin. In addition, while not being bound by theory as
hypothesized tigecycline did not increase the Cmax of digoxin. Furthermore, the 90% Cl
for plasma digoxin concentrations at
12, 16 and 24 hours were all within the equivalence window.
Mean and individual plasma digoxin concentrations over 24-hour intervals during period 2
(digoxin alone) and period 3 (digoxin plus tigecycline) are presented in Figures 1 and 2
respectively.
Digoxin Urinary PK
Tigecycline also did not affect the steady-state digoxin urinary PK as shown by
measurement of digoxin Ae,% and digoxin CLr. Descriptive statistics for urinary digoxin
parameters during periods 2 and 3, the results of ANOVA, and the results of the
bioequivalence analysis are summarized in Table 3.
(Table Removed)
The results for ANOVA in Table 3 show that there were no statistically significant
treatment effects on either total urinary digoxin excretion (p = 0.161)
or renal clearance (p = 0.320). Similarly, based on the bioequivalence analysis,
90% CIs for Ae,% and digoxin CLr were both within the 80% to 125% equivalence
window. Therefore, tigecycline did not affect digoxin urinary PK.
Tigecycline serum PK
Digoxin did not affect the steady-state AUC, CL, or MRT of tigecycline, although
the GLS mean ratios for serum tigecycline ti/2 and Vss fell outside the 80% to 125%
equivalence window.
The descriptive statistics for mean pharmacokinetic parameters for serum tigecycline
are summarized in Table 4.
(Table Removed)
Before statistical comparisons, the dose-dependent parameter AUC on day 1 of period
1 was normalized to a 50-mg tigecycline dose. Estimates from the ANOVA were used to
compute the geometric least-squares (GLS) ratios and associated 90% CIs for the treatment
comparisons.
The results for ANOVA in Table 4 show statistically significant treatment effects for all
tigecycline PK parameters except for AUC0.i2h (P = 0.12, power = 1.0). However, based on the
bioequivalence analysis, 90% CIs for the parameters AUC0.12h, AUC, CL, and MRT were all
within the 80% to 125% equivalence window, but the 90% CIs for ti« (Cl = 131% 162%) and
Vss (Cl = 109%-134%) were not within the equivalence window.
The results of the bioequivalence analysis therefore indicate that digoxin did not affect the
AUC, CL, or MRT of tigecycline. Also, because the AUC0-i2h values on days 1 and 19 were
equivalent without normalization for dose, the results indicate that a loading dose of 2 times
the maintenance dose reached steady state after the first dose. Although coadministration of
tigecycline and digoxin (period 3) increased both tigecycline terminal ti/2 and apparent Vss,
these increases did not affect the total exposure or IV clearance of tigecycline
Mean and individual serum tigecycline concentrations over 96 hours during period 1
(tigecycline alone) and period 3 (tigecycline plus digoxin) are presented in Figure 3.
ECG measurements
Tigecycline did not affect steady-state digoxin pharmacodynamic effects as measured
by changes from baseline in ECG parameters.The small concurrent decrease in Cmax (13%)
and increase in tmax (11%) would not be expected to alter the PD effect of digoxin.
Furthermore, the 90% CIs for plasma digoxin concentrations at 12, 16, and 24 hours were all
within the equivalence window.
The present study was designed to compare changes from baseline in ECG
parameters (PR, QRS, QT, and QTc intervals) at 24 hours after drug administration. At this
time point, serum digoxin concentrations would be expected to be in equilibrium with tissue
concentration, and the ratio of inotropic response to serum concentrations would be relatively
constant. (Reuning RH, Geraets DR. Digoxin. In: Evans WE, Schentag JJ, Jusko WJ, eds.
Applied Pharmacokinetics. Spokane: Applied Therapeutics, Inc., 1986:570-623)
Based on ANOVA, there were no significant differences in ECG parameters due to
treatment effects at 24 hours after drug administration, except for the QT interval (p = 0.007,
period 1 > 2 = 3). The QT interval decreased after digoxin (period 2) compared to tigecycline
alone (period 1) but was not changed further when tigecycline was added to digoxin (period 3).
These results indicate that coadministration of tigecycline did not produce significant changes
in steady-state digoxin PD as measured by changes from baseline in ECG parameters.
Assay comparisons
It should be noted that the 0-hour samples on days 14 and 19 were analyzed using the
MEIA monitoring assay, and the 24-hour samples on these days were analyzed using the RIA
PK assay. The mean ± SD ratios for trough samples at 0 and 24 hours (Oh/24h) on days 14
and 19 showed values of 22.3% ± 36.0% and 37.4% ± 44.1%, respectively.
Although the MEIA method was not intended for use in digoxin PK profiling in this
study, the hour 0 and hour 24 blood samples for digoxin PK on days 14 and 19 were
inadvertently analyzed using this assay. Because the plasma MEIA and plasma digoxin RIA
methods had not been cross-validated, it was decided that digoxin concentrations in serum
samples from the hour 0 time point on day 15 would be assayed using the serum digoxin RIA
method. The resulting data would then permit a comparison of digoxin concentrations at a
single time point based on a PK assay (serum digoxin RIA) and monitoring assay (plasma
digoxin MEIA). While the 2 assays are based on different biological matrices (plasma as
opposed to serum), this difference would not be expected to affect the measured
concentrations.
The results presented in Table 5 show that mean ± SD digoxin concentrations
measured by the MEIA method were increased by 27.0% ± 24.4% compared with digoxin
concentrations measured by the RIA method. The higher digoxin concentrations at 0-hour may
be partially because of the use of the MEIA assay.
(Table Removed)
A statistical comparison (ANOVA) of the concentrations at each time point during
periods 2 and 3 is presented in Table 6. The results show that tigecycline did not affect digoxin
concentrations at any time point except at 0 hours (p = 0.008) and 24 hours (p = 0.017) after
dose administration. The mean ± SD digoxin concentrations at 0 hour (MEIA monitoring
assay) and 24 hours (RIA PK assay) on day 19 were increased by 24.9% ± 35.1% and 16.4%
± 29.5%, respectively, compared to day 14.
(Table Removed)
Tolerability
No deaths, serious adverse events (SAEs), or clinically important changes in laboratory
values or vital signs occurred during this study.
Ten (10) subjects withdrew from the study; 9 did so because of AEs. Twenty-nine (29)
of 30 subjects (96.7%) reported at least 1 treatment-emergent adverse event (TEAE). The
most frequently reported (>10%) treatment-related TEAEs occurred during period 3
(tigecycline + digoxin): nausea (83%), dyspepsia (28%), headache (24%), vomiting (24%),
injection site reaction (21%) and injection site phlebitis (21%), abdominal pain (14%), anorexia
(17%), diarrhea (10%), dizziness (10%), insomnia (10%), and taste perversion (10%).
All 9 subjects who withdrew from the study did so during period 3; 4 subjects withdrew
because of vomiting and 3 withdrew because of nausea. One (1) subject withdrew because of
myalgia (musculoskeletal chest pain) of moderate intensity. One (1) subject withdrew because
of a worsening of a first-degree atrioventricular block that was not detected at screening; this
was judged by the investigator to be related to treatment with digoxin.

WE CLAIM:
1. A method of treating, controlling or reducing the risk of a bacterial infection and a
cardiac insufficiency condition in a human which comprises administering to said
human an effective amount of tigecycline and an effective amount of digoxin.
2. A method for controlling from increasing steady state digoxin plasma levels in a
human experiencing cardiac insufficiency condition and a bacterial infection, the
method comprising administering to said human in need thereof an effective amount
of digoxin and tigecycline.
3. A method of treating, controlling or reducing the risk of a bacterial infection and a
cardiac insufficiency condition in a human which comprises administering to said
human in need thereof an effective amount of tigecycline and an effective amount of
digoxin.
4. A method of treating, controlling or reducing the risk of a cardiac insufficiency
condition and a bacterial infection in a human which comprises administering to said
human in need thereof an amount of digoxin and an effective amount of tigecycline.
5. A method of treating, controlling or reducing the risk of a bacterial infection with
tigecycline in a patient having preexisting cardiac insufficiency and being treated with
digoxin said method having the advantage of controlling and stabilizing from decreasing
plasma digoxin levels in said patient.
6. Use of tigecycline in combination with digoxin in the preparation of a medicament for
treating or preventing a bacterial infection and a cardiac insufficiency condition in a
human.
7. Use of tigecycline in combination with digoxin in the preparation of a medicament for
controlling from increasing steady state digoxin plasma levels in a human
experiencing cardiac insufficiency condition and a bacterial infection.
8. Use of tigecycline and digoxin in the preparation of a medicament for treating,
controlling or reducing the risk of a bacterial infection and a cardiac insufficiency
condition in a human.
9. Use of tigecycline and digoxin in the preparation of a medicament for treating,
controlling or reducing the risk of a cardiac insufficiency condition and a bacterial
infection in a human.
10. Use of tigecycline in the preparation of a medicament for treating, controlling or
reducing the risk of a bacterial infection in a human undergoing treatment with digoxin.
11. Use of tigecycline in the preparation of a medicament for treating or preventing a
bacterial infection in a human which treatment also comprises administration of digoxin
for cardiac insufficiency.
12. A product comprising tigecycline and digoxin as a combined preparation for
simultaneous, sequential or separate use in the treatment or prevention of a bacterial
infection and a cardiac insufficiency in a human.
13. the invention substantially such as herein described.