Download pharmacokinetics of 7-day multiple-dose tedizolid

P1723
PHARMACOKINETICS OF 7-DAY MULTIPLE-DOSE TEDIZOLID PHOSPHATE IN HEALTHY JAPANESE SUBJECTS IN A PHASE I PLACEBO-CONTROLLED STUDY
Toshiaki Tanaka1, Yuko Hayashi1, Kazuhito Okumura1, Kenichi Yoshikawa1, Masaharu Kato2, Kumiko T Kanatani3, Ippei Ikushima4
Clinical Pharmacology Asia/Japan, Bayer Yakuhin, Ltd., Osaka, Japan; 2Clinical Statistics, Bayer Yakuhin, Ltd., Osaka, Japan; 3Health Informatics, Kyoto University Graduate School of Medicine, Kyoto, Japan; 4LTA Clinical Pharmacology Centre Sumida Hospital, Tokyo, Japan
INTRODUCTION
Gram-positive infections caused by drug-resistant pathogens such as
methicillin-resistant Staphylococcus aureus (MRSA) remain a challenge
for physicians as outcome may be associated with increased mortality.1
There is a high unmet medical need in the management of such infections
because the existing effective antibiotics often need monitoring of their
therapeutic level and require dose adjustment in special populations
(e.g. elderly, renal impairment) or are contraindicated due to comorbidities.
According to a survey conducted in Japan in 2010 by the Ministry of Health,
Labour and Welfare (MHLW), the prevalence of the Gram-positive MRSA
leading to nosocomial infections was much higher (90%) compared with
other drug-resistant Gram-positive pathogens such as penicillin-resistant
Streptococcus pneumoniae.2
The currently approved and marketed drugs to treat MRSA infections in
Japan are vancomycin, teicoplanin, arbekacin, daptomycin, and linezolid.
Tedizolid phosphate (TZDP) is a novel oxazolidinone antibiotic prodrug
for infections caused by Gram-positive bacteria, including MRSA. TZDP
is rapidly converted into tedizolid (TZD), its active moiety, by non-specific
phosphatases in vivo.3
Two recently completed Phase III clinical studies have demonstrated
non-inferior efficacy of tedizolid 200 mg once-daily treatment for 6 days
to linezolid 600 mg twice-daily treatment for 10 days in patients with
acute bacterial skin and skin structure infections (ABSSSIs).4,5,6
The objective of this Phase I study was to assess the pharmacokinetic (PK)
properties of tedizolid in Japanese subjects after 7-day administration of TZDP.
The safety results of this Phase I study have been reported previously.7
METHODS
This was a placebo-controlled, double-blind, randomised Phase I study.
Healthy male subjects received TZDP or placebo for 7 days once daily
between Day 0 and Day 6. In cohort 1, subjects received intravenous
TZDP 200 mg (IV, n=8) or saline infusion (n=4). In cohort 2, subjects
received oral (PO) TZDP 200 mg tablets (n=8) or placebo tablets (n=4).
Drug and/or alcohol abuse or suspicion of drug and/or alcohol abuse
Intake of alcohol-, grapefruit-, caffeine-, or high tyramine-containing foods
or beverages within 4 days before the first drug administration
Smokers or former smokers (cessation <3 months before the start of the study)
Clinically relevant ECG findings
Systolic blood pressure (BP) <90 or >140 mmHg or diastolic BP <45 or
>90 mmHg
Heart rate <45 or >95 beats/min
Clinically relevant deviations from the normal range in the clinical laboratory
test in the investigator‘s opinion
Key inclusion criteria
Japanese healthy male subjects aged 20 to 40 years
Body mass index (BMI) ≥ 17.6 and ≤ 26.4 kg/m²
Subjects provided signed informed consent before the study start.
Key exclusion criteria
Known hypersensitivity, intolerance, or allergy to oxazolidinone antibiotics
History of severe allergies, opportunistic infection or infections of
unexplained frequency or severity
Signs of infection or symptoms of constipation
Febrile illness within 1 week before the first study drug administration
RZ_BHC_ECCMID_PK-MD_Sivextro_Medical-Poster_140428.indd 1
Baseline demographics of subjects and compliance to study drug
A total of 24 subjects were randomised. There were no clinically relevant
differences in demographic parameters.
33.3% of subjects had previous history of smoking, and 41.7% of the
subjects had light alcohol intake.
All subjects completed the 7-day TZDP administration and had a
cumulative dose of 1400 mg TZDP. No subject who received TZDP
discontinued the study.
In the placebo group one subject discontinued administration of placebo
due to an adverse event (atrial fibrillation).
Pharmacokinetics
Deviations from the lower limit of normal range in white blood cells (WBC),
red blood cells (RBC) or platelets.
Pharmacokinetic assessments
Intravenous TZDP dissolved in 250 mL sterile saline was infused over
60 minutes. Subjects in the placebo group received intravenous saline over
60 minutes. Oral TZDP and placebo tablets were given with 240 mL water.
Use of selective serotonin re-uptake inhibitors (SSRIs), serotonin
5-hydroxytryptamine (5-HT1) receptor agonists (triptans), monoamine
oxidase (MAO) inhibitors, tricyclic antidepressants, buspirone, meperidine
and other serotonergic medications within 5 weeks before the first study
drug administration
Study design and treatments
Prolonged (> 2 weeks) exposure to linezolid within 1 year before the first
drug administration
Plasma samples in both cohorts were collected at baseline (Day 0) prior to
administration of TZDP and at subsequent timepoints up to 72 hours during
and after administration of the last dose of study drug on Day 6.
Blood samples were collected on Day 0 with respect to start of infusion at:
0 min, 15 min, 30 min, 60 min, 65 min, 70 min, 75 min, 90 min, 120 min,
3 h, 4 h, 6 h, 8 h, 12 h, 24h (=Day 1), Day 2, Day 3, Day 4, Day 5, and on
Day 6 with respect to start of infusion at: 0 min, 15 min, 30 min, 60 min,
65 min, 70 min, 75 min, 90 min, 120 min, 3 h, 4 h, 6 h, 8 h, 12 h,
24 h (=Day 7), Day 8, Day 9.
Blood samples were collected on Day 0 with respect to administration of
oral tablet at: 0 min, 15 min, 30 min, 60 min, 90 min, 120 min, 3 h, 4 h, 6 h,
8 h, 12 h, 24h (=Day 1), Day 2, Day 3, Day 4, Day 5, and on Day 6 with
respect to administration of oral tablet at: 0 min, 15 min, 30 min, 60 min,
90 min, 120 min, 3 h, 4 h, 6 h, 8 h, 12 h, 24 h (=Day 7), Day 8, Day 9.
TZDP and TZD concentrations were determined in human plasma and
urine samples using liquid chromatography coupled with tandem mass
spectrometric detection (LC-MS/MS). The calibration range of the procedure
was 5.00 μg/L (lower limit of quantification [LLOQ]) to 1000 μg/L (upper
limit of quantification [ULOQ]) for both substances.
Pharmacokinetic (PK) parameters including area under the concentration
curve (AUC), maximum concentration (Cmax), half-life (t1/2) and time to
reach Cmax (tmax) were calculated and expressed as geometric mean
(% coefficient of variance). PK parameters were compared between
Day 0 and Day 6.
Drug accumulation ratio (RA) was calculated as AUC0-24md / AUC0-24 and
linearity factor (RLin) of pharmacokinetics was calculated after repeated
administration of identical doses as AUC0-24md / AUC.
After IV administration of TZDP, the plasma concentration of TZD on Day 0
reached a Cmax of 3.54 (9.16) μg/mL approximately at the end of the 1 hour
infusion (tmax=1.03 hours; range: 0.983−1.17 hours). The AUC0-∞ was
33.8 (19.5) μg•h/mL and AUC0-24h was 28.1 (15.9) μg•h/mL.
After PO administration of TZDP, TZD plasma concentration on Day 0
reached a Cmax of 2.08 (24.6) μg/mL within ≈3 hours (range: 1.50−
4.00 hours). The AUC0-∞ was 24.9 (24.4) μg•h/mL and AUC0-24h was
20.7 (21.6) μg•h/mL.
CONCLUSIONS
The plasma concentration of TZDP after IV administration declined rapidly
to below LLOQ (5 µg/L) within 3 hours after end of the 60-min infusion on
Day 0 (t1/2=0.252 hours) and Day 6 (t1/2=0.648 hours) (Figure 2).
TZDP was not detected after PO administration in plasma and in urine.
Figure 1. Plasma concentration of TZD after multiple doses of IV or PO
TZDP in healthy Japanese subjects.
Plasma tedizolid concentrations were quantifiable in all subjects at
15 minutes after start of IV infusion (Figure 1). After PO administration
of TZDP, plasma tedizolid concentrations were quantifiable in all subjects
at 30 minutes (Figure 1).
On Day 6 accumulation of TZD was minimal with RA values of 1.22 (5.53)
for IV and 1.28 (6.31) for PO routes, and it was predicted by the single
dose kinetics RLin values of 1.02 (5.05) for IV and 1.06 (5.90) for PO routes.
Urinary excretion of TZD was negligible (IV: 1.2% and PO: 0.8%, arithmetic
mean) in a 24-hour period.
On Day 0 after IV administration of TZDP, TZDP plasma concentration
reached a Cmax of 2.68 (11.6) μg/mL within ≈ 30 minutes (tmax=0.50 hours;
range: 0.250−0.983 hours). The AUC0-∞ was 2.35 (14.6) μg•h/mL and
AUC0-24h was 2.36 (14.6) μg•h/mL.
On Day 6 after IV administration of TZDP, TZDP plasma concentration
reached a Cmax of 2.52 (14.0) μg/mL within ≈ 30 minutes (tmax=0.50 hours;
range: 0.250−0.500 hours). The AUC0-24h was 2.21 (15.2) μg•h/mL.
TZD plasma concentration reached steady state on Day 1 of TZDP
200 mg once-daily administration, regardless of the route of administration.
Pharmacokinetics of TZD showed minimal accumulation following 7-day
repeated-dose TZDP administration.
The PK profile of TZD after administration of multiple doses of TZDP
200 mg once-daily administration for 7 days, and considering high antibacterial activity against MRSA (MIC90: 0.25 µg/ml) seems appropriate
for the treatment of Gram-positive infections and allows the clinical
development of tedizolid for ABSSSI and nosocomial pneumonia in Japan.
REFERENCES
1. Sandiumenge A, Rello J. Ventilator-associated pneumonia caused
by ESKAPE organisms: cause, clinical features, and management.
Curr Opin Pulm Med. 2012 May;18(3):187−93.
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100
2. JANIS survey; Available at: http://www.nih-janis.jp/. Accessed:
08. November 2013.
3. Locke JB et al, Clin Infect Dis 2014; 58(Suppl 1): S35−S42.
10
4. Prokocimer P et al, Tedizolid phosphate vs linezolid for treatment of acute
bacterial skin and skin structure infections: the ESTABLISH-1 randomized
trial. JAMA 2013; 309: 559−569.
1
PK data on Day 6 were comparable to those on Day 0 in both cohorts
(IV: Cmax=3.82 (15.2) μg/mL; AUC0-24 = 34.4 (19.2) μg•h/mL;
PO: Cmax=2.51 (18.1) μg/mL; AUC0-24 = 26.4 (22.4) μg•h/mL).
On Day 6 the t1/2 of TZD was 11.9 hours (geometric means) and 11.2 hours
(geometric means) after IV and PO administration of TZDP, respectively.
Additionally, tmax was 1.08 hours (range: 0.983−1.25 hours) and 4.00 hours
(range: 2.00−6.00 hours) after IV and PO administration of TZDP, respectively.
Changes in the plasma concentration of TZD after IV or PO administration
of TZDP over time (between Day 0 and Day 6) is shown in Figure 1.
During multiple-dose administration of TZDP 200 mg once daily over
7 days, plasma tedizolid concentration reached steady state on Day 1,
regardless of administration route.
10000
Tedizolid plasma concentration (µg/L)
RESULTS
0
24
48
72
96
120
144
168 192
5. Fang E et al, 23rd European Congress of Clinical Microbiology and
Infectious Diseases, 27−30 April 2013, Berlin, Germany. Abstract LB-1964.
216
Time (h)
IV: intravenous, PO: oral
Tedizolid IV (n=8)
6. De Anda C et al, 53rd Interscience Conference on Antimicrobial Agents and
Chemotherapy, 10−13 September 2013, Denver, USA, Abstract L-203.
Tedizolid PO (n=8)
7. Tanaka T et al, 18th Asian Pacific Society of Respirology (APSR) meeting,
11−14 November 2013, Yokohama, Japan, PS095.
Figure 2. Plasma concentration of TZDP after IV administration on Day 0
and Day 6 in healthy Japanese subjects.
ACKNOWLEDGEMENTS
This analysis was sponsored by Bayer Yakuhin Ltd., Japan.
10000
TZDP plasma concentration (µg/L)
1
This poster was presented at the 24th European Congress of Clinical
Microbiology and Infectious Diseases in Barcelona, Spain, 10–13 May 2014.
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LLOQ: 5 µg/L
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Day 0:
Day 6:
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Time of sample collection (h)
Infusion of TZDP
Day 0 (n=8)
Day 6 (n=8)
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