Jpn

J Clin

Pharmacol

Ther

17(3)Sept

1986

559

Pharmacokinetics

of FK027 (Cefixime) in Healthy Injection

Volunteers after Intravenous

Mitsuyoshi Hideyo

NAKASHIMA*1

Mitsutaka

KANAMARU*2 KAJIHO*3

NOGUCHI*3 and Tokuaki (Received on Jan. 23, 1986)

*1 Department of Pharmacology Medicine

, Hamamatsu University School of

3600 Handa Cho, Hamamatsu City, Shizuoka, Japan *2 Maruyama Hospital *3 Research maceutical Laboratories Co., Ltd. and Clinical Research , Fujisawa Phar

The intravenous crossover biphasically. half-life compartment compartment 4.63ml/min drug

pharmacokinetics injection design. The (t1/2) (Vc) (Vt) and in the increased increased is and extent rapidly it is The distribution was was was the the serum of

of 100mg serum

FK027 both

was

investigated and of (t1/2) The L and The (Clr) the total was 64.8}3.5%. and area the Clr and mainly under volume was volume volume body with

in

6 healthy oral probenecid without

male

volunteers 1g by

after a two-way declined

without

concentrations half-life

FK027

probenecid and the of of (Clbody) The FK027 was the was

0.148}0.015hr of of distribution distribution

elimination the central

2.519}0.070hr. 4.032}0.379 7.074}0.576 renal 24-hr clearance urine was

peripheral 58.5}9

L.

clearance

37.40}1.82ml/min. When the of

unchanged given with curve

excreted

probenecid, AUC) (Vdss) FK027 body, some

concentrations and but to from renal Clbody the the tubular tissues kidneys, t1/2

concentration-time distribution These results eliminated filtration at steady indicate from

significantly slightly, distributed excreted

and and

( state that the to

decreased. thereafter through

gradually glomerular

and

through

secretion.

*1 431-31 *2 3600

*3 ()

560

Key words:FK027, probenecid

cefixime,

pharmacokinetic

parameters,

serum

concentration,

Introduction

FK027 developed of Japan. 7 Fujisawa Its

Cefixime) in the Central

is

a new

oral

cephalosporin Laboratories

Research Co., is

Pharmaceutical chemical nomenclature

Ltd., (6 R,

Osaka, 7 R )

Fig. 1

Structure

of FK027.

[(Z)-2-(2-amino-4-thiazolyl)-2 -8-oxo-3

(carboxymethoxyimino)-acetomido] vinyl-5-thia-1-azabicyclo-[4,2,0]-octo-2-ene 2-carboxylic Unlike penicillins, mases activity tive The tion hours, as tions unchanged These ly in ity gating dosing In kinetics after this of intravenous which secretion systemic of oral long of and acid. conventional FK027 has against organisms, time FK027 and as were the to is oral stable spectrum cephalosporins to

67 kg (mean:59.7kg)

took part in this study.

The six volunteers gave their written consent to participate in the study. after the purpose and methods of the study and possible side effects of FK027 were fully explained. The protocol and consent form for this inves tigation had prior review and approval of the Ethical Committee, Fujisawa Pharmaceutical Company Ltd., Osaka, Japan.
4.0 was

and

various -lacta of and antibacterial gram-nega bacilli. concentra 3.8 half-life serum excretion concentra of was 21-28%. is gradual excreted the to

a broad

gram-positive especially reach after apparent hours. maximum oral dosing 1) elimination The The the suggest oral dosing the is very 24-hr that and systemic

gram-negative serum was

All volunteers

were deemed healthy on the

basis of hematology, blood chemistry, urinalysis, and physical examination, and also were negative to the intradermal The volunteers reaction test. were randomly assigned to 2

2.3-2.5 prolonged. drug studies after in

urine FK027

absorbed the of urine. FK027 the has

slowly

groups of 3. Each group was given FK027 intravenously both without and with probenecid by a two-way crossover design. A five-day fasted be washout period was provided between the 1st and
oral

However, which pharmacokinetics not study, FK027 been we in injection is

bioavailabil for drug investi after

important of the

2nd dosing periods. The volunteers after intravenous intravenous reconstituted injection. FK027

elucidated. investigated 6 healthy both known the male without to inhibit pharmaco volunteers and with renal discussed dosing.

tween 10:00 p. m. of the night before and 4 hours The study was started from 9:00 a. m. For injection, 110mg and NaHCO3 33.4mg contained in a vial were freshly immediately before injection with saline. The pH was 22ml of 0.9% physiological

probenecid tubular the

antibiotics

2)3)4), and after oral

bioavailability

6.31 and the osmotic pressure was 334 mOsm/kg.

Materials and Methods

Twenty ml (100mg potency as FK027) of the

29 weighing and 49 55

Six years

healthy of age

male (mean:40

volunteers years)

between and

solution was given intravenously

for 3min at

constant rate. The injection doses of FK027 per

561

body m2 cid

surface (mean}S. was given

area

ranged

from

55.2

to

62.9mg/ Probene

serum acid The of g/ml The after

and (15:85:0.21) sensitivity for

acetonitrile-water-1.8M for limit and of analysis the analysis for FK027 analyzed in of

sulphuric urine. was urine. the by 0.05 serum the 2

E.:59.3}1.3mg/m2). in Japan oral doses of 1g (4 with of FK027.

tablets~250 200ml Blood in physical were made the

mg/tablet, water pressure, sitting interview, before ECG injection. made was 8, before collected 12, and and was one

Merck-Banyu) before rate, were injection and body measured, and 8, and before chemistry 24 percussion hours and and after 1/12, 30

serum

0.5g/ml of

hour pulse

pharmacokinetics intravenous open were analysis concentrations, parameters probenecid analysis in terms of of injection model. calculated computer

temperature and

was The

position auscultation 0.5, recorded Blood and before 24 before hours after at were and assayed. serum were E. coli each 4,

compartment parameters regression

pharmacokinetic with program a non-linear NONLIN excretion, FK027 statistically Each E. value both and with deter was 7).

after minutes

injection. after were Blood 1, Urine 2, 4, was and 6,

The

serum

urinary of were variance. mean}S.

urinary injection. 1/4, 1/2,

tests

pharmacokinetic out mined expressed and by with

24

hours and after 0-2,

hours and

injection. 2-4, and 4-6, the time. obtain the stored 6-8,

collected 12-24 determined samples serum until The FK027 with The for were using The delivery an ters detector Spectroscopic). The change Toyo (TSK-LS The nium solution automatic Assoc.)

8-12, volume The serum, at -20

Results
injection collection to was blood and

The mean serum concentration-time individual serum concentrations healthy male volunteers

curve and

centrifuged urine samples

of FK027 in 6

were

after intraveous injec-

and determined ATCC limit

urinary by 39188 of the the as assay

concentrations bioassay the test was method 5) organism. 0.08g/ml

of

sensitivity both also serum

and

urine. by

The the switching. with A;

concentrations HPLC method 6)

determined column. was (Model liquid and (at 295nm, a

automated HPLC pumps

equipped 6000 simpler variable UVIDEC

two

solvent Assoc.),

Waters 710

(WISP wave

B;

Wa UV Japan

length 100-III;

three column Soda) 410 mobile dihydrogen (pH2.5)

columns ( TSK-IEX and ODS, phases two

used

were 540

an DEAE,

anion-ex 5m; columns

reversed-phase 5m;Toyo were 73% 0.03M Soda).

Fig. 2

Mean serum concentrations of un changed drug after intravenous injec

tion of FK027 without()and in 6 healthy with volun () teers. probenecid

ammo acid

phosphate-phosphoric in methanol for analysis

of

562

563

tion both without and with probenecid are shown in Fig. 2 and Tab. 1. The serum concentrations of FK027 without probenecid rapidly decreased up to 2 hours after injection and thereafter gradually were eliminated. The serum concentrations of FK027 with probenecid were significantly higher 0.5 to 12 hours after injection than those of
FK027 concentration by the without of biexponential to probenecid. FK027 with equation, a two-compartment pharmacokinetic in tissues rapid, with Tab. after 2. The distribution without 0.148}0.015hr. gradually Clbody eliminated, was 58.59 The time decline was in serum

AUC FK027

(0-) was given

was with and

29.31}2.19gEhr/ml. probenecid, t1/2 by Clbody 31.65}2.60 of with t1/2 of (P i. e. 10.313 48.734.33 ml/min. without was of of shown of in 24 hours in These

0.1600.023hr <0.05), 0.839 ml/min values (P<0.05). , g hr/ml, The with urinary probenecid The enecid 64.8}3.5% urinary was i. e. Vdss L and were

2.7300.087hr about was 7%,

decreased (P<0.05). Clr lower AUC an was than

those (0-)

probenecid 35.44}2.83

expressed

increase

21% (P<0.05). without 3. without first 2 hours injection in 24 hours. the prob and and first There be 6-8, and

Ae-t+Be-t, open parameters of FK027 model. are

excretion is excretion 30.5}1.4% up to

FK027 Tab.

corresponding The calculated

FK027 the after

summarized to was serum with the

injection t1/2 of were

probenecid The

that

with

probenecid and 65.5}3.8%

was

28.4}1.7% up to

concentrations t1/2 of 2.519}0.070hr.

2 hours were tween no the

statistically two groups in

significant the 0-2,

differences 2-4, 4-6,

4.63m/min

and

Clr

was

37.401.82ml/min.

Tab. 2 Pharmacokinetic Parameters after Intravenous Injection of FK027 without and with Probenecid in Healthy Volunteers (dose:100mg)

564

Tab. 2

Continued

Tab. 3 Urinary Excretion Rates of Unchanged Drug after Intravenous Injection of FK027 without and with Probenecid in Healthy Volunteers (dose:100mg)

565

8-12 or 0-24 hr urinary -24hr excretion .

The and tween Serum P<0.01; =0 by .981, HPLC above HPLC the values method, values were with obtained

excretion

except

the 12

To urinary

investigate excretion of Probenecid the to renal

the of FK027 is tubular the There of probenecid such and probenecid and

effect FK027 with known

of in

probenecid detail, the

on pharma was

the

determined good by

by correlation both

bioassay be methods. r=0.989, r

cokinetics died. inhibit and

probenecid to

stu

competitively of antibiotics, of reports antibacterial ceftizoxime studies t1/2, in serum Clbody, study, AUC Vdss than shows was differences there two were groups suggest glomeru tubular affects were were after that inhi (1) 2), on

secretion serum have been on

(n=108):y=1.128x-0.156, urine P<0.01, and y (n=72):y=1.114x-1.025, where is x the is the value value

enhance

concentrations many the as 4). These

antibiotics 11). the effect of

obtained by

obtained

activity cefmenoxime 3)

antibiotics cefatrizine

bioassay. FK027 physical obtained the normal on auscultation was well tolerated and and range. verbal or after There interview, percussion by volunteers test were no abnormal or subjective and values within all

dicate

that

increases AUC but In decreases the

examination during

laboratory the study were

concentrations Clr t1/2 and and urinary (2) and after serum (3)

excretion. concentrations and with probenecid, secretion

present and

particular find

complaints ings on

higher lower injection the renal

Clbody

Clr

and

(4)

injection without tubular probenecid. these any values differences excretion. is to

probenecid which of FK027 the and the results by renal slightly FK027. of is not Vdss known.

symptoms.

Discussion bited The probenecid open hr, central ment. was ins cefaclor t1/2 lower findings to rial negative bacilli. from 64% excreted The 24-hr 2-hr urinary the of the Clr, the of than far model. and FK027 compartment The slower elimination than that 0.9hr8); and serum were t1/2 was concentrations well of fitted FK027 rapidly to of the to was of the as FK027 without between scarcely 0.148 the in total by However, were small, between These mainly extent only of by

2-compartment short as from compart the cephalospor 0.8hr9); 1.1hr10) with i. e. These distributed antibacte and gram-negative of an antibiotic i. e. that about is gram serum

urinary that FK027 and or that

distributed peripheral from oral

either lar

excreted some

filtration

FK027

secretion, the The the et renal

probenecid secretion

of other

tubular reason of for

(cephalexin, 9), 0.6hr; 2.519hr. that suggest target activity organs against organisms, an kidneys, Clbody mainly urinary index of

cephradine,

the probenecid out

decrease

values Gibaldi not of -lactam only

in

cefamandole, was 58.59

presence al. 12)13)pointed the

Clbody the that reference FK027 and

ml/min,

that

probenecid secretion

antibiotics. is rapidly a potent

inhibits antibiotics distribution. enecid liver,

renal but In

tubular also other at the tissues resulting

decreases words, binding and in

the antibiotics site enhance decreased in

volume and the the volume prob

of

exerts gram-positive especially

compete and other

kidneys, serum of

for was value from

excretion 37.40 and the ml/min, shows kidneys. was was 64.8%.

concentrations, distribution. However, enecid had of Vc FK027, and Vt our little

FK027

present effect since Vdss on

study the only no

showed volume slightly decrease. of

that

prob

distribu decreased After all,

excretion

30.5%

and

the

tion and

excretion

showed

566

FK027 eliminated through and tion. In the to

was

rapidly gradually

distributed from filtration through the

to

the body, the

tissues possibly main

and

and 33-43%, were sligtly excretion.

respectively; lower than

i. e. the AUC those

values

from the urinary

glomerular some extent

as renal

route, secre

tubular

There are some references pharmacokinetic findings. al. 14) stated values than

related

to the above

previous of the

study 1), drug at the

we after

reported oral

the dosing. of

pharma There oral follows: concen and

Gugler

et

that

the

systemic from AUSs

cokinetics fore, an

bioavailability are also lower

of phenytoin those from

attempt

comparison was made

the process

urinary exists

intravenous The tration ranged half-life equal injection serum dosing There ences dosing Tmax, variation from 31 to to time (Tmax) from

bioavailabillity to reach after 3.8 (biz) t1/2 in our of of to the oral 4.0 2.3-2.5 2.5 present (Cmax) hours

as serum

excretion,

since a capacity-limited of the drug.

maximum dosing hours,

in the metabolims
mg

with with an

50-200 apparent nearly

Nagwekar Menten secretion Chremos tive decline

et al. 15)reported is related

that the Michaelis to the renal tubular

kinetics

hours, after The AUC

i. e.

of p-methyl

mandelic

acid in rats.

intravenous maximum after oral

et al. 16)showed

that the postabsorp concentrations

study. and

of blood bethanidine

concentration were were between after t1/2 for and the

with time was noticeably ponding decline in renal

slower than the corres excretion rate.

dose-dependent 1). no statistically on in an any significant empty stomach differ and (Cmax, of ranged the were fasting con we after compare stable no

in the urinary was attributed clearance

This discrepancy decrease

to the continual

dosing breakfast AUC0-). absorption providing excretion.

of bethanidine. et al. 18) were

parameters The coefficient excretion of there non

Moreover, stated actively that

Lanman

et al. 17) and Axelson and riboflavin

tetracycline

and evidence Since and

transferred

to the bile. the drug was excreted excretion in rats

38%, and between

In the case unchanged and patients respectively.

of FK027,

absorption differences ditions used oral oral The calculated AUCs travenous and the dosing and in

and the 24-hr biliary

fasting pharmacokinetic

were as high as 22% 19)and 4-10% 5),

any AUC

parameters, urinary conditions excretion to

values under fasting

and

The discrepancy probably elimination related,

in systemic

bioavailability

is

at least in part, to the non-linear the non of the drug can be elimination process,

intravenous systemic by the

bioavailabilities. bioavailability following excretion of formulas after oral FK027 from and was the in

of FK027. However, whether of the excretion

linear aspect attributed

to the renal

or non-renal

urinary dosings:

process, especially is not known. As pointed

the biliary

excretion

out by Wagner et al. 20),AUC values to collection method. time There of

are known to differ according of blood samples fore, the and calculation

systemic

bioavailability

values

FK027 from the urinary excretion The systemic bioavailabilty values calculated accurate than those from the AUC and urinary excretion were 26-37%

would be more

from the AUCs. excretion of other cephalos

The oral urinary

567

porins such as cefaclor, cefadroxil and cephalex in was 50-90% 21), whereas that. of FK027 was 21 28%, reasons lower than other cephalosporins. excretion The -

for this low urinary

of FK027 to

are unknown, elucidate However, antibacterial concentrations available

and further studies reasons. has a broad

are needed

the rational FK027 activity

spectrum

of.

and its minimal

inhibition of currently

are lower than those

cephalosporins. FK027 is gradually with a longer absorbed half-life and than

Moreover, slowly

eliminated

other oral antibiotics, and urinary ly prolonged. Therefore, cient clinical excretion

and its serum concentration profiles are commensurate

FK027 is expected effects

to provide

suffi

in spite of its low urinary

excretion.
References

1) Nakashima, M., Uematsu, T., Takiguchi, Y. et al:Phase I study of cefixime, a new oral cephalosporin. J. Clin. Pharmacol., (in press) 2) LeBel, M., , Paone, R. P. and Lewis, G. P.: Effect of probenecid on the pharmacokinetics of ceftizoxime. J. Antimicrob. Chemother., 12: 147-155 (1983). 3) Sennello, L. T., Ouinn, D., Rollins, D. E. et al. Effect of probenecid of pharmacokinetics of cefmenoxime. Antimicrob. Agents Chemother., 23:803-807 (1983). 4) Ueda, Y., Matsumoto, F., Saito, A. et al.:A clinical study on cefatrizine. Chemotherapy., 24:1743-1749(1976). (in Japanese) 5) Saito, A.:Absorption, distribution, metabol ism and excretion of FK027. The 31st Annual Meeting of Eastern Branch, Japan Society of Chemotherapy New Drug Symposium, Yokoha ma (1984).(in Japanese) 6) Tokuma, Y., Shiozaki, Y. and Noguchi, H.: Determination of a new orally active cephalos porin in human serum and urine high-perform ance liquid chromatography using automated column switching. J. Chromatogr., 311:339 346 (1984). 7) Metzler, C. M., Elfring, G. L. and McEwen, A.

J.:A package of computer programs for phar macokinetic modeling. Biometrics, 30:562 564 (1974). 8) O'Callaghan, C. H., Tootill, J. P. R. and Robin son, W. D.:A new approach to the study of serum concetrations of orally administered cephalelexin. J. Pharm. Pharmacol., 23:50-57 (1971). 9) Welling, P. G., Dean, S., Selen, A. et al.: Probenecid:an unexplained effect on cepha losporin pharmacology. Br. J. Clin. Pharma col., 8:491-495 (1979). 10) Griffith, R. S., Black, H. R., Brier, G. L. et al.: Effect of probenecid on the blood levels and urinary excretion of cefamandole. Antimicrob. Agents Chemother., 11:809-812 (1977). 11) Cunningham, R. F., Israili, Z. H. and Dayton, P. G.:Clinical pharmacokinetics of probene cid. Clin. Pharmacokinet., 6:135-151 (1981). 12) Gibaldi, M. and Schwartz, M. A.:Apparent effect of probenecid on the distribution of penicillins in man. Clin. Pharmacol. Ther., 9: 345-349 (1968). 13) Gibaldi, M., Davison, D., Plaut, M. E. et al.: Modification of penicillin distribution and elimination by probenecid. Int. J. Clin. Phar macol., 3:182-189 (1970). 14) Gugler, R., Manion, C. V. and Azarnoff, D. L.: Phenytoin-pharmacokinetics and bioavaila bility-. Clin. Pharmacol. Ther., 19:135-142 (1976). 15) Nagwekar, J. B. and Unnikrishnan, A.: Michaelis-Menten kinetics of renal tubular secretion of D-(-) -p-methyl mandelic acid and D-(-)-p-ethyl mandelic acid in rats. J. Pharm. Sci., 60:375-380 (1971). 16) Chremos, A. N., Shen, D., Gibaldi, M. et al.: Time-dependent change in renal clearance of bethanidine in humans. J. Pharm. Sci., 65: 140-143 (1976). 17) Lanman, C., Muranishi, S. and Schanker, L. S. :Active transport of tetracycline into bile. Pharmacologist., 12:293 (1970). (Abstract) 18) Axelson, J. E. and Gibaldi, M.:Absorption and excretion of riboflavin in the rat-an unusual example of nonlinear pharmacokine tics-.J. Pharm. Sci., 61:404-407 (1972). 19) Sakamoto, H., Hirose, T., Nakamoto, S. et al.: Pharmacokinetics of FK027 in rats and dogs. J. Antibiotics, (in press) 20) Wagner, J. G. and Ayres, J. W..:Bioavailabil ity assessment-methods to estimate total area

568

(AUCo-)

and total

amount

excreted

(Ae)

and importance of blood and urine sampling scheme with application of digoxin. J. Pharma cokin. Biopharm., 5:533-557 (1977).

21 ) Lode, H., Stahlmann, R. and Koeppe, P.: Comparative pharmacokinetics of cephalexin, cefaclor, cefadroxil and CGP 9000. Antimicrob. Agents Chemother., 16:1-6 (1979).