Pharmacokinetic Study of Cefmenoxime (SCE 1365-CMX) in Healthy Adults

Pharmacokinetic Study of Cefmenoxime (SCE 1365-CMX) in Healthy Adults

PROF. JEAN-BERNARD FOURTILLAN Poitiers, France

ANDRE BRYSKIER, M.D. Argenteuil, France

ALAIN MIGNOT, M.D. Poitiers, France

F. BORSA, M.D. PROF. GUY HUMBi:RT Rouen, France

=

From the Cerom Center, Poitiers, France, the Laboratoire de Bacteriologie, Centre Hospitalier d'Argenteuil, France, and the Hospital de Rouen, Medecine Interne, Rouen, France. Requests for reprints should be addressed to Prof. J-B Fourtillan, 4 Rue des Gaillards, 86000 Poitiers, France.

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December 21, 1984

Cefmenoxime pharmacokinetics were investigated in six healthy volunteers after intravenous and intramuscular administration of 0.5, 1, and 2 g. Blood and urine samples were analyzed by reverse~­ phase high-pressure liquid chromatography using ultraviolet detection at 275 nm. The assay is precise and linear up to 200 p,g/ml- 1 , with 0.02 p,g/ml- 1 as the limit of detection. Linearity of cefmenoxime kinetics was demonstrated because the area under the plasmCi concentrations is proportional to studied doses. Eight hours after 1 g of cefmenoxime intramuscularly, rr-ean plasma co,centrations are, respectively, 0.6 ± 0.1 and 0.3 ± 0.1 p,g/ml- 1 .1ntramuscular cefmenoxime is rapidly absorbe~ (Ka = 7.28 hours- 1) with complete bioavailability (F 0.99); apparent volume of distribution is 0.35 liters/kg- 1 and elimination half-life 1.5 hours. The fraction of cefmenoxime excreted unchanged in the urine after intramuscular administration is 0.72, indicating a major contribution of renal clearance in total clearance. Experimental data after intramuscular administration were well fitted with a two-compartment model. The pharmacokinetic study of cefmenoxime (C 1820-SCE 1365) (Figure 1), a new cephalosporin of the third generation, active against most gram-positive and gram-negative bacteria, was carried out in six healthy male volunteers with a mean age of 26.5 ± 1.5 years and a mean weight of 71 ± 2 kg. During this five-phase study, each subject was given, at eight-day intervals, the following: a single dose of 0.5 g of cefmenoxime by intravenous bolus (time of infusion three minutes) and then by an intramuscular route; a single dose of 1 g of cefmenoxime by an intravenous route (intravenous bolus, time of infusion equal to three minl!tes) and by an intramuscular route; and an intravenous injection (intravenous bolus, time of infusion equal to three minutes) of a 2-g dose of cefmenoxime. After each administration of cefmenoxime, 16 blood samples were withdrawn into heparinized tubes between time 0 and 12 hours (0, 0.5, 0.083, 0.166, 0.25, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, and 12), and six urinary samples were collected, at different intervals, between time 0 and 24 hours (0-2, 2-4, 4-6, 6-8, 8-12, and 12-24). The samples were stored at -8ooc until assay. To improve the procedure and the sensitivity of methods recently reported (J Chromatogr 1982, 229: 149; and 1983, 273: 458-463), a new procedure for determination of cefmenoxime was developed. MATERIALS AND METHODS

Cefmenoxime was extracted from plasma by a mixture of chloroform/pentanol-2 (60/20, volume/volume) in hydrochloric acid buffered at pH 3 (Titrisol buffer). The organic phase was extracted with an aqueous solution buffered

The American Journal of Medicine

Volume 77 (suppl 6A)

SYMPOSIUM ON CEFMENOXIME-FOURTILLAN ET AL

at pH 7 (acetoacetic buffer 0.2 M). Cefmenoxime is recovered in the aqueous phase, an aliquot of which, varying from 20 to 40 p.l, is injected into the chromatograph. Urinary samples are simply diluted in doubly distilled water (dilution varying from 1/10 to 1/1 ,000) before injection into the chromatograph. The chromatograph mode selected for measurement was a reversed-phase system operating with a '!.tBondapak C18 column (10 p.m, Waters Assoc., France). The mobile phase was composed of methanol, 140 ml; acetic acid, 20 ml; and acetoacetic buffer, 0.2M, 840 mi. The flow of the mobile phase was set at 1 ml/min- 1 . Cefmenoxime was detected by Ultraviolet absorption spectrophotometry at a wavelength set at 275 nm. The liquid chromatograph used was a HewlettPackard model 1084 B.

0

1~c-~-NH~~s 11 .L~r

H N/---N 2

~

0

OCH3

~

N ,.--::

CH 2

COOH

I~ s-fN--.. w-N I

CH 3

·1/2 HCl

Figure 1. Chemical structure of cefmenoxime (A-50912, SCE-1365).

RESULTS

Repeatability assays performed in four series of 10 blood specimens titrating 100, 25, 10 and 1 p.g of cefmenoxime per milliliter of plasma gave variation coefficients equal to 0.9, 1.7, 1.0, and 4.5 percent, respectively. The limit of detection was estimated at 0.02 p.g of cefmenoxime per milliliter of plasma or urine. Therefore, we may state that the assay technique is precise, sensitive, and reproducible (Figure 2). The mean plasma level evolution observed after each administration of cefmenoxime is shown in Table I and Figures 3 and 4. The mean values of cefmenoxime plasma concentrations observed eight hours after 1-g dosing by the intramuscular or intravenous route are respectively equal to 0.6 ± 0.1 and 0.3 ± 0.1 p.g/ml- 1 . The kinetics of cefmenoxime cumulated excretions in the urine samples are presented in Table II. After intravenous and intramuscular administration of 0.5- and 1-g doses, comparison of areas under the plasma concentration$ (AI,)C)/time curve along with the amount of cefmenoxime excreted in the urine after 24 hours allowed determination of the bioavail-

ability coefficients F of cefmenoxime for intramuscular administration. lhe following equations were used: F = AUCo--.oo IM/AUCo--.oo IV and F = Ua--.241hours (IM)/ Uo--.24/hours (IV). The mean values of the parameters characteristic of cefmenoxime bioavailability in the intramuscular route (peak: CMAX and T MAX. Ka absorption rate constant: 0.693/T1/2 Ka, bioavailability factor F) are indicated in Table Ill, COMMENTS

When these values are considered, cefmenoxime bioavailability in the intramuscular route appears to be complete. The mean values of the pharmacokinetic parameters related to distribution (apparent volume of distribution [AVO] = F X Dose x T 112/0.693 x AUCo--.oo) and Clrenal = (Cibody = F · Dose/AUCo--.oo, elimination Uo--.24ihours1AUCo--.24ihours = Uo--.24/hoursiAUCo--.oo, apparent elimination half-life T%), are gathered in Table IV.

CALIBRATIOliT : 6.28-200 l'g.m.I -1 h

= 1.83

c + 0.18

Peak htigh1: 36?.001'-----------~

193.00

aoo pg.ml -1

I

aao.ao 100 lt-6.80 73.4.0

HPLC CEI'ME!TOXJME ASSAY

C::oncen1:ra~io

/4.0ll-l

••:.. ••---;:;;,.--;-::110;;------;-;16;;--0-:o: o.oo ~~-----J;; BEl'EATABILIT-,r TEST

o:n 1 o plasma !lllJ!lp1es : • 100 l'jl·ml-1 : c.v. = • 28 l'g.ml-1: C.V. = • 10 l'g.Jnl-1 : C.V. = 1 l'g.ml -1 : c.v. = •

so

11.8

Figure 2. Cefmenoxime assay using high pressure liquid chromatography; standard curve and precision of the assay.

0.$1 p. 100 1.74 p.100 1.01]1. 10!) 4.81 p. 100

SEliTSITIVITY THBEIJHOLD : 0.08 ~.ml -1

r~,f~ "'"---''-''"----'~ U"-r,'I"---6.A.·c.B'"r----_._o injection v=lOpl

ao pi ao pi

December 21, 1984

ao p1 ao p1 ao pi ao p1 s = o.os AUFS

The Americ!ln Journal of Medicine

Volume 77 (suppl 6A)

29

SYMPOSIUM ON CEFMENOXIME-FOURTILLAN ET AL

Mean Cefmenoxime Plasma Concentrations/Time Runs after Several Single Dosings of Cefmenoxime in Six Human Healthy Volunteers

TABLE I

Mean Plasma Concentrations ( ± SEM) (JLU • ml- 1 ) At5 Minutes At 10 Minutes At15 Minutes AI 30 Minutes At1 Hour At 2 Hours AI 4 Hours AI 6 Hours At 8 Hours Al12 Hours

Dose

0.5-g IV 1.0-g IM 1.0-g IV 2.0-g IV

15.4 (1.7) 10.9 (0.8) 32.2 (1.6) 25.0 (0.9) 50.9 (4.8)

18.0 (1.8) 19.9 (1.1) 39.2 (2.1) 44.0 (1.8) 89.9 (8.2)

17.0 (1.8) 31.5 (1.7) 35.3 (3.5) 68.7 (2.1) 130.2 (10.5)

16.8 (2.2) 38.7 (2.2) 27.7 (4.8) 84.2 (5.2) 150.2 (9.3)

10.6 (1.7) 54.1 (1.7) 20.4 (3.9) 117.4 (4.2) 181.5 (8.9)

0.5-g IM

0.6 (0.1) 0.3 (0.1) 1.7 (0.2) 0.8 (0.1) 1.7 (0.4)

2.1 (0.3) 1.0 (0.1) 5.0 (0.4) 2.4 (0.2) 6.3 (1.1)

7.8 (0.6) 4.1 (0.4) 17.5 (0.3) 10.2 (0.7) 22.5 (3.2)

0.10 (0.03) 0.6 (0.1) 0.3 (0.1) 0.7 (0.2)

0.2 (0.1)

SEM = standard error of the mean; IM = intramuscular; IV= intravenous. Pluma concentrations (pg.ml -1)

Pluma concentrations (pg.ml -1)

100

1000 100

10 10

Time

.10

[.l__ _

0

Time

L..__-1.---'----~----:'::+ (H) 10 8 6 4

.10 '7--~:----~--..__--:':::-----+ (H)

II

3

Urinary Excretion of Cefmenoxime in Human Normal Subjects after Several Single Dosings of Cefmenoxime in Six Human Healthy Volunteers: Total Urinary Amount Excreted UG-+1 (mg)Mean Values Excreted Amount Uo--.1 Cumulated in the Urine at Time I (mg) (Mean Values)

Cefmenoxime Dose 0.5-g 0.5-g 1.0-g 1.0-g 2.0-g

IM IV IM IV IV

111

9

Figure 4. Mean cefmenoxime plasma concentrations. Time runs in normal adults 1-g intramuscular or intravenous and 2-g intravenous single dosings (mean values in six subjects).

Figure 3. Mean cefmenoxime plasma concentrations. Time runs in normal adults after 0. 5-g intramuscular or intravenous single dosings (mean values in six subjects).

TABLE II

6

2 Hours

4 Hours

6 Hours

8 Hours

12 Hours

213 231 428 605 1,033

285 296 585 682 1,244

311 306 623 706 1,296

324 311 643 712 1,317

327 312 653 717 1,324

24 Hours ( ± SEM) 327 313 655 720 1,326

Percent of Dose Excreted after 24 Hours 65.4 62.6 65.5 72.0 66.3

(±11) (± 9) (±22) (±30) (±94)

(±2.3) (±1.8) (±2.2) (±3.0) (±4.7)

Abbreviation as in Table I.

TABLE Ill

Bioavailability of Cefmenoxime When Given Intramuscularly Peak F = AUC (IM)/AUC (IV}

TMAX (hours)

Dose 0.5-g IM 1.0-g IM

19.3 (1.8) 40.1 (2.1)

0.30 (0.05) 0.50 (0.05)

7.28 (1.56) 6.68 (1.75)

0.98 (0.05) 0.99 (0.02)

AUC = area under the plasma concentration curve; other abbreviations as in Table I.

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December 21, 1984

The American Journal of Medicine

Volume 77 (suppl 6A)

F = Uo--.24

hours

(IM)/Uo--.24

1.00 (0.08) 0.92 (0.05)

hours

(IV)

SYMPOSIUM ON CEFMENOXIME-FOURTILLAN ET AL

TABLE IV

Dose

0.5-g IM 0.5-g IV 1.0-g IM 1.0-g IV 2.0-g IV AUC

Mean Values ( ± SEM) of Pharmacokinetic Data Estimated after Five Single Administrations (at Different Doses) of Cefmenoxime in Six Healthy Adults

T112

AUCo,...oo (I-'D· ml- 1 ·hour)

AVD (liters)

Clbody (liters/hour-1)

Clnnal (litersthour- 1)

Fe = Clrenai/Cibotly

1.11 (0.06) 1.21 (0.10) 1.41 (0.15) 1.34 (0.12) 1.58 (0.17)

39.8 (3.6) 40.3 (2.0) 88.7 (3.3) 90.2 (3.8) 179.1 (16.9)

20.3 (0.7) 21.7 (1.7) 23.6 (2.4) 21.9 (2.8) 25.8 (2.2)

12.6 (0.7) 12.6 (0.7) 11.2 (0.5) 11.2 (0.5) 11.9 (1.5)

8.5 (0.8) 7.9 (0.6) 7.4 (0.4) 8.0 (0.5) 7.6 (0.5)

0.67 (0.03) 0.63 (0.02) 0.66 (0.02) 0.72 (0.03) 0.66 (0.05)

= area under the

plasma concentration curve; AVO

= apparent volume of distribution; CL = clearance;

For each route of administration, the values of the area under the plasma concentrations/time curve are in direct proportion to the administered doses. Student's t test showed no significant differences between the relations of area under the plasma concentrations/dose at different doses. Therefore, we may state that cefmenoxime pharmacokinetics are linear, at least in the range of doses used in this study. Furthermore, the relative values of renal and total clearance as well as urinary excretion point to a predominance of renal excretion of unchanged cefmenoxime compared with total clearance. Parameter values such. as the elimination half-life and the apparent volume of distribution, obtained for 2-g dosing, constitute the best estimations, because plasma levels were measurable for 12 hours. Cefmenoxime kinetics being of a first order, parameter values such as the elimination half-life and the apparent volume of distribution are constants and dose-independent. For this reason the 2-g intravenous bolus values are considered most representative of the pharmacokinetic profile of cefmenoxime (after an intravenous bolus) and of other injectable cephalosporins as demonstrated in our laboratory. For modelization (Figure 5), good data fitting was performed using a two-compartment open body model for 1-g intramuscular dosing and a three-compartment open body model for 1- and 2-g intravenous bolus dosing. The equations associated with the selected models are: 1 g intramuscular: Cp = -58.26e- 5 ·7141 + 11.78e-0 ·7961 + 45.08e- 0 ·5501 ; 1 g intravenous: Cp = 108.74e- 11 ·2771 + 63.1ae- 1·4451 + 19.42e-0 ·5281 ; and 2 g intravenous: Cp = 99.67e-s.o41 + 104.45e- 1·1241 + 31.87e- 0 ·4261 •

December 21, 1984

TABLE V

Cefotaxime Ceftazidime Cefmenoxime Cefoperazone Moxalactam

Fe

= fractional

excretion.

Pharmacokinetic Handling of Cefmenoxime in Normal Subjects Compared with Other Third-Generation Cephalosporins T112

(h)

AVD (literslkg-1)

0.75 2.01 1.5 2.53 2.74

0.24 0.29 0.35 0.24 0.26

Fe

= Clnnai/Cibody 0.45 0.77 0.72 0.21 0.56

Abbreviations as in Table IV.

Pluma concentrations CP&.ml -1) 1000 '-----r.;===~~=:::'ii~~~':-=cr..-.. • ~· = 99.6fi=OIT'+ 104.48 • - 1.11' +

:il.i?o..:-o:ii1J

100

C pluma = lo~~8,18 •- Uat + 19.4:1 •- o,n'

a pluma~~-··"' + 11,78 0 - '·"'+ 48.08 0 - .....

10

Figure 5. Modelizations of mean plasma cetmenoxime concentrations versus time runs after 1-g intramuscular, 1-g intravenous bolus, and 2-g intravenous bolus single dosings in six healthy subjects.

The American Joumal of Medicine

Volume 77 (suppl &A)

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