Europ. J.cl±n.Pharmacol. 9, 125-129 (1975) © by Springer-Verlag 1975

Serum Concentrations of Ampicillin and Probenecid and Ampicillin Excretion after Repeated Oral Administration of a Pivampicillin-Probenecid Salt (MK-356) H. G. Kampffmeyer, I. Hartmann, H. Metz, G. O. Breault, H. R. Skeggs, A. E. Till and L. Weidner P h a r m a k o l o g i s c h e s I n s t i t u t and Max von P e t t e n k o f e r - I n s t i t u t , U n i v e r s i t y of Munich, Germany, and Merck, Sharp and Dohme R e s e a r c h L a b o r a t o r i e s , W e s t Point, Pa. 19486, U.S.A. Received: J a n u a r y June 10, 1975

9,

1975,

and in r e v i s e d

form: April

28,

1975,

accepted:

summary. Twenty male v o l u n t e e r s r e c e i v e d oral doses (21OO, 1050, and 525 mg) of a p i v a m p i c i l l i n - p r o b e n e c i d salt in a I to I m o l a r ratio (MK-356) at 12 hour intervals. A f t e r each dose peak s e r u m c o n c e n t r a t i o n s of p r o b e n e c i d were o b s e r v e d 2 hours later than peak c o n c e n t r a t i o n s of ampicillin. F o l l o w i n g the first dose of M K - 3 5 6 the a p p a r e n t e l i m i n a t i o n rate of a m p i c i l l i n was d o s e - d e p e n d e n t and did not f o l l o w first order kinetics, as it showed a longer a p p a r e n t half life after a h i g h e r dose. An equal dose of M K - 3 5 6 a d m i n i s t e r e d 12 hours later c a u s e d an i n c r e a s e in the peak serum a m p i c i l l i n level g r e a t e r than e x p e c t e d from the c o n c e n t r a t i o n of a m p i c i l l i n after the p r e c e d i n g dose. In twelve male v o l u n t e e r s who r e c e i v e d at r a n d o m 525 mg of MK-356 or 350 mg of p i v a m p i c i l l i n , each three times daily for 4 days, the areas under the a m p i c i l l i n c o n c e n t r a t i o n curve were the same after the first or last dose of either drug. When 2100 or 1050 mg of MK-356 was taken as an initial dose, 30 to 40 per cent of the a m p i c i l l i n was r e c o v e r e d from urine in the e n s u i n g 12 hours. The results indicate that w h e n at least 400 mg p r o b e n e c i d was c o a d m i n i s t e r e d twice daily with 700 mg p i v a m p i c i l l i n (MK-356), the peak serum c o n c e n t r a t i o n s of a m p i c i l l i n were i n c r e a s e d and its e l i m i n a t i o n rate slowed f o l l o w i n g s u c c e s s i v e doses. Key words: P i v a m p i c i l l i n ,

ampicillin,

probenecid,

A salt of p i v a m p i c i l l i n with p r o b e n e c i d at a 1:1 m o l a r ratio, M.W. 748 (MK-356) l has been d e s i g n e d to sustain a high blood c o n c e n t r a t i o n of a m p i c i l l i n after single oral doses of p i v a m p i c i l l i n (I, 2, 3, 4, 5, 6, 7, 8). The p r e s e n t studies were u n d e r t a k e n to i n v e s t i g a t e the e f f e c t of various oral m u l t i - d o s e regimens of the piva m p i c i l l i n - p r o b e n e c i d salt on the blood c o n c e n t r a t i o n s of a m p i c i l l i n and p r o b e n ecid, and the u r i n a r y e x c r e t i o n of ampicillin. In addition, s e r u m concentrations of a m p i c i l l i n were c o m p a r e d

i Merck, Sharp & Dohme Research Laboratories, Pennsylvania, USA.

pharmacokinetics.

after oral a d m i n i s t r a t i o n of p i v a m p i c i l lin or M K - 3 5 6 a c c o r d i n g to a t h e r a p e u tic regimen. EXPERIMENTAL

DESIGN

a) Multi-Dose Regimen with MK-356

Twenty male volunteers, 23 to 34 years of age, r a n g i n g in w e i g h t from 57 to 86.9 kg, were r a n d o m l y d i v i d e d b e t w e e n 4 groups. W i t h i n each group each subject was a l l o c a t e d at r a n d o m to one of five drug regimens (A-E). Each subject r e c e i v e d four oral doses of MK-356 at 12 hour intervals as filmcoated tablets c o n t a i n i n g 525 mg of MK-356, w h i c h r e p r e s e n t e d an a m p i c i l l i n e q u i v a l e n t of 244 mg a c c o r d i n g to bio-

126

assay and 199.6 mg of probenecid. The dose sequence of MK-356 for each drug regimen was as follows: Number

and size

(in mg) 2

of doses

Regimen

I

3

4

A

21OO

2100

1050

1050

B

21OO

1050

1050

1050

C

21OO

1050

525

525

D

1050

1050

1050

1050

E

1050

1050

525

525

The first dose was a d m i n i s t e r e d w i t h the subjects fasting. Meals lacking foods rich in fats were served not e a r l i e r than 3 hours before or 2 hours after taking the drugs. For d e t e r m i n a t i o n of a m p i c i l l i n and p r o b e n e c i d in serum, blood samples were o b t a i n e d at I, 1.5, 2, 3, 4, 6, and 12 hours after the first dose, and at I, 1.5, and 2 hours after s u b s e q u e n t doses. The amount of a m p i c i l l i n e x c r e t e d in urine after the first dose of MK-356 was m e a s u r e d by c o l l e c t i n g urine d u r i n g the periods O to I, I to 2, 2 to 3, 3 to 6, and 6 to 12 h into sterile flasks, m e a s u r i n g its volume and saving a 20 ml aliquot. S p e c i m e n s of serum were assayed for a m p i c i l l i n and probenecid, and of urine for ampicillin, at the Merck, Sharp & Dohme R e s e a r c h Laboratories, Pennsylvania, USA. b) Pivampicllin vs MK-356

For this trial 12 male volunteers, 25 to 32 years of age, r a n g i n g in w e i g h t from 59 to 82 kg, were chosen. A c c o r d ing to a r a n d o m i s e d open c r o s s o v e r design each subject r e c e i v e d both of the following regimens, w i t h a 2-week interval b e t w e e n treatments: A. P i v a m p i c i l l i n h y d r o c h l o r i d e (Pivatil), one 350 mg capsule at eight hour intervals for 10 doses B. MK-356, one 525 mg tablet at eight hour intervals for 10 doses. Thus, each dose of r e g i m e n A or B contained an almost equal amount of pivampicillin. The subjects fasted from m i d n i g h t until the m o r n i n g on the first 4 days of each treatment. The test drug was given at 7.00, 13.00, and 23.00 h w i t h 250 ml of water. The a f t e r n o o n and e v e n i n g doses were a d m i n i s t e r e d at least two hours before or after meals; foods rich in fats w e r e avoided. Blood samples for estimation of serum a m p i c i l l i n were c o l l e c t e d after the first and tenth doses at O, 0.5, I, 1.5, 2, 3, 4, 6, and 8 hours,

and i m m e d i a t e l y prior to the second to ninth doses. The amounts of a m p i c i l l i n excreted after the first and tenth doses of each drug regimen were d e t e r m i n e d for the O-I, I-2, 2-4, and 4-8 hour intervals. All specimens c o l l e c t e d d u r i n g the latter trial were stored until completion of the study. They were a n a l y z e d for a m p i c i l l i n at the Max yon P e t t e n k o f e r - I n s t i t u t fHr Hygiene und Medizinische M i k r o b i o l o g i e . ASSAY Ampicillin c o n c e n t r a t i o n s were determined by m e a s u r i n g a n t i m i c r o b i a l activity against Sarcina lutea by a c u p - p l a t e procedure. Probenecid in serum was a n a l y z e d by the gas c h r o m a t o g r a p h i c m e t h o d of Zacchei and W e i d n e r (9). C a l c u l a t i o n s for renal clearance were p e r f o r m e d using the formula

V c l , r ( t l - t 2) = U(t1-~t2! AUC(tl-t2) where U (t1_t2) is the u r i n a r y recovery of a m p i c i l l i n for the p e r i o d t I to t2, and A U C ( t ~ - t 2 ) is the area under the serum a m p l c i l l i n curve for the time period tl to t2 c a l c u l a t e d by the t r a p e z o i d method. STATISTICAL

ANALYSIS

Mean d i f f e r e n c e s were tested by the F-test, or t-test for d e p e n d e n t data, by a desk computer. The apparent individual terminal b i o l o g i c a l half lives of a m p i c i l l i n and p r o b e n e c i d in serum were c o m p u t e d by least square l o g a r i t h m i c r e g r e s s i o n from data 180 to 720 min and 240 to 720 min after drug administration, respectively. RESULTS a. Multi-Dose Regimen with MK-356

The mean serum c o n c e n t r a t i o n s of ampicillin and p r o b e n e c i d a g a i n s t time after r e p e a t e d oral doses of pivampic i l l i n - p r o b e n e c i d salt (MK-356) according to 5 d i f f e r e n t dose schedules (A-E) are shown in Fig. I. The v e r t i c a l arrows indicate doses of drug. Following the initial dose of 21OO or 1050 mg of MK-356, the serum c o n c e n t r a t i o n of a m p i c i l l i n r e a c h e d its m e a n peak conc e n t r a t i o n of a p p r o x i m a t e l y 8.5 ~g/ml or 5.7 ~g/ml, respectively, after about 2 hours. During the s u b s e q u e n t 10 hour period, a m p i c i l l i n c o n c e n t r a t i o n s fell to 0.25 or O.O5 ~g/ml, respectively.

127

Probenecid pg / ml

Ampicillin pg / ml mg X I0

Dose of MK-356

Regimen A



i/ 10

]

"-o t2

N

I

20

[----7 I0

8

22

2i n

Day Time

Regimen t0

B

,.,o/rTb

t

7

_A/_~

0

$

$

Regimen C

d"

Regimen D

8, , 4 0

,..2o [ I% "~.. 2 -

Regimen E

.I0

~ '~.

0

8 ~ •40

7 8

Io

12

)4

20

22

8 m

I

m z2

I2

Day Time 3 Day

Fig. I. Mean serum concentrations (pg/ml) of ampicillin (line) and probenecid (broken line) after repeated oral administration of a pivampicillin-probenecid salt (MK-356) in various dose regimens (A-E)

Table 1. Mean incremental urinary excretion (mg) of ampicillin (Am.) and renal clearance (ml/min; ± S.E.) of ampicillin (Am.C) after single oral doses of a pivampicillin-probenecid salt (MK-356) in man Dose

Time After Drug Administration

21OO mg Am. Am.C

O-] 27.3 ±

I-2 5.4

162.7 + 22.4

71.4 ±

2-3 8.4

168.6 ± 15.9

52.4 ±

3-6

(h) 6-i 2

7.3

106.7 ± 14.5

147.7 ± 20.2

133.4 ± 20.2

34.9 ±

4.7

109.1 ± 25.2

Total 29.1 ± 1.9% of dose

1050 mg Am. Am.C

24.4 ±

4.6

74.1 ± 10.4

201.5 ± 32.8

215.2 ± 23.9

41.0 ±

8.1

138.3 ± 23.0

50.1 ±

8.2

148.7 ± 22.9

13.4 ±

1.8

98.8 ± 13.9

40.9 ± 4.1% of dose

128

The p e a k s e r u m c o n c e n t r a t i o n of p r o b e n ecid came I to 2 hours later than that of a m p i c i l l i n and it had an a p p r o x i m a t e l y 6 times s m a l l e r v o l u m e of distribution. D e p e n d i n g on the dose of MK-356, p r o b e n e c i d c o n c e n t r a t i o n s of about 10 - 20 ~g/ml w e r e found 12 hours after dosing. In drug regimens A, D, and E, the same dose of M K - 3 5 6 was g i v e n 12 hours later and it p r o d u c e d h i g h e r m a x i m u m c o n c e n t r a t i o n s of a m p i c i l l i n than after the first dose. The h i g h e r c o n c e n t r a tion of a m p i c i l l i n was not the r e s u l t of its a c c u m u l a t i o n since the c o n c e n t r a t i o n r e m a i n i n g after the first dose was m u c h less than the i n c r e a s e in m a x i m u m c o n c e n t r a t i o n found after the s e c o n d dose. However, a c o n s i d e r a b l e s e r u m c o n c e n t r a t i o n of p r o b e n e c i d from the first dose of M K - 3 5 6 was still p r e s e n t w h e n the s e c o n d dose was given. In drug s c h e d u l e D, e q u a l doses of 1050 mg MK-356 were a d m i n i s t e r e d at 12 hour intervals, and f r o m the s e c o n d dose o n w a r d s they p r o d u c e d a l m o s t i d e n t i c a l m a x i m u m c o n c e n t r a t i o n s of ampicillin, the r e s u l t a n t m e a n t e r m i n a l p r o b e n e c i d c o n c e n t r a t i o n b e i n g 10 ~g/ml. Twelve hours after drug intake the s e r u m c o n c e n t r a t i o n of a m p i c i l l i n was 0.05 to 0.08 ~g/ml. D u r i n g r e g i m e A, a m p i c i l l i n concent r a t i o n i n c r e a s e d from 0.2 to 0.6 ~g/ml at 12 hours after d o s i n g f o l l o w i n g the first and second doses of 2100 mg MK-356, and d r o p p e d again to about O.15 > g / m l d u r i n g f u r t h e r t r e a t m e n t w i t h the lower dose. D u r i n g r e g i m e B the m a x i m u m s e r u m c o n c e n t r a t i o n of a m p i c i l l i n was about the same after an initial dose of 2100 mg M K - 3 5 6 and s u b s e q u e n t 1050 mg doses of M K - 3 5 6 t a k e n at 12 hour intervals. The p r e d o s e a m p i c i l l i n c o n c e n t r a t i o n d r o p p e d from 0.3 to O.1 ~g/ml w i t h cons e c u t i v e doses, w h e r e a s the s e r u m conc e n t r a t i o n of p r o b e n e c i d r e m a i n e d about e q u a l l y high (20 to 25 ~g/ml). C a l c u l a t i o n s of the a p p a r e n t indiv i d u a l t e r m i n a l s e r u m h a l f - l i v e s of a m p i c i l l i n r e v e a l e d that in the p r e s ence of p r o b e n e c i d the e l i m i n a t i o n of a m p i c i l l i n a p p e a r e d dose dependent, and that it did not follow first order kinetics. A f t e r 21OO mg of MK-356, a m e a n a p p a r e n t t e r m i n a l h a l f - l i f e of 85.3 ± 3.1 (min; x ± S.E.) was calculated from the data 180 to 360 m i n after drug ingestion, w h e r e a s from the 18o-720 m i n p e r i o d a h a l f - l i f e of 102.5 ± 4.4 m i n (FI,20; p

Serum concentrations of ampicillin and probenecid and ampicillin excretion after repeated oral administration of a pivampicillin-probenecid salt (MK-356).

Twenty male volunteers received oral doses (2100, 1050, and 525 mg) of a pivampicillin-probenecid salt in a 1 to 1 molar ratio (MK-356) at 12 hour int...
607KB Sizes 0 Downloads 0 Views