Clinical pharmacology and safety evaluation of timentin

,

Clinical Pharmacology and Safety Evaluation of Timentin DERRICK JACKSON, M.D., ANDREW COCKBURN, Ph.D., DENIS L. COOPER, PETER F. LANGLEY,

B.Sc., TIM C.G. TASKER, M.D., and DAVID J. WHITE, Ph.D.

T imentin, BRL 28500, is clavulanate-potentiated ticarcillin. The clinical pharmacology of ticarcillin has

been extensively studied, and the antibiotic is in widespread clinicatuse. Timentin, like ticarcillin, is intended for parenteral administration only. Clavulanate is a constitu- ent of the oral antibiotic Augmentin (clavulanate-potentiated amoxicillin), which is approved for use in a number of countries, including the United States. The absolute bioavailability of clavulanate following oral administration is approximately 70 percent [l]. Forty percent of the administered dose appears unchanged in the urine, the remain- der being metabolized.

METABOLISM OF CLAVULANATE

Extensive investigations have been undertaken to determine the metabolism of clavulanate [2]. The metabolic patterns in urine and plasma have been compared in male dogs, rats, and humans after the oral administration of 14C-clavulanate to animals and the intravenous administration of potassium clavulanate to humans. The major substance found in the urine of humans is clavulanate and, in lesser quantities, 1-amino-4-hydroxybutan-2-one. These substances are also found in the urine of dogs and rats. In addition to clavulanate and I-amino-C hydroxybutan-2-one, a yet unidentified metabolite has been detected in the urine of humans and much greater relative amounts of this unidentified substance have been found in the urine of rats and dogs. In plasma, clavulanate is found in addition to its metabolite l-amino-C hydroxybutanQ-one. Unidentified zones of radioactivity representing less than 10 percent of the radioactivity have been found in the plasma for all three species studied. They are nqt of toxicologic importance by themselves as they occur in the species used for the toxicologic investigations, as well as in humans. Although studies on the stability of clavulanate in solution have shown that some degradation occurs [3], the major metabolites of clavulanate excreted in the urine of animals and humans have not

arisen as a result of degradation of clavulanate during this isolation process since adequate controls were used. Ti- carcillin, in contrast to clavulanate, is largely excreted unchanged in the urine (92 percent) [4].

Timentin, therefore, contains two substances with good safety records in humans, and the metabolism of both components is analogous with, if not identical to, that in the species used in the toxicology investigations.

TOXICOLOGY STUDIES OF CLAVULANATE IN ANIMALS

The toxicology of oral clavulanate [5] is also relevant to the safety assessment of Timentin, and additional toxicology studies with Timentin in animals were designed to demonstrate that no synergistic, antagonistic, or unex- pected effects are produced when Timentin is administered, compared with any effects produced by the administration of the two components alone.

Toxicology studies have been conducted in mice, rats, and dogs with both Timentin and clavulanate alone using parenteral routes of administration (Tables I and II).

Ticarcillin has been in widespread clinical use for a number of years and its safety profile is well known. Toxi- cology studies conducted in animals prior to general re- lease of ticarcillin for therapeutic use demonstrated no changes of significance, apart from activation of extramedullar hematopoiesis in the spleen at a very high dose of 1,000 mg/kg for six months.

The methodology used in these experiments is extensively described in the guidelines issued by many regula- tory bodies, e.g., U.S. Food and Drug Administration.

Studies of the disposition and metabolism of clavulanate have been performed in rats, mice, and dogs using “C-clavulanate to support the toxicologic investigations and to provide a basis on which the safety of Timen- tin can be assessed in humans. These species have al- ready been shown to be suitable for the assessment of ticarcillin.

From the Beecham Pharmaceuticals Research Division, Brockham Park, Betchworth, Surrey, United King- dom. Requests for reprints should be addressed to Dr. Derrick Jackson, Chemotherapeutic Research Cen- ter, Brockham Park, Betchworth, Surrey, RH3 7AJ, United Kingdom.

Timentin and Augmentin are registered trademarks of Beecham Group p.1.c.

44 November 29,1955 The Amerlcan Journal of Mediclne Volume 79 (suppl5B)

Radiolabeled clavulanate was produced by fermenta- tion, and all the carbon atoms were labeled. In a number of studies, the concentrations of ticarcillin and clavulanate were determined by microbiologic assay and also by high- pressure liquid chromatography, both assays producing comparable results [2]. Radiolabeled clavulanate was administered by the same routes as those used in the toxicology investigations, i.e., both subcutaneously and intravenously in rats and dogs and subcutaneously in mice. The kidney was the major route of excretion, with approximately 80 percent of the radioactivity being excreted in the urine of all species within 24 hours of administration. Only a small amount (less than 5 percent) was excreted in the feces.

Approximately 10 percent of the administered radioactivity was found in the respired air, indicating some metabolism of the compound, although not to such an extent as that which occurs after oral administration (30 percent). This is supported by biliary excretion studies in rats, in which only 2 to 3 percent of the administered radioactivity was found in the bile 24 hours after administration. There- fore, it is extremely unlikely that bacterial action on material excreted into the intestine could account for the breakdown of clavulanate. This finding also excludes extensive enterohepatic circulation in this species. In dogs, a mean of 4.6 percent of the administered dose was found in the feces after administration. There is no apparent difference in the elimination pattern after either intravenous or sub- cutaneous administration in rats or dogs. The findings in mice are similar to those in rats. A separate study in rats has compared ticarcillin alone, clavulanate alone, and the two drugs together, with assays conducted by high-pressure liquid chromatography. There were no significant dif- ferences in the pharmacokinetic parameters obtained when the substances were given alone or as Timentin.

SYMPOSIUM ON BETA-LACTAMASE INHIBITION-JACKSON ET AL

TABLE I Toxicology Studies with Timentin

Acute toxicity in rats and mice Dogs, 28 days’ therapy, intravenously Rats, 35 days’ therapy, intravenously Dogs, 3 months’ therapy, intravenously Rats, 3 months’ therapy, subcutaneously Cardiovascular studies in dogs Mutagenicity

TABLE II Toxicology Studies with Parenteral Clavulanate

Acute toxicity in rats and mice, intravenously Dogs, 30 days’ therapy, intravenously Rats, 30 days’ therapy, intravenously Cardiovascular studies in dogs Mutagenicity

Approximately 60 percent qf the administered dose of ticarcillin appeared unchanged in the urine during the 24 hours after administration of ticarcj(lin itself compared with approximately 67 percent after administration of Timentin; the corresponding values for clavulanate were 56 and 52 percent. A similar study was conducted in dogs (Figure l), and again there was no significant difference in the values obtained when the substances were administered alone or together as Timentin. The apparent volume of distribution of ticarcillin, 439 ml/kg, approximates to the total body water. Clavulanate does not affect the apparent volume of distribution of ticarcillin, since the apparent volume of distribution and plasma levels of ticarcillin when administered with clavulanate are similar to those for ticarcillin alone. Similarly, ticarcillin has no effects on clavulanate pharmacokinetic parameters,

10,000 5000 1000 500 100

z 50 2 10

5 1-o

o-5

Figure 1. Urinary excretion after single intravenous injaction in dogs.

O-6 6112 12-24 Time (hr)

200mg/kg

187,5mg/kg 12.5mg/kg

November 29, 1995 The Amerlcen Journal of Medicine Volume 79 (suppl 58) 45


TABLE III Acute Toxicity of Timentin

Median Lethal Dose Species Route bw~g)

Mouse Rat Neonatal acute

(Gday-old rats)

Intravenously 2,669 Intravenously 3,061 Subcutaneously >5,000

TOXICOLOGY STUDIES OF TIMENTIN IN ANIMALS

Toxicology studies conducted in mice, rats, and dogs demonstrate good tolerance of Timentin in these species. The intravenous median lethal dose of Timentin is 2,669 mg/kg in mice and 3,061 mg/kg in rats (Table Ill). A rat neonatal acute study was carried out in four-day-old animals at dose levels of 5,000 and 2,500 mg/kg of Timentin administered subcutaneously. There were no deaths, and no target organ was identified. A dose-related decrease in weight gain was observed in females, but not in males.

In rats, repeat intravenous dose studies with clavulanate alone showed transient changes in glycogen content in the liver, which were related to treatment. These changes are considered to represent an adaptive process in rats and to result from extensive hepatic metabolism of the compound. There is no evidence to suggest that these changes represent a toxic potential for humans. No changes in the clinical chemistry suggesting hepatic impairment, even at the highest dose level used, were noted. Similar effects on glycogen in rat livers have been described with other substances, e.g., tetracycline, and after glucose loading [6]. In dogs, a species in which clavulanate is metabolized in a manner similar to that in humans, treatment with clavulanate alone for 30 days re- sulted in no such changes with identical doses. Analogous changes in rat livers and the absence of such changes in dogs were also noted in the one-month intravenous studies with Timentin, the clavulanate content of which was identical to the doses used in the toxicologic investigations of clavulanate alone.

A study in humans, in which 1.2 g of clavulanate was administered daily for five consecutive days showed no effect on hepatic function. Toxicity studies in animals showed no changes that could not be attributed to that particular amount of ticqcillin or clavulanate. There was no evidence of synergy with respect to the changes found at the high-dose lev@s employed in the animal toxicology investigations.

General toxicology studies in rats and dogs have been carried out by the intravenous route. In rat studies, the intravenous infusion rate was 0.05 ml per second, which is equivalent to 3 ml per minute with a standard dose volume of 10 ml/kg body weight. In dogs, the infusion rate was 3.0 ml per minute employing a dose volume of 3 ml/kg. Clini- cally, 3.1 g of Timentin is dissolved in 100 ml of water,

physiologic saline, sodium lactate, or Hartmann’s solution and infused over a period of 30 minutes. The antibiotic is, therefore, administered at a rate of infusion of 3.3 ml per minute and in a volume of approximately 2 ml/kg. None of these solutions at the volume recommended is likely to cause problems of osmotic stress or other deleterious ac- tions. The solutions are used routinely in clinical practice and do not give rise to clinical problems when infused at the recommended rate and volumes.

The one-month toxicity studies in rats and dogs have, therefore, approximated, or have exceeded, the clinical situation in terms of the rate of infusion and dose volume when considered on a body weight basis. In fact, the dose volume in dogs was up to twice, and in rats, five times, that of the clinical situation. Therefore, osmotic and volume stress due to the higher concentrations utilized have been investigated in existing general toxicology studies.

PHARMACOLOGY STUDIES

A number of general pharmacology studies have been performed with clavulanate and Timentin. Clavulanate does not affect gastric motility. On isolated rat and guinea pig ileum, only concentrations of clavulanate in the range of 1 to 10 mg/ml have a stimulant effect, possibly due to the potassium content. Neither Timentin nor clavulanate antagonize acetylcholine, histamine, serotonin, barium chloride, or adrenaline. Studies on the central nervous system showed clavulanate to be devoid of significant effects on the following: Irwin profile, barbiturate-induced hypnosis, anticonvulsant activity, anti-aggressive activity, analgesia, body temperature, muscle relaxation, metro- nidazole-induced convulsions, and electroshock-induced convulsions. In rabbits, a stimulatory effect was seen on the electroencephalogram with very high doses (600 mg/kg of potassium clavulanate). There are no significant efjects on the respiratory system. An additional study has investigated the effect of intravenous Timentin on the cardiovascular system of anesthetized beagle dogs. Very few effects were seen in that study, and those that did occur were attributable to the potassium content.

It is well recognized that the beta-lactam antibiotics give rise in humans and animals to antibodies in all the major immunoglobulin classes. Penicillin allergy itself is well described [7]. Clinical experience with Timentin suggests that the incidence of allergic reactions in humans will be the same as with ticarcillin alone. Contact sensitization studies in guinea pigs demonstrate that, under experi- mental conditions, potassium clavulanate has no ability to sensitize. Timentin was not found to have significant he- molytic potential in an in vitro test using rabbit erythro- cytes.

A battery of tests have been performed to evaluate the mutagenic potential of Timentin. A gene conversion test in yeast (Saccharomyces cerevisiae) has been performed, in addition to the traditional Ames test with Salmonella typhimurium and Escherichia coli. No significant increase

45 November 29,1985 The American Journal of Mudlclne Volume 79 (suppl5B)

SYMPOSIUM ON BETA-LACTAMASE INHIEITION-JACKSON ET AL

in the mutation rate was observed in the presence and absence of metabolic activation in either of these studies. The effect of Timentin on chromosomal structure was investigated in cultured human peripheral lymphocytes. Timentin did not induce any significant chromosomal damage. An in vivo micronucleus test was performed in mice, and no significant genetic activity was seen. From the results of these studies, it is concluded that Timentin is without mutagenic hazard.

REPRODUCTIVE STUDIES IN ANIMALS

Reproductive studies with ticarcillin alone, clavulanate alone, and Timentin have been conducted in rats and mice (Table IV). Rabbits were not used since it is known that high doses of antibiotics with gram-negative activity cannot be administered to this species and produce a sat- isfactory assessment of teratogenic potential.

In pregnant rats and mice, the patterns of excretion of the 14C-isotope are similar to those in nonpregnant animals. It is known that drug-related material in rats will cross the placenta to reach the fetus in concentrations on the order of those found in plasma. This transplacental passage is reversible. Similar results are obtained in mice. Clavulanate is also found in the milk of lactating animals. Thus, both mice and rats are suitable species for the study of the effect of clavulanate on the reproductive process.

Clavulanate has not been shown to have any toxic ef-

TABLE IV Reproductive Studies

Timentin Teratology in rats and mice Perinatal and postnatal studies in rats Fertility and general reproductive performance in rats

Clavulanate Teratology in rats and mice Perinatal and postnatal studies in rats Fertility and general reproductive performance in rats

Ferres and Nunn [8] have shown that the intact ticarcillin molecule must be administered to produce these effects, and the changes are not associated with the administration of the penicilloic acid of ticarcillin. In the same system, Ferres and Nunn (personal communication, 1985) have shown that the addition of clavulanate to ticarcillin, as in Timentin, does not increase this effect of ticarcillin. Thus, the effect of Timentin on the coagulation mechanism is expected to be the same as that produced by ticarcillin, i.e., confined to very high-dose therapy, particularly in patients with renal impairment. This is a different mechanism from that described for some cephalosporins, e.g., moxa- lactam, where the characteristic finding is hypoprothrom- binemia.

PHARMACOKINETIC STUDIES OF TlMENTlN

fects on the embryo or teratogenic effects in either rats or mice, and in both species it has been demonstrated that the compound reaches the fetus. Perinatal and postnatal studies in rats have shown no adverse effects on labor and parturition, nor on the subsequent viability and development of the offspring. Fertility and general reproductive studies in rats have shown no adverse effects on male or female fertility, on pregnancy, or on the general survival and development of offspring to weaning. When offspring from each perinatal, postnatal, and fertility study were al- lowed to reach maturity, reproductive function was normal, and no latent effects on the subsequent generation were observed.

In view of the extensive research program just outlined, studies with Timentin have been limited to teratology in rats, in which there was no evidence of toxicity to the embryo or teratogenic potential.

The effect of ticarcillin on pregnancy in mice and rats has been adequately investigated, and there were no teratogenic effects. Similarly, there was no effect on fertility, general reproductive performance, or perinatal and postnatal development in rats.

MINIMAL RISK OF BLEEDING

The pharmacokinetics of Timentin have been investigated in a number of experiments carried out under standard conditions, i.e., diet, age, weight of volunteers, and other pertinent variables were controlled.

Each subject was required to fast overnight before the study and, unless stated otherwise, received the requisite dose of clavulanate or Timentin in the fasting state by either bolus intravenous injection or infusion. Food and fluid intake was accurately controlled, and sampling of body fluids was accurately timed. All subjects enrolled in these studies had a full medical examination with hematologic and clinical chemistry tests. All crossover studies were performed on the same day of the week at the same time of day.

A breakfast consisting of fried egg, bacon, sausage, tomato, toast with butter and marmalade, and tea or cof- fee with milk and sugar was provided and eaten two hours after drug administration.

An ascending dose study was performed with two groups of eight volunteers. One group received sinale

Samples of blood and urine were assayed for the pres-

30-s&d bolus injections of clavuianate at doses of 0.4,

ence of clavulanate by the method described by Jackson

1.5, and 3.0 mg/kg body weight and the other group received doses of 0.8, 2.0, and 4.0 mg/kg body weight. The

et al [9] and ticarcillin by the method described by

first measurements of mean serum concentrations, obtained three minutes after the injection, were 2.2, 4.7,

Staniforth and colleagues [lo].

It is known that high doses of some beta-lactams may effect hemostasis by altering platelet function. Ticarcillin in high doses, particularly in patients with renal impairment, can produce a prolongation in the platelet time and changes in platelet function. Using an in vivo model,

November 29, 1985 The American Journal of Medicine Volume 79 (suppl 5B) 47


% Urinary excretion

hours

13.0, 18.9, 31.7, and 42.8 pg/ml for the 0.4, 0.8, 1.5, 2.0, 3.0, and 4.0 mg/kg doses, respectively.

The mean serum concentration time curves are shown in Figure 2. The serum elimination half-life was shown to be dose independent and was calculated to be approximately one hour. The urinary excretion of clavulanic acid during the six hours after administration was approximately 50 percent of the dose administered.

In a two-part crossover study, six volunteers received a four-hour infusion of 0.878 mg/kg per hour of clavulanate on one occasion and a 0.8 mg/kg bolus injection over 30 seconds followed by the four-hour infusion on another

Wml

hours I I Figure 3. Serum concentrations of clavulanic acid in humans after infusion of 0.678 mglkg per hour of clavulanic acid for four hours, with and without a prior bolus injection of 0.8 mglkg.

Figure 2. Serum concentrations in humans after 30-second infusions of 0.4 to 4.0 mglkg clavvlanic acid.

occasion. In three subjects, a plateau concentration of about 5 &ml was achieved after infusion both with and without the bolus injection. In the other three subjects, a plateau concentration of 3.5 pg/ml was reached after the infusion alone and of 3.0 &ml after the bolus injection and the infusion. The mean serum concentration time curves from both dose regimens are shown in Figure 3. A post-infusion serum half-life of approximately 45 minutes was calculated. Urinary excretion during the six hours after administration of the drug was again about 50 percent of the administered dose.

A dose study was performed with 12 volunteers in whom 200 mg clavulanate was administered by intravenous infusion over 20 minutes, six times a day for five days. Blood and urine samples were taken to determine clavulanic acid concentration with the two doses on Days 1, 3, and 5. Clinical monitoring was carried out with a full medical examination prior to this study, on the last day that clavulanic acid was administered, and on the seventh day after discontinuation of therapy. Electrocardiographic results, blood pressure values, hematologic findings and, clinical and chemistry profiles, were monitored daily through the study. Urinalysis was also performed daily.

The highest concentrations of clavulanic acid were obtained 30 minutes after the start of the infusion. The mean concentrations at this time point for the two doses studied on Day 1 were 10.0 and 9.7 M/ml; on Day 3, they were 9.7 and 9.4 pg/ml, and on Day 5 they were 10.8 and 10.8 a/ml (Flgure 4). There was no change in urinary excretion between Day 1 and Day 5 of therapy (Table V). Jack- son et al [l] have shown the half-life of distribution after

4s November 29,1985 The American Journal of Medicine Volume 79 (suppl5B)

SYMPOSIUM ON BETA-IACTAMASE INHIBITION-JACKSON ET AL

intravenous administration of clavulanate to be about 11 minutes and the elimination half-life to be 54 minutes. In this experiment, the mean steady state volume of distribution was 15 liters, which suggests that the compound re- mains in the extracellular compartments. There were no drug-related changes during clinical monitoring or in clinical chemistry or hematologic parameters during the study.

THE PHARMACOKINETICS OF INTRAVENOUS CLAVULANATE IN HUMANS

The pharmacokinetics of intravenously administered clavulanate with co-administration of ticarcillin have been investigated in a series of studies involving 54 volunteers in whom 200 mg of clavulanate had been given as a 30-minute infusion, with 2, 3,5, 6, and 10 g of ticarcillin [l 11. The mean pharmacokinetic parameters of clavulanic acid at each of these doses are given in Table VI, and it can be seen that concurrent administration of increasing amounts of ticarcillin does not affect the mean maximal serum concentrations of clavulanic acid, which were about 10 pg/ml. In all cases, the serum elimination half-life was about one hour and the urinary excretion during the first six hours accounted for about 50 percent of the administered dose of clavulanic acid.

Ten subjects participated in a study in which they received a bolus injection of either 3.1 g of Timentin or 3.2 g of Timentin and 3.0 g of ticarcillin over three minutes. Peak concentrations of ticarcillin and clavulanic acid in the serum were reached at the end of the injection. The mean

11 ” 0 0 57 E s5

53 & uJ 1

0 1 2345676

lgure 4. Serum concentrations of potassium clavulanate in humans after intravenous administration of 200 mg every four hours for five days.

maximal serum concentration for ticarcillin from the 3.1 g and 3.2 g formulations of Timentin was 408.37 +- 67.39 pg/ml, and for clavulanic acid, the mean peak serum concentration was 11.2 ~fr 2.00 pg/ml (Figures 5 and 6). For ticarcillin (3 g) alone, the mean maximal concentration was 413.70 2 99.36 pglml. Total urinary recovery during the eight hours after drug administration was 53 percent of the administered clavulanic acid and 84 percent of ticarcillin from the 3.1 g formulation (Table VII). After adminis-

TABLE V Intravenous Administration of Potassium Clavulanats to Humans

O-2 hr

Urlnaty excretion (polml)

2-4 hr 4-6 hr 6-8 hr

Total

O-8 hr

Day 1

Day 3

Day 5

Mean 366 114 401 59 SD 210 81 187 29 Percent 17.5 3.5 17 3 41 Mean 440 99 291 72 SD 207 65 140 45 Percent 20.5 4.5 17 2.5 44.5 Mean 355 113 320 110 SD 230 70 127 64 Percent 19 5 16.5 3.75 44.25

TABLE VI Mean Pharmacokinetic Parameters for Clavulanate When Administered Intravenously with Tlcarcillln as an Infusion over 30 Minutes

200 mfl Clavulanate with Ticarelllln (0)

Parameters 20 30 50 60 10 II

Mean peak serum concentration (m/ml) 12.1 14.3 9.2 8.5 8.7 Half-life (hr) 1.09 0.70 0.95 0.99 0.98 Area under the cutve (M . hr/ml) 14.1 25.1 12.5 10.1 11.6 Mean percent urinary (O-6 hr) recovery 47 58 46 53 45

November 29,1955 The American Journal of Medlclne Volume 79 (suppl5B) 49

SYMPOSIUM ON BETA-LACTAMASE INHISITION-JACKSON ET AL

m/ml

400 A 3g ticarcilim 0 319 Timentii V 32g T!mentm

200-

loo-

O- , 0 1 2 3 4 5 6 7 8

time, h

Figure 5. Mean serum concentrations of ticarcillin after bolus injection of ticarcillin or Timentin.

9 0 1 2 3 4 5 6

hours hours

igure 7. Serum concentrations of ticarcillin after a single dose of Timentin (3.2 g injection).

tration of the 3 g of ticarcillin alone, the recovery was 85 percent of the administered dose.

Pharmacokinetic analysis of the results fit a two-compartment model. Ticarcillin from the 3.1 g formulation of Timentin had a mean half-life of 66.9 minutes, and a mean half-life of 69.5 minutes for ticarcillin (3 g) alone. For clavulanic acid from Timentin, the mean half-life was 81.2 minutes. Other mean pharmacokinetic parameters are shown in Table VII.

Nine subjects took part in a study in which they received a bolus injection of 3.2 g of Timentin over two minutes. Peak concentrations of ticarcillin and clavulanic acid in the serum were achieved at the end of the injection. The mean peak serum concentration for ticarcillin was 386.6 ? 68.0 pg/ml, and the mean peak serum concentration for clavulanic acid was 20.13 + 4.3 pg/ml (Figures 7 and 8).

Total urinary recovery during the six hours after drug administration was 75.7 percent of the administered ticarcillin and 51.6 percent of the clavulanic acid (Tables VIII

25

20 A 32g Timenhn

$ l5 0 2 v 319 Timenih ClavlJbc 02g acid

10

time,h I

Figure 6. Mean serum concentrations of clavulanic acic after bolus injection of Timentin or clavulanate.

si

1

fgufe 8. Serum concentrations of clavulanic acid after a hgle dose of Timentin (3.2 g injection).

and IX). Pharmacokinetic analysis of the results fit a two- compartment model. The distribution phase had a mean half-life of 11.03 2 4.11 minutes for ticarcillin and a mean half-life of 11.95 ? 3.69 minutes for clavulanic acid. Other mean pharmacokinetic parameters are given in Tables VIII and IX.

One subject experienced localized discomfort in the arm during drug administration, but this effect was short lived. The injections were generally well tolerated, and there were no drug-related changes in the clinical chemistry and hematologic parameters studied before and after the investigation.

Four subjects took part in a study with intravenous infusion of 3.2 g of Timentin over 30 minutes. Peak serum concentrations were reached at the end of the infusion (Figure 9). The mean peak serum concentration was 262.78 ~?r 30.6 @/ml for ticarcillin and 14.33 & 2.13 pg/ml for clavulanic acid. These levels declined to 100.20 pg/ml for ticarcillin and to 3.25 pg/ml for clavulanic acid after two hours (Figure 9). Total urinary recovery during the six

50 November 29,1985 The American Journal ol Medicine Volume 79 (suppl5B)

SYMPOSIUM ON BETA-IACTAMASE INHIBITION-JACKSON ET AL

TABLE VII Pharmacokinetic Parameters for Ticarcillin and Clavulanic Acid after Bolus Injections of Ticarcillin and Timentin

Parameter Ticarcillin

(3 9)

Timenlin (3.1 g)

Ticarcillin Clavulanic acid

Mean area under the curve, 0 to 8 hr (@. hdml) 450.2 450.6 a.3 Mean urinary 0 to 8 hr (mg) recovery, 2,537 (85%) 2,516 (84%) 52.8 (53%) Mean beta-phase half-life (min) 69.5 66.9 61.2 Mean total clearance (ml/min) 114.8 116.2 224.0 Mean renal clearance (ml/min) 97.4 98.0 113.1

Mean nonrenal clearance (ml/min) 17.4 18.2 110.9

TABLE VIM Mean Pharmacokinetic Parameters for Ticarcillin after Mravenous Bolus Injection or Infusion of Timentin

Parameter Bolus Intravenous

Injectlon (3.2 g) Infusion (3.2 g)

Mean peak serum concentration (&ml) Mean urinary recovery Wml)

O-2 hrs (mg) (Percent of total)

(@ml) 2-4 hrs 0-v)

(Percent of total) Wml)

4-6 hrs (md (Percent of total)

Total

Half-life

b-d (Percent of total)

Mean 2 SD

Area under the curve (pg hr/ml) Mean * SD

386.63 k 68.0 4,237 k 3,238 1,468 ? 99

48.9 5,875 2 3,168

604” 129 20.1

1,680 r?: 76’8 200 * 92

6.7 2,271 k 141

75.7 1.1 .o 2 4.11 (00 (min)

66.63 t 10.64 (PI (min)

496.7 k 105

262.78 k 30.6 3,577 * 1,946 1,396 5 222

46.6 7,803 k 4,360

646? 102 21.5

2,392 + 759 264 * 102

8.8 2,307 -t 155

76.9 1.0 hrs

566.4

TABLE IX Mean Pharmacoklnetic Parameters for Clavulanic Acid after Intravenous Bobs Injection or Infusion of Timentin

Parameter Bolus

lnjectlon (3.2 g) Intravenous

Musion (3.2 g)

Mean peak serum concentration (@ml) Mean urinary recovery b.WW

O-2 hrs (ms) (Percent of total)

WmU 2-4 hrs (m9)

(Percent of total) Wml)

4-6 hrs (w) (Percent of total)

Total (wi (Percent of total)

Half-life

Mean + SD

Area under the curve (w . hr/ml) Mean + SD

20.13 k 4.33 254 + 196

85 + 6 42.3

135 + 62 14 + 4

7.25 34 + 20

4*3 2.0

103 2 7 51.6

11.95 t- 3.69 (4 (min)

60.04 ? 3.69 W (min)

17.3 + 2.88

14.33 + 2.13 225? 116

90 2 25 44.9

244 * 129 20 I? 2

9.9 60 2 34

6~3 3.2

116 + 28.9 58

0.7 hrs

25.1

November 29,1999 The American Journal ol Medlclne Volume 79 (suppl56) 51


ticarcillin

So1 260 - 220 -

clavulanic

z 180- acid

lFkL?!J

18

%40- 0 ticarcillm

0 c!avu!anii .md 14 z

100 - 10 --, 60- 6=

20- 2 05 1 2 4 6

hours

Lure 9. Serum concentrations of ticarcillin and clavulanic acid after a 30-minute infusion of Timentin (3.2 g).

250 -25 0 clawlank acid 5200 -202 -E

.g 150 s

-15 i

ii 100 .g -10 f

50 -5 5

0 012 4 612 4 6

-0

hours igure 10. Serum concentrations of ticarcillin and clavu- fnic acid after two do-minute infusions of Timentin (lj.2 g).

hours after administration of the dose was 76.9 percent of the administered ticarcillin and 58 percent of the administered clavulanic acid (Tables VIII and IX).

Results from this study fit a one-compartment model, with mean half-lives of 60 minutes for ticarcillin and 56 minutes for clavulanic acid. The infusion was well tolerated, and there were no drug-related changes during qlini- cal monitoring or in hematologic or clinical chemistry parameters during this study.

In another study, 1.2 g of Timentin was given as a bolus intravenous injection, followed by an infusion of 3.2 g over three hours. That study used a crossover design in six subjects with and without administration of 1 g of probenecid orally twelve and one hour before dosing with Timen- tin. Immediately after the bolus injection without probenecid, the mean serum level of ticarcillin was 145.24 +- 31.14 pg/ml, which fell and then rose to a mean of 139.5 + 29.17 pg/ml at the end of the infusion. With probenecid, the corresponding figures were 136.24 pg/ml after the bolus injection and 173.9 pg/ml after the infusion. The mean serum level of clavulanic acid without probenecid at the end of the bolus injection was 27.98 2 8.64 pg/ml and 6.93 + 2.35 pg/ml after the infusion. Corre- sponding figures with probenecid were 20.8 pg/ml after the bolus injection and 6.15 kg/ml after the infusion (Fig ures 11 and 12). Areas under the serum concentration time curves were calculated and showed a significant difference (p ~0.02) for ticarcillin, but no difference for clavulanic acid.

Other pharmacokinetic studies have been performed The infusions were well tolerated with no adverse reac- with the 3.2 g formulation of Timentin. In the first study, tions or drug-related changes during clinical monitoring or

3.2 g of Timentin was given as an infusion over 60 minutes on two occasions separated by six hours. Subjects had serum samples obtained after each dose so that assays for ticarcillin and clavulanic acid could be performed. Paired t tests show no significant difference between the areas under the curves obtained for ticarcillin and clavulanic acid after the first and second doses. (Ticarcillin was 584.8 and 563.5 pg . hr/ml and clavulanic acid was 16.1 and 17.7 pg . hr/ml after the first and second doses, respectively; Figure 10, Table X).

Mean serum levels of ticarcillin after the first dose were 9.29 pg/ml and at six hours after the second dose, were 9.54 pg/ml. The corresponding figures for clavulanic acid were 0.22 and 0.22 pg/ml for the first and second doses. The continued low level of ticarcillin at six hours before the next dose is reflected in the 117 percent total urinary recovery after the second dose (Table X).

The infusions were well tolerated, and there were no drug-related changes in hematologic or clinical chemistry parameters, in blood pressure values or in electro- encephalographic findings.

TABLE X Pharmacokinetlc Parameter Means for Two Intravenous Infusions of Timentin

Assay

Mean Peek Serum Concentration

(pQ/nll) f SD

0 to 6 Hour Urlnafy Recovery

Area Under the Curve Percent Total (pfi . hml)

mfi Dose *SD

1st infusion Ticarcillin 281.9 2 44.3 2,673 2 203 89.1 584.77 k 109.1 Clavulanic acid 9.27 2 0.9 115 + 21 56 16.05 k 3.38

2nd infusion Ticarcillin 264.4 2 28.5 3,523 2 868 117.4 563.46 f 98.5 Clavulanic acid 9.76 2 2.3 134 2 39 67 17.67 + 5.03

52 Novembr 29,1955 The American Journal of Medicine Volume 79 (suppl5B)


in clinical chemistry or hematologic parameters during the study.

Probehecid administration produced the expected effect on serum concentrations of ticarcillin, an antibiotic mainly excreted via the renal tubules and had no effect on clavulanate, which is excreted via the glomerulus (Table XI).

In a two-compartment model, probenecid produces a change in the central compartment from 5.7 to 4.5 and an increase in the peripheral compartment from 2.4 to 4.4, with corresponding changes in the rate constant for transfer from the central to the peripheral compartment and in the rate constant for transfer from the peripheral to the central compartment, indicating an action of probenecid in addition to its effect on the renal tubules, either as a con- sequence of the high sustained levels or as a result of an effect on some inter-compartment mechanism. Whatever the mechanism, the result would appear to be a beneficial increase in ticarcillin concentrations in the tissue, although this is only a hypothesis developed from the data presented herein.

TISSUE PENETRATION STUDIES

Detailed tissue distribution studies after oral administration of clavulanate have been performed in rats using whole body autoradiography and excision of tissues [9]. The peak levels of radioactivity occurred between one and two hours in most tissues. After 24 hours, the level of radioactivity had dropped below 5 pg equivalents of clavulanate per g of tissue. The highest concentrations were found in the liver and kidneys. Ten days after a single oral dose of 5 mg/kg “C-clavulanate, there were very low levels of radioactivity in all tissues, with adipose tissue containing the higher levels. The small amount of radioactivity remaining in tissues and carcasses is most likely due to the incorporation of one-, two-, or three-carbon frag- ments derived from the breakdown of clavulanate into endogenous molecules in rats. It is concluded from these studies that neither radiolabeled clavulanate nor its metabolites would accumulate in the tissues of rats.

As stated previously, ticarcillin does not have any effect on the distribution of clavulanate, or vice versa. Distribu-

0 wilhPmbeneca A wnout probenecld

Figure 11. Ticarcillin serum concentrations after 3.2 g of Timentin with and without probenecid.

w/ml

30

25

20

15

10

5

0

q With probenecld A Without prdmh?cid

hours

Figure 12. Clavulanic acid serum concentrations after 3.2 g of Timentin with and without probenecid.

tion studies have been carried out in which ticarcillin and clavulanate levels were determined by microbiologic assay. Both ticarcillin and clavulanate penetrated into tissue cage fluid and inflammatory exudate in amounts demonstrated to be adequate for antibacterial activity against beta-lactamase-producing organisms [12].

TABLE XI Urinary Excretion after 3.2 g of Timentin with and without Probenecid

Hours after Dosing

Ticarcillin Wtih probenecid Without probenecid

Clavulanate With probenecid Without probenecid

o-2 2-4 4-6 6-6 O-6

t4Vml Percent Mm1 Percent Mm1 Percent b4Vml Percent Percent

1,873 22 5,603 30 2,130 11 1,678 7 70 4,044 28 9,514 32 2,734 12 1,044 4 76

275 32 328 18 59 3 25 1 54 483 32 576 19 93 4 29 1 56

November 29, 1985 The American Journal of Medicine Volume 79 (suppl6B) 63


A study has been conducted in humans to determine the penetration of ticarcillin and clavulanate into the peripheral lymph node after an intravenous slow bolus injection of 3.2 g of Timentin. The elimination-phase half-lives for both ticarcillin and clavulanate in serum and lymph were similar (approximately one hour)., The mean area under the curve for clavulanate in lymph was 79 percent of the area under the curve in serum, and the area under the curve for ticarcillin was a mean of 58 percent of that in serum. The concentrations in lymph became greater than those in serum between 1 and 1.5 and 2 and 2.5 hours after dosing for clavulanate and ticarcillin, respectively v31.

Both ticarcillin and clavulanic acid have been shown to penetrate blister fluid rapidly; significant amounts have been found in blisters within 30 minutes after intravenous administration, with the highest concentration of clavulanate at 30 minutes and the highest concentration of ticarcillin at one hour [14].

These studies are of considerable importance since Timentin would not be so effective if clavulanate was dis- tributed to the tissues more slowly than ticarcillin. Clavu- lanate needs to arrive at the same time or before the antibiotic so as to neutralize the beta-lactamases and prevent the degradation of ticarcillin.

PHARMACOKINETICS OF TICARCILLIN AND CLAVULANATE IN PATIENTS WITH RENAL IMPAIRMENT

Two studies have investigated the influence of renal impairment upon the pharmacokinetics of ticarcillin and clavulanate. In the studies, a 1.2 g formulation and a 3.2 g formulation of Timentin were employed. The formulations were administered as single intravenous bolus injections.

The 3.2 g formulation of Timentin was given to 21 patients who were divided into three groups with different degrees of renal impairment (group ranges for patients with creatinine clearance normalized for body surface area were 67 to 83 ml/minute/l .73 m2, 11 to 37 ml/minute/ 1.73 m*, and 4.3 to 7.3 ml/minute/l.73 m*). Beta-phase half-life and the area under the curve increased with di- minished renal function because of a reduction in renal clearance for both ticarcillin and clavulanate. No major change in the distribution of ticarcillin or clavulanate was observed. The magnitude of the changes in the beta- phase half-life and the area under the curve was less for

clavulanate than for ticarcillin. Group mean beta-phase half-lives for ticarcillin were 1.9, 4.9, and 8.5 hours, respectively.

The group mean total serum clearance for ticarcillin was reduced to approximately 20 ml per minute in the group with the most severe renal impairment, whereas the corresponding figure for clavulanate was 108 ml per minute. Mean total serumclearance for subjects with normal renal function receiving the same formulation was 105 ml per minute for ticarcillin and 197 ml per minute for clavulanate. The difference in the influence of renal impairment results from the more extensive metabolism of clavulanate compared with ticarcillin.

In the second study, the 1.2 g formulation of Timentin was given to 24 patients with varying degrees of renal impairment. In the most severely affected group, creatinine clearance, not normalized for surface area, ranged from 10 to 20 ml per minute. In this group, mean beta- phase half-lives for ticarcillin and clavulanate in plasma were, respectively, 8.6 and 2.8 hours. The administration of the formulations in patients with renal impairment was well tolerated without adverse effects.

These data on ticarcillin from formulations of Timentin in patients with renal impairment are significantly different from published data on ticarcillin alone [15]. Those previously published data, however, contain insufficient infor- mation on individual patients and pharmacokinetic meth- ods to allow meaningful comparison.

Dosing regimens for ticarcillin in patients with renal impairment have been established to be clinically effective and free from any toxicity resulting from accumulation. In- travenous administration of clavulanate together with the administration of ticarcillin in any patient, with or without renal impairment, ensures that the beta-lactamase inhibi- tor is present in the body at the time of the highest concentration of ticarcillin. Despite the more rapid elimination of clavulanate compared with ticarcillin in patients with severe renal impairment, serum levels of clavulanate are in excess of those seen in subjects with normal renal function. Mean serum or plasma clavulanate concentrations after 200 mg of clavulanate from 3.2 or 1.2 g formulations of Timentin at six hours after administration were 2.2 or 1.7 pg/ml in patients with severe renal impairment compared with 0.2 pg/ml in subjects with normal renal function. Thus, effective concentrations of clavulanate are maintained longer in patients with renal impairment.

REFERENCES

1. Jackson D, Cooper DL, Filer CW, Langley PF: Progress and 3. Foreman M: in: Croydon EAP, Michel MF, (eds). Augmentin: perspectives on beta-lactamase inhibition: a review of Aug- proceedings of the European symposium. Amsterdam: Ex- mentin. Postgrad Med 1964; 51-70. cerpta Medica, 1962; 122.

2. Bolton G; Allen GD, Filer CW, Jeffery DJ: Absorption, metabo- 4. Davies BE, Humphrey MJ, Langley PF, Lees L, Legg 6, Wadds lism, and excretion studies on clavulanic acid in the rat and GA: Pharmacokinetics of ticarcillin in man. Eur J Clin Pharma- dog. Xenobiotica 1964; 14:6: 463-490. col 1982; 23: 167-172.

54 November 29,1985 Tha American Journal of Madlcine Volume 79 (suppl58)


5. Jackson D, et al: Pharmacological, toxicological, and metabolic studies with Augmentin. In: Rolinson GN, Watson A, (eds). Augmentin: proceedings of the first symposium. Amsterdam: Excerpta Medica, 1980; 87-l 05.

6. Von Proksovci EG: Quantitative Glykogenverand-erungen in der Rattenleber nack Tetracyklin. Anat Anz 1973; 134: 87-93.

7. Levine BB: Immunological mechanisms of penicillin allergy. In: Seminars in Medicine. Boston: Beth Israel Hospital, 1966; 20: 1115-1125.

8. Ferres H, Nunn B: Penicillin metabolites and platelet function. Lancet 1983; 23: 226-227.

9. Jackson D, Cooper DL, Horton R, et al: Absorption, pharmacokinetic, and metabolic studies with Augmentin. In: Croydon EAP, Michel MF, (eds). Augmentin: proceedings of the Euro- pean symposium. Amsterdam: Excerpta Medica, 1982; 83- 99.

10. Staniforth DH, Coates P, Davies BE, Horton R: Pharmacokinet- its of parenteral ticarcillin formulated with clavulanic acid- Timentin (in press).

11. Jackson D, Tasker TCG, Staniforth DH, Horton R, Murray AT, Swaisland A: The bioavailability of parenteral Timentin over the dose range 1.2 to 10.2 g (poster). Presented at the 13th International Congress on Chemotherapy, Vienna, 1983.

12. Unpublished data. Intravenous clavulanate formulations: inves- tigative studies of an idiosyncratic reaction in the dog. Report 14151/IP/IV/CA, July 1982.

13. Bergan T: Personal communication. 1985. 14. Bennett S, Wise R, Weston D, Dent J: Pharmacokinetics and

tissue penetration of ticarcillin combined with clavulanic acid. Antimicrob Agents Chemother 1983; 23: 631-834.

15. Neu HC, Parry MF: Pharmacokinetics of ticarcillin in patients with abnormal renal function. J Infect Dis 1976: 133: 46-49.

November 29, 1995 The American Journal of Medlclne Volume 79 (suppl5B) 55

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Clinical pharmacology and safety evaluation of timentin

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