Br. J. clin. Pharmac. (1990), 30, 237-243

The effect of food on serum concentrations of metopimazine J0RN HERRSTEDTl*, MORTEN J0RGENSEN2 & HELLE RIIS ANGELO3 'Department of Internal Medicine C, Bispebjerg Hospital, University of Copenhagen, DK-2400 Copenhagen NV, 2Department of Oncology, Herlev Hospital, University of Copenhagen, DK-2730 Herlev and 3Department of Clinical Chemistry, Bispebjerg Hospital, University of Copenhagen, DK-2400 Copenhagen NV, Denmark

1 Six healthy volunteers were given single oral doses of the antiemetic metopimazine (MPZ), starting with trial (a) 20 mg preprandially and followed by trial (b) 50 mg preprandially. In trials (c) and (d) the doses were similar to those in trials (a) and (b), but MPZ was given postprandially. To evaluate intra-individual variation in serum concentrations, trial (a) was repeated three times in four of the volunteers (trial (e)). 2 Blood samples were drawn and the serum concentrations of MPZ and its acid metabolite (AMPZ) were measured by h.p.l.c. 3 There was no evidence of dose-dependent kinetics at the dose levels studied. 4 Median AUC values were 22.6, 16.2, 52.4 and 35.2 (trials (a), (b), (c) and (d), ng ml-' h). Food intake decreased the serum concentrations of MPZ, suggesting that MPZ should be taken preprandially. Keywords antiemetics metopimazine food

serum

concentrations

Introduction

Nausea and vomiting are prominent adverse reactions to cancer chemotherapy and established antiemetics have been found to be effective in no more than 40% of patients receiving highly emetogenic cancer chemotherapy (Craig & Powell, 1987). Metopimazine (MPZ) a piperidine derivative of phenothiazine, has a significant antiemetic effect compared with placebo. Thus in a randomized double-blind trial Moertel & Reitemeier (1973) showed that 10 mg oral MPZ three times daily was as effective as 5 mg prochlorperazine three times daily and that both drugs were significantly better than placebo in the treatment of 5-fluorouracil-induced nausea and vomiting. The only adverse reaction was sedation, but there was no difference in sedation between MPZ and placebo. In contrast prochlorperazine was more sedative than both placebo and MPZ. Clavel et al. (1978) found that 50 mg i.v. MPZ was superior to 10 mg of MPZ in the treatment of nausea and vomiting induced by cancer chemotherapy. Except for two patients with

small asymptomatic decreases in blood pressure on the 50 mg dose, there were no differences in the frequency of adverse reactions at the two doses. In order to optimize the dosage and dose interval of MPZ, we have investigated its oral absorption under standard conditions. As MPZ undergoes considerable first-pass metabolism, (Rhone-Poulenc report IBP/Biodyn. No 561 1985), we also evaluated the possibility of saturable kinetics. Methods

The subjects of the study were six healthy volunteers: three women and three men, aged 24-35 years. They all participated in four trials, as described below. Four of the volunteers participated in a fifth trial. MPZ was given as 5 mg tablets and 15 mg capsules (Vogalene®). Trial (a): 20 mg MPZ as a single, oral dose

*Present address and correspondence: Department of Oncology, Herlev Hospital, University of Copenhagen, DK-2730 Herlev, Denmark

237

238

J. Herrstedt, M. J0rgensen & H. R. Angelo

All six volunteers fasted for 8 h before the trial, and for 4 h after dosage. Blood samples were drawn at 0, 15, 25, 35, 45, 60, 90, 120, 180, 240, 300, 360 and 480 min after MPZ. Blood pressure was recorded at 0, 35, 90, 180 and 480 min.

Trial (b): 50 mg MPZ as a single, oral dose Procedure as in trial (a). Trial (c): 20 mg MPZ as a single, oral dose + meal All six volunteers fasted for 8 h before the trial. MPZ was taken together with a standard meal. The total energy content of the meal was 1840 kJ and comprised 20 g protein (20%), 17 g fat (35%), and 50 g carbohydrate (45%) (Melander, 1978). After administration of MPZ and following the meal, the subjects fasted again for 4 h. Blood samples were drawn at 0, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, 360 and 480 min after dosage. Blood pressure was recorded as in trial (a).

Trial (d): 50 mg MPZ as a single, oral dose + meal

Results

The serum concentrations of MPZ and of AMPZ in each individual are shown in Figures 1 (MPZ) and 2 (AMPZ). Areas under the curves to 8 h, calculated by the linear trapezoidal rule, are listed in Table 1. The oral absorption of MPZ in the five trials (a-e) was evaluated from comparative analyses of the variation in the sum of the AUCs of MPZ and AMPZ and from comparative analyses of the differences in Cmax and tmax.

The effect of food MPZ AUC values were significantly higher in the preprandial trial (a) than in the postprandial trial (c) (median 22.6 and 16.2 ng ml-1 h, respectively, P < 0.05, Wilcoxon's test, Table 1). The 50 mg trials were not carried out in subject 6, and therefore a significant effect of food could not be demonstrated at this dose level. When the AUC values in the two preprandial trials were combined (a + b), they were found to be significantly higher than those for the two postprandial trials combined (c + d) (P < 0.01, Wilcoxon's

test).

Procedure as in trial (c). Trial (e) To evaluate the extent of intra-individual variation in the serum concentrations of MPZ trial (a) was repeated three times in subjects 3, 4, 5 and 6.

Analytical method Serum concentrations of metopimazine and its acid metabolite (AMPZ) were measured by h.p.l.c., as described by Angelo et al. (1989). The coefficient of variation of the assay was 3-8% (100-8ngmlP).

Ethics The volunteers gave informed consent to the study, which was carried out in accordance with the Helsinki II Declaration and was approved by the Ethics Committee of Central Copenhagen and by The Danish Medical Health Authorities.

MPZ + AMPZ The combined AUC values for MPZ + AMPZ were significantly higher in the preprandial trials (median 107.1 and 77.8 ng ml-1 h, respectively, for 20 mg MPZ and median 258.7 and 188.0 ng ml-1 h, respectively, for 50 mg MPZ, P < 0.01, Table 1).

Cmax and tmax Cmax values of MPZ in the preprandial trials were all higher than those in the postprandial trials (P < 0.01, Table 2). At the 20 mg dose (trials a and c), the preprandial median tmax (MPZ) was 52 min and the postprandial median tmax (MPZ) was 90 min. The corresponding values for AMPZ were 120 and 150 min, respectively. At the 50 mg dose (trials b and d), the preprandial median tmax (MPZ) was 60 min and the postprandial median tmax (MPZ) was 90 min. The median tmax (AMPZ) was 120 min preprandially and 150 min postprandially. These differences in tmax were not statistically significant (P > 0.05). The effect of dose

Statistics The Wilcoxon matched-pairs test and the Friedman test were used with a significance level of 5% (Siegel, 1956).

MPZ The ratio of mean AUC values for the 20 mg vs the 50 mg dose was 2.56 for MPZ and 2.57 for AMPZ, indicating linear increases in AUC with dose.

The effect offood on serum concentrations of metopimazine

239

ioot 1 80 60 40 * 20 1 ~~~~~

4

4~1

.P

8

100t 4-

60 ....

A.

25

.loot 6 *80 60

-

4Q , X

'

.'-

.

i .:

4.

5.

8 -1

1.

'

riW (h) Figure 1 Serum concentrations of metopimazine (MPZ) in six healthy volunteers (1-6) taking oral MPZ: o * 20 mg preprandially; * 0 20 mg postprandially and * * 50 mg preprandially; 050 mg postprandially. 0

Individual variation

Adverse reactions

Serum concentrations of MPZ in the four individuals participating in trial (e) are shown in Figure 3. AUC values showed no statistically significant intra-individual variation (P = 0.43, Friedman's test). A highly significant interindividual variation in AUC was apparent (P < 0.01).

Except for a slight dryness of the mouth which occurred in all four trials, adverse reactions were few. Two subjects experienced slight sedation which was not dose-related, and two felt slightly dizzy. Three subjects had minor palpitations during trial (b) which was associated with tmax and the highest Cmax values. One h after 20 mg

J. Herrstedt, M. J0rgensen & H. R. Angelo

240

a-

E. 0

300

6

200

100

1

8

3

4

5

6

7

8

Time (h) Figure 2 Serum concentrations of the acid metabolite of metopimazine (AMPZ) in six volunteers (1-6) taking oral MPZ: * -* 20 mg preprandially; * o 20 mg postprandially U* S0 mg preprandially; 0 o 50 mg postprandially. and 0

of MPZ subject 6 had an orthostatic decrease in blood pressure of 30 mm Hg. She felt uncomfortable and had to lie down. There was no decrease in the blood pressure in the supine position. Her Cma. value was 61 ng ml-1 with a tmax of 35 min; the maximum sum of the concentrations of MPZ and AMPZ was seen at 60 min. No adverse reactions were encountered on repeating the

trial twice in this subject, except for dry mouth. However, she did not participate in the 50 mg trials. Subjects 1-5 had minor orthostatic decreases in systolic blood pressure, but only in trial (b) where the highest serum drug concentrations were observed. The decreases in blood pressure were all less than 15 mm Hg and did not cause any

symptoms.

The effect offood on serum concentrations of metopimazine

241

Table 1 AUC values (ng ml- l h) of MPZ, AMPZ and MPZ + AMPZ after oral administration of metopimazine with and without food 20 mg MPZ AUC Preprandial

AUC Postprandial AMPZ MPZ + AMPZ

Subject

MPZ

AMPZ

MPZ + AMPZ

MPZ

1 2 3 4 5 6

27.0 11.6 30.3 12.4 19.7 25.5

71.2 41.7 70.5 101.0 130.9 116.8

98.2 53.3 100.8 113.4 150.6 142.3

15.6 6.4 16.8 8.3 17.1 18.9

59.2 36.3 40.1 72.5 117.9 92.8

74.8 42.7 56.9 80.8 135.0 111.7

Median

22.6

86.1

107.1

16.2

65.9

77.8

50 mg MPZ A UC Preprandial A UC Postprandial AMPZ MPZ + AMPZ MPZ AMPZ MPZ + AMPZ

Subject

MPZ

1 2 3 4 5 6

66.9 28.1 72.5 28.3 52.4

191.8 116.5 184.8 240.0 354.8

258.7 144.6 257.3 268.3 407.2

39.5 22.7 43.7 33.2 35.2

148.5 100.5 100.7 221.7 249.3

188.0 123.2 144.4 254.9 284.5

Median

52.4

191.8

258.7

35.2

148.5

188.0

Discussion Table 2 Cmax (ng ml -1) and tmax (min) values of metopimazine after oral administration of the drug with and without food 20 mg MPZ Preprandial

Postprandial tmax

Cma

tma

Cmnax

1 2 3 4 5 6

38 14 69 22 49 61

120 45 90 60 25 35

24 8 20 11 29 32

90 90 90 120 90 60

Median

43

52

22

90

Subject

50 mg MPZ Preprandial

Subject 1 2 3 4 5 6

Median

Postprandial

Cmax

tma

Cmax

tma

83 34 160 72 145

90 240 45 45 60 _

65 26 58 50

51

90 90 120 35 90

83

60

51

90

The absolute bioavailability of a 10 mg oral dose of MPZ is reported to be about 19% with ratios of AMPZ to MPZ of 1.9 following intravenous and 7 following oral administration (Rhone Poulenc report IBP/Biodyn. No 561, 1985). These findings suggest that MPZ is subject to considerable first pass metabolism. In the present study the linear increase in the AUC values of AMPZ and MPZ found on raising the dose from 20 to 50 mg indicates that enzyme saturation does not occur over this range. We presume, that the lower serum concentrations of MPZ and its metabolite after a meal result from a reduction in drug absorption, as described by Melander (1978) for various other drugs. As this finding can probably be extrapolated from young, healthy subjects to patients with cancer (Barry, 1974; Benet et al., 1984; Crooks & Stevenson, 1979; Ohnuma & Holland, 1977), it seems reasonable to prescribe MPZ preprandially. A significant interindividual variation in the AUC of MPZ is consistent with a marked variation in the antiemetic effect of MPZ. Str0yer et al. (1976) found no difference in the antiemetic effect of chlorpromazine 25 mg three times daily and MPZ 10 mg three times daily. Others (Israel & Rodary, 1978; Moertel &

242

J. Herrstedt, M. J0rgensen & H. R. Angelo

100 t

3

100' 4

801-

80

*60

60

-

40

40

c

20'

20

1- I

c

1

N

4

3

2

5

4

6 7-

5

6

-7

Iv 1-

8

2

3

5

6

7

8j

5

6

7

8

coo

100t 6 E L-

(a

IF.-

801

60

60

40

40

-

20

20

1.

1

2

...I'r

3

4'

'-;

7

5

a

6

.&

----

7

E

I

F

I

1

2

3

4

Time (hI) Figure 3 Serum concentrations of metopimazine (MPZ) in four volunteers (3-6) taking oral MPZ 20 mg, preprandially. The trial was repeated three times (° *, * *. 0 o) in each volunteer to investigate intra-individual variation. Each diagram represents one subject.

Reitemeier, 1969, 1973) investigated the antiemetic effect of MPZ compared with placebo, metoclopramide and prochlorperazine, but only using doses up to 45 mg day-'. Clavel et al. (1978) found that MPZ 50 mg i.v. was well tolerated. There are no studies of MPZ at a dose higher than 50 mg day -1. From our observations it seems that MPZ may be tolerated at doses larger than those used conventionally (30-45 mg day-1). Figures 1 and 2 show that the serum concentrations of both MPZ and AMPZ at 8 h after intake are very low. Therefore appreciable accumulation of MPZ or AMPZ should not occur on repeating a 50 mg dose every 8 h. A trial of administration at this dose level seems worthwhile, since no major adverse reactions were recorded after a single 50 mg dose. The possibility of orthostatic hypotension in individual patients should, however, be taken into account, since one subject had a significant decrease in blood pressure in one of three trials on the 20 mg dose. Orthostatic hypotension was also described by Clavel et al. (1978) in two patients. Recent preliminary results suggest that MPZ might be prescribed in much higher doses. Vallejo et al.

(1988) evaluated the safety and efficacy of intradoses of MPZ in 20 patients receiving 2 100 mg m-2 cisplatin schedules. The MPZ doses were 20, 40, 66 and 100 mg m-2 given by slow i.v. infusion 30 min before and then at 2, 4 and 6 h after the start of cisplatin infusion. The mean numbers of emetic episodes were 4.0 and 3.7 on the 66 and 100 mg m-2doses, respectively. Total antiemetic protection was described in three of 12 patients. On the 100 mg m-2 x 4 dose, two patients had severe orthostatic hypotension. It is possible that the dose-limiting side effect of MPZ is the tendency of phenothiazines to cause orthostatic hypotension. Further studies on the optimum dose level and dose interval of venous

MPZ are necessary in order to determine whether the antiemetic efficacy of MPZ is greater than hitherto recognized. This work was supported by Rhone-Poulenc Pharma Norden A/S. We thank J. P. Kampmann for clinical pharmacological advice and J0rgen Andersen for skilful technical assistance.

The effect offood on serum concentrations of metopimazine

243

References Angelo, H. R., Herrstedt, J. & J0rgensen, M. (1989). A high-performance liquid chromatographic method with fluorescence detection for the simultaneous determination of metopimazine and its acid metabolite in serum. J. Chromatogr., 496, 472-477. Barry, R. E. (1974). Malignancy, weight loss and the small intestinal mucosa. Gut, 15, 562. Benet, L. Z., Massoud, N. M. S. & Gambertoglio, J. G. (1984). In Pharmacokinetic basis for drug treatment, pp. 283-288. New York: Raven Press. Clavel, M., Bolot, J. E., Philippe-Bert, J., Putot, J. P., Rodary, Ch. & Pommatau, E. (1978). Doubleblind comparative trial with metopimazine (50 mg and 10 mg i.v.) as a preventive treatment for nausea and vomiting attending anticancer drug therapy. Lyon Medical, 293, 307-309. Craig, J. B. & Powell, B. L. (1987). Review: The management of nausea and vomiting in clinical oncology. Am. J. med. Sci., 293, 34 44. Crooks, J. & Stevenson, I. H. (1979). Drugs and the elderly: Perspectives in Clinical Pharmacology, pp. 51-55. London: The Macmillan Press Ltd. Israel, L. & Rodary, C. (1978). Treatment of nausea and vomiting related to anti-cancerous multiple combination chemotherapy. J. int. med. Res., 6, 235-240. Melander, A. (1978). Influence of food on the bioavailability of drugs. Clin. Pharmacokin., 3, 337351.

Moertel, C. G. & Reitemeier, R. J. (1969). Controlled clinical studies of orally administered antiemetic drugs. Gastroenterology, 57, 262-268. Moertel, C. G. & Reitemeier, R. J. (1973). Controlled studies of metopimazine for the treatment of nausea and vomiting. J. clin. Pharmac., 57, 283287. Ohnuma, T. & Holland, J. F. (1977). Nutritional consequences of cancer chemotherapy and immunotherapy. Cancer Res., 37, 2395-2406. Siegel, S. (1956). Nonparametric statistics in the behavorial sciences. New York: McGraw-Hill. Str0yer, I., Walbom-J0rgensen, S. & Hansen, H. S. (1976). Clinical assessment of the antiemetic, metopimazine (Vogaleneg) in an open and a double-blind trial. Ugeskr. Laeger, 138, 17691770. Vallejo, C., Rabinovich, M., Leone, B. & Gonzalez, J. (1988). Toxicity and dose-response of intravenous (i.v.) metopimazine (MPZ) as preventive of high-dose cisplatin (CDDP)-induced emesis. Proceedings Am. Soc. clin. Oncol., 7, 286.

(Received 11 July 1989, accepted 19 March 1990)

The effect of food on serum concentrations of metopimazine.

1. Six healthy volunteers were given single oral doses of the antiemetic metopimazine (MPZ), starting with trial (a) 20 mg preprandially and followed ...
875KB Sizes 0 Downloads 0 Views