Med. OncoL & TumorPharmacother. Vol. 1, No. 3, pp. 193-194, 1984 0736-0118]84 $3.00 + .00 Printed in Great Britain �9 1984 Pergamon Press Ltd.

P L A S M A P H A R M A C O K I N E T I C S O F A D R I A M Y C I N A F T E R I N T R A P L E U R A L A D M I N I S T R A T I O N

STAFFAN EKSBORG* and ASTRID LINDFORS Karolinska Pharmacy, Box 60024, S-104 01 Stockholm, Sweden

and BJORN J. CEDERMARK

Department of Surgery, Karolinska Hospital, S-104 01 Stockholm, Sweden

(Accepted for publication 26 May 1983)

The plasma pharmacokinetics of adriamycin after intrapleural administration have been studied. The maxi- mum plasma concentration found after intrapleural instillation of 50 mg was 100 ng m1-1, the adriamycin half-life being about 2.5 h.

Large amounts of the drug are adsorbed from the pleura. Hence risks for cardiomyopathy, previously associated with the repeated intravenous administration of adriamycin, must also be considered after intra- pleural administration.

Key words: Adriamycin, Intrapleural, Cancer, Chemotherapy, Pharmacokinetics, Pleural effusions.

INTRODUCTION

Adriamycin, an anthraquinone glycoside, is one of the most effective drugs in the treatment of a large variety of malignant neoplasms. 1'2 However, like most other neoplastic drugs, adriamycin, at therapeutic doses, exhibits serious toxic side effects like leucopenia, thrombocytopenia and stomatitis. In addition, adria- mycin has cardiotoxic properties. The possibility for congestive heart failure increases with increasing total dose of adriamycin. Thus it has been recommended that the cumulative dose of adriamycin should not exceed 550 mg m1-1.2-4 Intravesically instilled adriamycin has successfully been used for the treatment of superficial tumours of the urinary bladder. 5-7 No toxic side effects were observed, and measurements of the plasma con- centration of adriamycin after such treatment indicated no systemic absorption to occur. 8' 9

Intracavitary instillation of adriamycin has been reported useful in the treatment of malignant effu- sions. 1~ Following such treatment mild side effects including nausea and vomiting were recorded, while neither myetosuppression nor alopecia occurred. This indicates that at least some of the drug enters the systemic circulation. There are no pharmacokinetic studies reported so far. tn the present preliminary report

*To whom correspondence should be addressed.

the results of plasma pharmacokinetic studies after intra- pleurally administrated adriamycin in four patients are presented.

PATIENTS AND METHODS

Four patients with cytologically confirmed malignant pleural effusions were included in this study. Before the intrapleural instillation of adriamycin the pleura was drained by simple needle thoracocentesis. Adriamycin (2 mg m1-1 in normal saline) was then injected as a bolus.

Blood samples ( 5 - 7 ml) were taken at various time intervals up to 4 h postinjection by venipuncture and collected in 10 ml glass test tubes (Vacutainer | contain- ing 250 i.u. heparin (freeze dried). The plasma fraction was isolated by centrifugation and assayed for adriamycin and adriamycinol according to the procedure reported by Eksborg et al. 13

193

RESULTS

Plasma levels after intrapleural administration of adriamycin in four patients are presented in Fig. 1. The maximum plasma concentrations were in all instances low, compared to what has previously been recorded after an intravenous bolus injection) 3' 14 The adria-

194 Staffan Eksborg, Astrid Lindfors and BjOrn J. Cedermark

t,.o Z

Z C3

7= rr" i..-.- z

Z 0

,-r

200

lO0

SO-

20-

I0 0

I

i . �9 i �9 �9 , i , , , i

I 2 3 4 POSTINJECTION TIME, HOURS

Fig. 1. Adriamycin plasma levels after intrapleural admini- stration: (I-q) Patient IH; (O) Patient ALO; (A) Patient KG; (X) Patient KO. Administered dose: 50 mg adria-

mycin in 25 ml normal saline.

mycin plasma half life was about 2.5 h after intrapleural administration.

In none of the patients did the plasma level of adria- mycinol, a reduced metabolite to adriamycin with approximatively similar cytotoxic activity, ~s exceed the analytical detection limit (5 ng ml -I ).13

DISCUSSION

The cardiomyopathy associated with adriamycin treatment has been referred to the cumulative dose of adriamycin. 3'4 Large amounts of intrapleuraIly instilled adriamycin will be distributed to the plasma, which is clearly shown by the comparison of the area under the plasma concentration time curve, AUC, after intrapleur- ally, Fig. I, and intravenously 13' ~4 administered adria- mycin. Hence the risk for cardiomyopathy after such a route of administration must be considered. 16

REFERENCES

1. Blum R H, Carter S K: Adriamycin, a new anticancer drug with significant clinical activity. Ann intern Med 80,249--259 (1974).

2. Carter S K: Adriamycin - a review. J natn Cancer Inst 55, 1265-1274 (1975).

3. Minow R A, Benjamin R S, Lee E T, Gottlieb J A: Adriamycin cardiomyopathy - risk factors. Cancer 39, 1397-1402 (1977).

4. Lenaz L, Page J A: Cardiotoxicity of adriamycin and related anthracyclines. Cancer Treat Rev 3, 111-120 (1976).

5. Banks M D, Pontes J E, Izbicki R M, Pierce J M Jr: Topical instillation of doxorubicin hydrochloride in treatment of recurring superficial transitional cell carcinoma of the bladder. J Urol 118, 757-760 (1977).

6. Ozaki Y: Bladder instillation of adriamycin in the treatment of bladder tumours. Report 1: Clinical results. Jap J Urol 68 ,934-944 (1977).

7. Eksborg S, Nilsson S O, Edsmyr F: Intravesical instil- lation of adriamycin - a model for standardization of the chemotherapy. EurJ Urol 6, 218-220 (1980).

8. Eksborg S: Measurements of plasma levels of adria- mycin and adriamycinol after intravesical instilla- tion of adriamycin, in: Diagnostics and Treatment o f Super]'iciat Urinary Bladder Tumours, pp. 55-58. Stockholm, Montedison L~ikemdel AB (1979).

9. Jacobi G H, Kurth K H: Studies on the intravesical action of topically administered G3H-doxorubicin hydrochloride in men: plasma uptake and tumour penetration. J Urol 124, 34-37 (1980).

10. Tattersall M H N, Fox R M, Newtands E S, Woods R L: Intracavitary doxorubicin in malignant effu- sions. Lancet 8112,390 (1979).

11. Desal S D, Figueredo A: Intracavitary doxorubicin in malignant effusions. Lancet 8121,872 (1979).

12. Kefford R F, Woods R L, Fox R M, Tattersall M H N: Intracavitary adriamycin, nitrogen mustard and tetracycline in the control of malignant effusions. Med J Aust 2 ,447-448 (1980).

13. Eksborg S, Ehrsson H, Andersson I: Reversed-phase liquid chromatographic deternaination of plasma levels of adriamycin and adriamycinol. J Chromatog 164,479-486 (1979).

14. Benjamin R S: Pharmacokinetics of adriamycin in (NSC-123127) inpat ients with sarcomas. Cancer Chemother Rep 58, Part 1 ,271-273 (1974).

15. Bachur N R: Adriamycin (NSC-123127)pharmaco- logy. Cancer Treat Rep 6, Part 3, 153-158 (1975).

16. Praga C, Beretta P L, Vigo G R et al.: Adriamycin cardiotoxicity: a survey of 1237 patients. Cancer Treat Rep 63 ,827-834 (1979).