Leuprorelin Acetate Blood Levels and Dialysanceafter the Administration of Sustained-Release

Leuprorelin Acetate in a Dialysis CaseComplicated by Prostate Cancer

Kazuhisa Saruki,1* Tetsuo Sekihara,1 Masamichi Mashimo,1Hidenori Matsuo,2 and Hiroyuki Sekiguchi2

1Department of Urology, Hidaka Hospital, Takasaki, Japan2Dialysis Center, Hidaka Hospital, Takasaki, Japan

BACKGROUND. The objective of this study is to determine whether in a dialysis patientwith prostate cancer leuprorelin acetate blood levels were abnormally high or low due tokidney failure or because of dialysis.METHODS. Sustained-release leuprorelin acetate 3.75 mg was given every 4 weeks for pros-tate cancer in a 79-year-old dialysis patient. Changes in serum level of leuprorelin acetate inthis patient were measured before and after dialysis.RESULTS. Leuprorelin acetate appeared to have a dialysance close to that of vitamin B12,which has a similar molecular weight. The amount dialyzed did not exceed 8.3% of theamount released per day. Mean blood levels of leuprorelin acetate, as measured in thispatient, were higher (0.64 to 1.31 ng/ml) than those in prostate cancer patients with normalkidney function (mean ± SD, 0.24 ± 0.12 to 0.50 ± 0.32 ng/ml).CONCLUSIONS. Sustained-release leuprorelin acetate can be used safely in dialysis patientswith prostate cancer. Prostate 34:191–194, 1998. © 1998 Wiley-Liss, Inc.

KEY WORDS: leuprorelin; prostate; neoplasms; dialysis

INTRODUCTION

As dialysis patients grow older, their condition mayfrequently become complicated by various forms ofmalignant tumor. Anuria is common in dialysis pa-tients, and since these patients do not complain ofdysuria, tests for prostate disease are generally notperformed. In the present case, swelling of the pros-tate was detected accidentally during a digital rectalexamination in testing for diarrhea. The patient wasreferred to the department of urology, where prostatecancer was discovered. The patient was given hor-mone therapy in the form of leuprorelin acetate.

The objective of this study was to determine wheth-er leuprorelin acetate blood levels were abnormallyhigh because of kidney failure, and whether leuprore-lin acetate levels were abnormally low because of di-alysis.

MATERIALS AND METHODS

Presentation

On May 30, 1995, during detailed testing for diar-rhea, a surgeon performing a digital rectal examina-tion on a 79-year-old man discovered swelling of theprostate, and the patient was referred to the Depart-ment of Urology. The patient had developed highblood pressure at approximately 50 years of age. At 65years of age, he underwent surgery for hemorrhoids.In July of 1990 (at the age of 73) he developed kidneyfailure due to chronic glomerulonephritis, and dialysiswas initiated. The patient currently receives dialysis

*Correspondence to: Dr. Kazuhisa Saruki, Department of Urology,Hidaka Hospital, 886 Nakaomachi, Takasaki, Gunma 370, Japan.Received 5 November 1996; Accepted 11 June 1997

The Prostate 34:191–194 (1998)

© 1998 Wiley-Liss, Inc.

for 4 hours three times each week. There were no no-table findings in a review of his family history.

Clinical Findings

Although the patient was completely incapable ofvoluntary urination, no symptoms such as dysuriawere noted. Digital examination showed the prostateto be swollen to the size of a small hen’s egg (about 3.5× 3.5 × 4.5 cm). The right lobe was elastic hard, andthe left lobe was stony hard with uneven irregulari-ties. His prostate-specific antigen (PSA; Tandem-R,Hybritech, Inc., San Diego, CA, USA) level was 82.4ng/ml.

Prostate cancer was suspected, and on June 20, ul-trasound-guided transperineal needle biopsy of theprostate was performed. Pathologic findings showedmoderately-to-poorly differentiated adenocarcinoma.Results of cystoscopy, pelvic computed tomography,pelvic magnetic resonance imaging, drip intravenouspyelography, abdominal ultrasound, and bone scintig-raphy showed infiltration into the bladder neck, mul-tiple metastasis to the lymph nodes within the pelvis,and multiple bone metastasis. The diagnosis was pros-tate cancer, T3N2M1 [1].

Treatment

Treatment was begun by giving fosfestrol 250 mg/day for 3 consecutive days. However, the patient de-veloped nausea and anorexia, so administration wasterminated. Written consent was obtained from thepatient to begin leuprorelin administration and tomeasure blood levels of this drug. Beginning on July17, subcutaneous injection of sustained-release leupro-relin acetate 3.75 mg was initiated. Subsequently, thepatient was treated every 4 weeks with subcutaneousinjection of 3.75 mg leuprorelin.

Dialysis

Dialysis was performed by using a BK-1.6U dia-lyzer (Toray Industries, Inc., Tokyo, Japan), with dial-ysate (Kindaly AF-2; Fuso Pharmaceutical Industries,Ltd., Osaka, Japan). The dialysate flow rate was 500ml/min, and the blood flow rate was 150 to 170 ml/min.

Leuprorelin Assay

After the fourth leuprorelin injection (12 weeks af-ter the first injection), it was assumed that blood levelswould have nearly stabilized. Blood samples weredrawn on day 9, 12, 13, and 14 after the fourth injec-tion. Immediately after blood samples were drawn,

the serum was separated and stored frozen until mea-surement. On the 12th day, the dialysate was sampled10 minutes, 20 minutes, and 30 minutes after the startof dialysis, and these samples were stored frozen untilthe leuprorelin levels could be measured.

The total leuprorelin level in the serum was mea-sured by radioimmunoassay [2], (Takeda AnalyticalResearch Laboratories, Ltd., Osaka, Japan).

RESULTS

Leuprorelin Concentrations

On the 9th day after the 4th injection, serum leu-prorelin levels were 1.31 ng/ml before dialysis, and1.00 ng/ml after dialysis. On the 12th day, these val-ues were 0.82 ng/ml before dialysis and 0.64 ng/mlafter dialysis. On the 13th day (24 hours after the startof dialysis on 12th day), the leuprorelin level was 0.90ng/ml, and before dialysis on the 14th day, it was 0.89ng/ml (Table I). No postdialysis leuprorelin values forthe 13th and 14th days were not available because nodialysis was performed on the 13th day, and no post-dialysis sample obtained on the 14th. The mean leu-prorelin level of the dialysate during dialysis on the12th day was 0.073 ng/ml (Table II).

Dialysance Calculations

Using a dialyzer BK-1.6U, dialysance was calcu-lated from leuprorelin levels in the blood and in thedialysate (data from the 12th day). The following re-sults were obtained.

The leuprorelin serum level before dialysis was 0.82ng/ml. The protein binding rate is approximately 49%[2], so the free leuprorelin level in the dialyzed serumwas calculated as the serum concentration multipliedby the percentage of nonbound drug (0.82 ng/ml ×0.51), which is equal to 0.42 ng/ml. The total hemat-

TABLE I. Concentration of Leuprorelin Acetate* in theSerum of a 79-Year-Old Dialysis Patient With

Prostate Cancer

Day afterleuprorelininjection

Before hemodialysis(ng/ml)

After hemodialysis(ng/ml)

9th 1.31 1.0012th 0.82 0.6413th 0.90 —14th 0.89 —

*Dosage: subcutaneous injection of 3.75 mg leuprorelin every 4weeks. No postdialysis leuprorelin values for the 13th and 14thdays were available because no dialysis was performed on the13th day, and no postdialysis sample obtained on the 14th.

192 Saruki et al.

ocrit was 29.7%, so the free leuprorelin level in theblood was calculated as the concentration of free drugin the serum multiplied by the percentage of serumvolume of the blood (0.42 ng/ml × 0.703), which is 30ng/ml. The mean leuprorelin level in the dialysateup to 30 minutes after the start of dialysis was 0.073ng/ml.

Dialysance was calculated from the following for-mula:

D = FCdo − Cdi

Cbi − CdiGQd

where Cd is concentration in dialysate; Cb is concen-tration in blood (subscripted ‘‘i’’ is intake, ‘‘o’’ is out-put); Qd is dialysate flow volume; and D is dialysance.In this case, no leuprorelin was added to the dialysate(Cdi = 0), so the equation for the dialysance of freeleuprorelin is as follows:

D =Cdo × Qd

Cbi

substituting the appropriate values (Cdo, 0.073 ng/ml;Qd, 500 ml/min, and Cbi, 0.30 ng/ml) gives a value of122 ml/min for the dialysance of free leuprorelin.

DISCUSSION

Because dialysis patients frequently experience cir-culatory complications, estrogen therapy can be dan-gerous. Castration is both simple and effective, buteven with the added complication of dialysis, patientsare resistant to castration. In this situation, hormonetherapy can be obtained from drugs. Leuprorelin re-sults in fewer adverse effects on the circulatory systemthan estrogen [4].

However, leuprorelin metabolism and excretion ishandled primarily by the kidneys, making it possible

that abnormally high leuprorelin levels could occurduring kidney failure. In the present study, althoughleuprorelin levels were higher than the values mea-sured in prostate cancer patients with normal kidneyfunction (mean ± SD, 0.24 ± 0.12 to 0.50 ± 0.32 ng/ml)[5], the leuprorelin concentration peaked at only 1.31ng/ml in a dialysis patient with prostate cancer. Leu-prorelin is metabolized in the heart, liver, brain, andmuscles, as well as in the kidney [3]. In kidney failure,the drug is apparently still metabolized by these otherorgans to the extent that leuprorelin levels, althoughgreater than normal, do not reach extraordinarily highvalues.

We also considered it possible that dialysis mightremove so much leuprorelin that adequate blood lev-els of this drug would not be maintained. The molecu-lar weight of leuprorelin is 1269.4, so we reasoned thatthis substance should be dialyzed similarly to vitaminB12 (molecular weight, 1355.4). Dialysance calculationsyielded a value of 122 ml/min. This would varyslightly depending on conditions, but is nearly iden-tical to the dialysance of 113 ml/min given for vitaminB12 in the manual for the dialyzer used in this case.

In animal studies, sustained-release leuprorelin ac-etate was found to be released at a rate of 2.8% per day[6]. Projected for humans, this would be 3.75 mg mul-tiplied by 0.028 per day, which equals 0.105 mg/day.If we assume that the leuprorelin level does not de-crease during the 4 hours of dialysis, then the totalamount dialyzed in 1 day would be 0.073 ng/ml × 500ml/min × 60 min/h × 4 h, which equals 8760 ng or0.00876 mg. This amount is no more than 8.3% of theamount released per day. Thus, we conclude that di-alysis does not produce clinically problematic reduc-tions in leuprorelin levels. The actual measurementsperformed in this study showed that serum leuprore-lin levels, even after dialysis, were a minimum of 0.64ng/ml, higher than the mean values for prostate can-cer patients with normal kidney function (0.24 ± 0.12to 0.50 ± 0.32 ng/ml). No adverse reactions have beennoted, and it has been possible to continue treatment.To some extent, high leuprorelin levels can be ex-pected to suppress testosterone secretion more effec-tively than lower levels.

CONCLUSIONS

Sustained-release leuprorelin acetate was given to a79-year-old dialysis patient who had developed pros-tate cancer. In this case, even with kidney failure, theserum leuprorelin level peaked at only 1.31 ng/ml.Leuprorelin acetate appeared to have a dialysanceclose to that of vitamin B12, which has a similar mo-lecular weight. The amount of leuprorelin acetate re-moved in a single dialysis did not exceed 8.3% of the

TABLE II. Concentration of Leuprorelin Acetate in theDialysate 12 Days after Subcutaneous Injection of 3.75mg Leuprorelin in a 79-year-old Dialysis Patient With

Prostate Cancer

Time afterstart of dialysis(min)

Leuprorelinacetate

(ng/ml)Average(ng/ml)

10 0.06720 0.078 0.07330 0.074

Leuprorelin Dialysance in Prostate Cancer 193

amount released in a day. Even during dialysis, serumleuprorelin levels did not drop to the mean valuesseen in patients not undergoing dialysis. We believethat sustained-release leuprorelin acetate 3.75 mg canbe used safely in dialysis patients.

ACKNOWLEDGMENTS

We thank Mr. Shigeki Matsuo of Takeda AnalyticalResearch Laboratories, Ltd., for his assistance in mea-suring serum leuprorelin levels.

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