A Radionuclide Generator and Infusion System for Pharmaceutical

9 A Radionuclide Generator and Infusion System for Pharmaceutical Quality Rb-82 G. P. GENNARO, R. D. NEIRINCKX, B. BERGNER, W. R. MULLER, A. WARANIS, T. A. HANEY, S. L. BARKER, M. D. LOBERG, and A. YARNAIS

Downloaded by IOWA STATE UNIV on February 21, 2017 | http://pubs.acs.org Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch009

The Squibb Institute for Medical Research, New Brunswick, NJ 08903

The short l i v e d p o s i t r o n - e m i t t e r Rb-82 ( t 1/2=1.26m) has p o t e n t i a l a p p l i c a t i o n in c a r d i o v a s c u l a r diagnos t i c nuclear medicine. A generator system c o n t a i n ing the parent Sr-82 has been developed that will provide an eluate o f Rb-82 s u i t a b l e f o r d i r e c t in fusion. The Rb-82 i s eluted by a syringe pump from a hydrous stannic oxide column in a continuous stream of p h y s i o l o g i c a l s a l i n e s o l u t i o n . The r a t e o f elu tion ( i n f u s i o n ) can be c o n t r o l l e d from 10 to 100 ml/ min. At e l u t i o n rates o f 25, 50, and 75 ml/min, 100% o f l a b e l potency (Rb-82 a c t i v i t y d i v i d e d by Sr-82 a c t i v i t y X 100) is d e l i v e r e d i n 47, 51, & 57 ml, r e s p e c t i v e l y . At these same e l u t i o n rates the peak of Rb-82 a c t i v i t y (bolus) emerges i n 45 sec, 22 sec, and 15 sec, r e s p e c t i v e l y . The breakthrough o f Sr-82 i s t y p i c a l l y l e s s than 1 x 10- u C i Sr-82/ml/mCi Rb-82 i n 50 ml. A p o s i t r o n s e n s i t i v e detector moni tors and i n t e g r a t e s the eluted activity. This in strument may be s e t to s e l e c t any f r a c t i o n of the eluate a c t i v i t y f o r a d m i n i s t r a t i o n and to terminate, the d e l i v e r y at any preset dose. 5

Rubidium-82 ( t 1/2=1.26 min) i s produced by e l e c t r o n capture de cay o f Sr-82 ( t 1/2=25 days). As an a l k a l i metal c a t i o n , the p h y s i o l o g i c a l behavior o f rubidium i s analagous to potassium and, t h e r e f o r e , has been considered as a d i a g n o s t i c agent f o r myocardial p e r f u s i o n s t u d i e s . B e n e f i t s of Rb-82 over other r a d i o n u c l i d e s f o r d i a g n o s t i c s c i n t i g r a p h y include reduced p a t i e n t and personnel r a d i a t i o n exposure ( 1) , a short h a l f - l i f e that per mits r a p i d sequential imaging to evaluate the e f f e c t s of i n t e r vention, and a decay scheme that permits f u l l u t i l i z a t i o n of p o s i t r o n emission tomography. Rubidium-82 can be conveniently obtained on demand from a r a d i o n u c l i d e generator system loaded with parent Sr-82, p r o v i d i n g the r a d i o n u c l i d i c separation i s e f f i c i e n t enough to insure the absence o f l o n g - l i v e d Sr-82 i n the generator e l u a t e . 0097-6156/ 84/ 0241 -0135506.00/ 0 © 1984 American Chemical Society

Knapp and Butler; Radionuclide Generators ACS Symposium Series; American Chemical Society: Washington, DC, 1984.


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P r e v i o u s l y reported Sr-82/Rb-82 generators have been based upon both organic (2) and inorganic (.3,4) exchangers (Table I ) . Organic r e s i n s , such as Bio-Rex 70 and Chelex 100, are subject to r a d i o l y t i c degradation which may reduce radiochemical separation e f f i c i e n c y and may produce chemical, and p o s s i b l y pyrogenic, con taminants. R a d i o l y t i c a l l y s t a b l e i n o r g a n i c exchangers are there fore p r e f e r r e d . The i d e a l Rb-82 generator would maintain low Sr-82 breakthrough a t high e l u t i o n r a t e s with p h y s i o l o g i c e l u e n t s . I t must a l s o provide a high y i e l d of Rb-82 and be usable f o r large numbers o f e l u t i o n s . Drawbacks to many other promising systems included the need to maintain a high eluent pH and use of hyper t o n i c eluent ( 4 ) . Recent i n v e s t i g a t i o n s (5^,6) have focused a t t e n t i o n on hydrous t i n oxide as a s u i t a b l e adsorbent f o r Sr-82. As with other hydrous metal oxides, such as alumina and z i r c o n i a , t i n oxide i s an amphoteric i o n exchanger that e x h i b i t s c a t i o n ex change p r o p e r t i e s at b a s i c pH. Hydrous t i n oxide, however, ap pears to be p a r t i c u l a r l y favored by v i r t u e o f i t s high S r ( l l ) d i s t r i b u t i o n c o e f f i c i e n t (Kd*=Sr-bound/Sr-free) and high separation f a c t o r , K d [ S r ( l l ) / R b ( l ) ] , over a broad pH range (Table I I ; Figure 1). The p o t e n t i a l y i e l d o f a Rb-82 generator i s d i c t a t e d by the nature o f s e c u l a r e q u i l i b r i u m . Thus, the a c t i v i t i e s o f parent (Sr-82) and daughter (Rb-82) are n e a r l y equivalent at e q u i l i b r i u m (Rb-82/Sr-82 = 1.00004). A f t e r s e p a r a t i o n o f the Rb-82 by genera tor e l u t i o n , e q u i l i b r i u m i s r e - e s t a b l i s h e d q u i c k l y . The f r a c t i o n a l regeneration o f daughter a c t i v i t y i s given by (Eq. 1): A(T)/A(eq) = ( l - e ~

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(1)

where λ = decay constant f o r Rb-82. A Sr-82/Rb-82 generator i s 75% recharged at 2.5 minutes and 95% recharged at 5.4 minutes. As a consequence o f the short daughter h a l f - l i f e , generator y i e l d s are dependent on the eluent flow r a t e . For bolus e l u t i o n s , maxi mum flow r a t e and minimum dead volume are r e q u i r e d to minimize the l o s s o f Rb-82 through decay during t r a n s i t to the subject. In a continuous i n f u s i o n mode, the e x t r a c t i o n y i e l d (and hence the a t t a i n a b l e steady s t a t e i n f u s e d r a d i o c o n c e n t r a t i o n ) w i l l increase with flow r a t e . A f u l l d i s c u s s i o n o f e l u t i o n k i n e t i c s f o r genera tor produced isotopes of short h a l f - l i f e has been given by Guillaume and Brihaye ( 2 ) , who have observed that the c l i n i c a l l y optimum flow r a t e w i l l be that which d e l i v e r s the minimum volume necessary to achieve an image o f d i a g n o s t i c v a l u e . T h i s may be achieved at an intermediate, r a t h e r than at maximum, flow r a t e . When d e a l i n g with a s h o r t - l i v e d r a d i o n u c l i d e generator, an i n f u s i o n system w i l l be needed f o r e l u t i o n of the generator, r e cording o f p a t i e n t dose, and a d m i n i s t r a t i o n of the a c t i v i t y . The e f f e c t i v e u t i l i z a t i o n of 76 sec Rb-82 w i l l depend on i t s r a p i d e x t r a c t i o n from the generator. Thus, the foremost feature o f an i n f u s i o n system w i l l be the attainment of a high and uniform flow


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r a t e . Furthermore, other considerations i n the design of an i n f u s i o n system should include the f o l l o w i n g : 1. The pharmaceutical requirement to maintain eluate s t e r i l i t y and a p y r o g e n i c i t y , 2. Minimum dead volume o f eluate tubing to reduce decay during a d m i n i s t r a t i o n , 3. P h y s i c a l strength to withstand frequent use over long periods, 4. Control o f volume and r a t e o f d e l i v e r y , 5. Real-time d i s p l a y of e l u t e d a c t i v i t y and the means o f terminating the i n f u s i o n at a pre-set p a t i e n t administered dose, 6. Choice o f continuous or bolus i n f u s i o n modes, and 7. V a l v i n g to d i v e r t low s p e c i f i c concentration eluate to "waste". Syringe d e l i v e r y systems containing many of these f e a tures have been developed at the U n i v e r s i t y of C a l i f o r n i a (8-11), and t h i s system i s described i n d e t a i l by Yano, Budinger, Cahoon and Huesman i n t h e i r chapter i n t h i s volume. We have developed and tested a Rb-82 i n f u s i o n system that incorporates a l l o f these features (Figure 2). The system i s a mobile, s e l f - c o n t a i n e d pump, generator, and dosimeter (Figure 3 ) . The electromechanical syringe pump can be set to d e l i v e r s a l i n e at any flow r a t e from 10 to 100 ml/minute. S a l i n e i s t r a n s f e r r e d through s t e r i l e tubing to a 150 ml s t e r i l e , disposable p l a s t i c syringe. Check valves at the syringe output a u t o m a t i c a l l y d i r e c t the eluent i n e i t h e r f i l l i n g or i n f u s i o n modes. The generator i s connected to the system by s t e r i l e , PVC l u e r - l o c k tubing and i s contained w i t h i n a lead s h i e l d one and one h a l f inches t h i c k . The eluate a c t i v i t y i s c a r r i e d through PVC tubing past a r a d i a t i o n de t e c t o r and through a two-way microprocessor c o n t r o l l e d v a l v e , which d i r e c t s the eluate to e i t h e r the subject or to a waste c o l l e c t i o n b o t t l e , both o f which terminate i n a 0.22 μ s t e r i l i z i n g filter. The p o s i t i o n of t h i s valve i s determined by the e l u t i o n mode s e l e c t e d at the c o n t r o l module. The i n f u s i o n system may be set to e l u t e the generator a t any preset flow r a t e i n any of the f o l l o w i n g modes: 1. Volume p r i o r i t y , i n which the i n f u s i o n w i l l stop when the p a t i e n t has r e c e i v e d a preset volume ( m l ) . 2. Dose p r i o r i t y , i n which the i n f u s i o n w i l l stop when the p a t i e n t has r e c e i v e d a preset dose (mCi). 3. Bolus p r i o r i t y , i n which the eluate i s d i r e c t e d i n i t i a l l y to the waste c o l l e c t i o n b o t t l e u n t i l the onset of the bolus (adjustable onset l e v e l , mCi/sec) d i v e r t s the eluate stream to the p a t i e n t l i n e u n t i l the preset dose i s accumulated. Experimental Generator P r e p a r a t i o n . Strontium-82 i s obtained from Los Alamos National Laboratory (LASL). The isotope i s produced by a high energy s p a l l a t i o n r e a c t i o n on molybdenum and the p u r i f i e d mixture contains other strontium isotopes, notably Sr-83/Rb-83 and Sr-85.


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F i g u r e 3. M o b i l e , s e l f - c o n t a i n e d i n f u s i o n s y s t e m f o r Rb-82 g e n e r a t o r .



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R a d i o n u c l i d i c analyses are performed with e i t h e r a l i t h i u m - d r i f t e d germanium or i n t r i n s i c germanium d e t e c t o r . The assay f o r Sr-82 i s based upon i t s 777 keV photon of 13.6% abundance. Strontium-85, which i s o f t e n present i n amounts comparable to that o f Sr-82, i s assayed by i t s 514 keV photopeak, which must be resolved from prominent 511 keV a n n i h i l a t i o n r a d i a t i o n by a curve s t r i p p i n g procedure (L2). Up to 150 mCi of Sr-82 ( c o n t a i n i n g up to 300 mCi of Sr-85) i s t r a n s f e r r e d to a column containing hydrous t i n oxide. The column i s washed with 0.9% sodium c h l o r i d e to remove Rb-83 radiocontami n a n t s . This column i s f i t t e d with l u e r - l o c k connectors to f a c i l i t a t e i t s use with s t e r i l e PVC tubing. The generator i s eluted with 0.9% sodium c h l o r i d e . The eluent i s d e l i v e r e d by the syringe pump of the i n f u s i o n system. Eluates are c o l l e c t e d i n 50 ml stoppered v i a l s f o r nuclear and chemical analyses. Rb-82 may be conv e n i e n t l y measured i n an i o n chamber (dose c a l i b r a t o r ) . We have confirmed that the potentiometer s e t t i n g recommended by the i n strument manufacturer (Capintec, Montvale, Nj) i s accurate. A sample of f r e s h l y eluted Rb-82 was measured by both a dose c a l i brator and, a f t e r s u i t a b l e decay, a c a l i b r a t e d G e ( L i ) spectrometer system. Data f o r both instruments l a y along a s i n g l e exponential decay of 76 sec h a l f - l i f e . Our e v a l u a t i o n of the Sr-82/Rb-82 generator performance i s based p r i m a r i l y on measurement of y i e l d , breakthrough, and e l u t i o n p r o f i l e . Y i e l d . The Rb-82 content of 50 ml of e l u a t e , decay c o r r e c t e d to end of e l u t i o n , c o l l e c t e d at 50 ml/min i s measured i n a Capintec CRC-17 dose c a l i b r a t o r using the potentiometer s e t t i n g recommended by the manufacturer f o r Rb-82. While t h i s datum i s not as s i g n i f i c a n t as the dynamic y i e l d information obtained from measurement of e l u t i o n p r o f i l e s , i t i s valuable i n p r e l i m i n a r y development work and i n monitoring the performance of a given u n i t through an extended use p e r i o d . Breakthrough. Eluate r a d i o n u c l i d i c p u r i t y i s determined by Nal s c i n t i l l a t i o n spectrometry on 50 ml of e l u a t e . Samples must be held at l e a s t one hour before measurement to allow f u l l decay of Rb-82. To improve s e n s i t i v i t y o f measurement, the most prominent 511+514 keV peak i s counted. Computations are based upon comparison with an a l i q u o t of Sr-82+Sr-85 s o l u t i o n used to prepare the generator.. Data are expressed i n u n i t s of y C i Sr-82/ml of eluate/ mCi Rb-82 at end of e l u t i o n . E l u t i o n P r o f i l e . E l u t i o n p r o f i l e s are determined with the i n - l i n e r a d i a t i o n detector. For c a l i b r a t i o n of the i n - l i n e detector, equations developed f o r q u a n t i t a t i v e radiochromatography may be adapted. For a s i n g l e d e t e c t o r , isotope, and geometry, which i s i n e f f e c t c o n t r o l l e d by the tubing used to c a r r y the eluate past the detector, a simple expression can be w r i t t e n (Eq. 2): A = C-F/K


(2)



144

where A = the i n t e g r a t e d a c t i v i t y i n mCi; C = counts; F = flow r a t e of eluate i n ml/min; and Κ = constant of p r o p o r t i o n a l i t y . The flow r a t e term i s kept independent of the p r o p o r t i o n a l i t y constant to allow f o r separate adjustment of the flow r a t e without the need to r e a d j u s t the c a l i b r a t i o n f a c t o r f o r the d e t e c t o r . Thus, the s c a l e r s on the dosimeter module may be set to d i s p l a y i n mCi of Rb-82, since the c i r c u i t incorporates an adjustable pulse d i v i d e r corresponding to the p r o p o r t i o n a l i t y constant. In a d d i t i o n to d i s p l a y i n g the a c t i v i t y of Rb-82 passing the detector at any i n s t a n t , the second s c a l e r provides a summation of t o t a l a c t i v i t y e l u t e d . The flow r a t e constant, F, i s set equal to the flow r a t e c o n t r o l of the i n f u s i o n pump. The c a l i b r a t i o n of the i n - l i n e detector i s accomplished by comparing the e n d - o f - e l u t i o n c o l l e c t e d dose (as measured i n a dose c a l i b r a t o r ) to the d i f f e r e n t i a l e l u t i o n p r o f i l e (as measured by the i n - l i n e d e t e c t o r ) . With data c o l l e c t i o n at 1 sec i n t e r v a l s , a 50 ml e l u t i o n at 50 ml/min w i l l produce 60 data p o i n t s ( t O , each of which must be c o r r e c t e d to e n d - o f - e l u t i o n . The c a l i b r a t i o n f a c t o r f o r the i n - l i n e detector may be c a l c u l a t e d from a s i n g l e e l u t i o n (Eq. 3) where EOE i s the end of e l u t i o n . ΣΝ. e ^ K

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Results and D i s c u s s i o n The Rb-82 generators thus prepared were evaluated by r e p e t i t i v e , high volume e l u t i o n s using the i n f u s i o n system described e a r l i e r . Eluent was e x c l u s i v e l y s t e r i l e , 0.9% sodium c h l o r i d e s o l u t i o n with c o l l e c t i o n s made i n t o s t e r i l e , vented serum v i a l s .

Y i e l d . The Rb-82 content of 50 ml eluates c o l l e c t e d at 50 ml/min i s 71.7±6.5% of the Sr-82 potency of the generator. Frequent e l u t i o n s over extended periods w i l l s l i g h t l y improve t h i s value. 4 f t e r three weeks e l u t i o n with 2 l i t e r s o f 0.9% sodium c h l o r i d e , the c o l l e c t e d end of e l u t i o n y i e l d w i l l be 5-10% greater than i n i t i a l yields. 1

E l u t i o n P r o f i l e . The d i f f e r e n t i a l e l u t i o n p r o f i l e s at three d i f f e r e n t flow r a t e s are shown i n Figure 4. As expected, the Rb-82 y i e l d improves at f a s t e r flow r a t e s with l e s s a c t i v i t y being l o s t to decay. I n t e g r a l outputs are shown i n Figures 5 and 6. These values represent, r e s p e c t i v e l y , the administered dose and the c o l l e c t e d dose. The former data, which represent the i n t e grated dosimeter readings of the o n - l i n e d e t e c t o r , must be con sidered i n e s t a b l i s h i n g the d u r a t i o n of i n f u s i o n c o n s i s t e n t with



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Figure h. Elution p r o f i l e of Rb-82 as a function of time for three selected flow rates.


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146 RADIONUCLIDE GENERATORS


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Δ 75 ml/min

(Minutes) F i g u r e 6. S t e a d y - s t a t e a d m i n i s t e r e d a c t i v i t y f r o m a Rb-82 g e n e r a t o r a s a f u n c t i o n o f t i m e f o r t h r e e s e l e c t e d flowrates .

American Chemical Society Library 1155 16th St. N. W. Knapp and Butler; Radionuclide Generators Washington. D. C. 20038 ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

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the p a t i e n t absorbed dose. The l a t t e r data, which are decay c o r r e c t e d , i n d i c a t e the i n - v i v o r a d i o c o n c e n t r a t i o n during the i n f u s i o n . At a nominal flow r a t e of 50 ml/min, approximately 8 0 % of the f u l l generator potency w i l l be a v a i l a b l e f o r d i a g n o s t i c imaging. Chemical P u r i t y . Selected eluates from a 4 l i t e r e l u t i o n program were subjected to analyses f o r chemical and b i o l o g i c a l p u r i t y . At the end o f four weeks o f continued use, during which 4 l i t e r s of eluate were c o l l e c t e d , samples were s t e r i l e and non-pyrogenic. I s o t o n i c i t y was confirmed (NaCl = 8.94±.03 mg/ml) and n e u t r a l i t y maintained (pH = 6.27±0.16). No t i n was detected i n generator eluates by d i f f e r e n t i a l pulse polarography above a d e t e c t i o n l i m i t o f 0.1 yg/ml. The r a d i o n u c l i d i c i d e n t i t y o f Rb-82 i s e a s i l y confirmed by v e r i f i c a t i o n of i t s 76 sec h a l f - l i f e or through gamma spectrometry. Breakthrough. Strontium-82 contamination of e l u a t e s from three generators i s shown i n F i g u r e 7 f o r t o t a l e l u t i o n volumes o f 4 liters. Breakthrough i s l e s s than 1 χ 10 y C i Sr-82/ml/mCi Rb-82 throughout the t e s t p e r i o d . Other generators have been e l u t e d to t o t a l volumes o f 20 l i t e r s , with no i n c r e a s e i n break through above 1 χ 10 y C i Sr-82/ml/mCi Rb-82. Furthermore, low breakthrough l e v e l s are maintained up to flow r a t e s o f 100 ml/min (Figure 8 ) . Summary The rubidium-82 eluate from t h i s generator system i s pharmaceutic a l l y s u i t a b l e f o r d i r e c t venous i n f u s i o n . Imaging may be based on p o s i t r o n emission tomography (1^) . A l t e r n a t i v e l y , images o f d i a g n o s t i c q u a l i t y should be a n t i c i p a t e d from s i n g l e photon de t e c t i o n systems, provided that the instrumentation i s compatable with these high energy photons. The f e a s i b i l i t y o f modifying con v e n t i o n a l instruments f o r Rb-82 has been demonstrated by Ryan, e t . a l . ( 1 4 ) and Cochavi, £t.al. (15). Thus Rb-82, as produced and administered by t h i s system, may have p o t e n t i a l c l i n i c a l u t i l i t y f o r myocardial p e r f u s i o n (16) , e v a l u a t i o n o f b r a i n tumors (1J3), and kidney imaging ( 15) . Literature Cited 1. 2. 3. 4.

K e a r f o t t , K.J. J. Nucl. Med. 1 9 8 2 , 2 3 , 1128-1132. Yano, Y.; Roth, E. P. I n t . J. Appl. Radiat. Isotopes 1979, 3 0 , 382-385. K u l p r a t h i p a n j a , S.; Hnatowich, D.J.; Beh, R. I n t . J. A p p l i e d Radiat. Isotopes 1979, 3 0 , 447-449. Horlock, P.L.; C l a r k , J.C.; Goodier, I.W.; Barnes, J.W.; Bentley, G.E.; Grant, P.M.; O'Brien, H.A. J . Radioanal. Chem. 1 9 8 1 , 6 4 , 257-265.


150 5.

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N e i r i n c k x , R.D.; Kronauge, J.F.; Gennaro, G.P.; Loberg, M.D.; Los Alamos Medical Radioisotope Group, J. Nucl. Med. 1982, 23, 245-249. Brihaye, Cl.; Guillaume, M.; Cogneau, M. Radiochem. Radioa n a l . L e t t e r s 1981, 48, 157-164. Guillaume, M.; Brihaye, Cl. J. Biophys. Med. Nucl. 1982, 6, 137-142. Yano, Y.; Anger, H.O. J . Nucl. Med. 1968, 9, 412-415. Budinger, T.F.; Yano, Y.; Hoop, B. J. Nucl. Med. 1975, 16, 429-431. Yano, Y.; Budinger, T.F.; Chiang, G.; O'Brien, H.A.; Grant, P.M. J . Nucl. Med. 1979, 20, 961-966. Yano, Y.; Cahoon, J.L.; Budinger, T.F. J . Nucl. Med. 1981, 22, 1006-1010. Waters, S.L.; B u t l e r , K.R.: C l a r k , J.C.; Horlock, P.L.; Kensett, M.J.; Goodier, I.W.; Makepeace, J . ; Smith, D.; Woods, M.J.; Barnes, J.W.; Bentley, G.Ε.; Grant, P.M.; O'Brien, H.A. I n t . J . Appl. Radiat. Isotopes 1983, in p r e s s . Yen, C.-K.; Yano, Y.; Budinger, T.F.; F r i e d l a n d , R.P.; Derenzo, S.E.; Huesman, R.H.; O'Brien, H.A. J . Nucl. Med. 1982, 23, 532-537. Chua, K.G.; Ryan, J.W.; A l - S a d i r , J . ; Resnekov, L.; Harper, P.V. IX World Congress of Cardiology, Moscow, June 20-26, 1982. N e i r i n c k x , R.D.; Cochavi, S.; Gennaro, GP.; Loberg, M.D.; Kronauge, J.F.; Goldsmith, S.L.; O'Brien, H.A. III World Congress of Nuclear Medicine and B i o l o g y , P a r i s , Aug. 29 Sept. 2, 1982. Budinger, T.F.; Yano, Y.; Derenzo, S.E.; Huesman, R.H.; Cahoon, J.L.; Moyer, B.R.; Greenberg, W.L.; O'Brien, H.A. J . Nucl. Med. 1979, 20, 603.

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August 19, 1983


A Radionuclide Generator and Infusion System for Pharmaceutical

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