Application for Investigational Exemption for a New Drug

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APPLICATION FOR INVLSTICATIONAL LK DIP TION FOR A NE!.[ DXUC FIedical and Health Sciences Division, Oak Ridge Associated NAME OF DRUG: ZINC TRISODIUM PENTETATE, TRISODLIJX ZINC PENTHAYIL, Common Chemical Name : Trisodium zinc di ethylene tr i amine penta ac etate. Common Abbreviations in the Literature : Drug Administration : The drug,supplied as a 0.50 i4 solution of ZnNa3DTPA i n water, is to be administered by either intra muscular injection of the undiluted solution,intravenous infusion(dose diluted inhalation of then ebu liz ed solution (1:l dilution with water)overa period of 15 minutes or longer.

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COXPONENTS OF THE DRUG: The concentration of the aqueous solution of ZnUajDTPh should be 0.50 ;.I gat ional stage should be small, less than 5% (0.475-0.525 ? I). Variations from this Concentration during th s invest i - SOURCE OF NEW DRUG SUBSTANCE: The ZnNa3DTPA solution to be used clinically was purchased in bulk for n nuder 4-12-6. Sigma Chemical Company has filed with the Food and DrQg Admin is r ration an IbD Plaster File which provides details of the prep a - ration of this new drug substance. METHODS, FACILITIES AND CONTROLS: The aqueous solution of ZnNa3DTPA obtained from Sigma Chemical Coz?any (see Section4) was analyzed for DTPA content by a modification of the method of Doan, Parks, and Lindenbaum [Do75]. TVJO samples from each ofthe two containers of ZnNa3DTPA were analyzed,giving an overall average DTPA concentration of 0.4932 0.002 Pi (mean -+ S.E.). Ali quo ts from each of the &IO containers were submitted to an independent laboratory which specializes in quantitative nii cro analyses (C:!lbrnith cobalt,lead,arsenic,and mercury (all by atomic absorption flame photo me try). The results,along with the theoretical v n lr les for nitrogen and zinc in a 0.50 M solution of Ztl\!a3DTPA, are tabulated below. The values for nitro g2n and zinc are i n very good agree mz ut with the theoretical values, and the analyses for the trace metals tested, most o f which are potentially toxic, are well within the acceptable levels.

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The aqueous ZnNa3DTPA solution was found to be sterile and nonpyrogenic by the standard United States Pharmacopeia techniques. glass, Wheaton Scientific,Mill ville, New Jersey) were rinsed with distilled water and then heated in an oven at2RW C for 30 miiiutes t o de sr roy the pyro gen icc on tarn i nation. Tiif ampules were then transferred to are circulating laminar fLow hood € or cooling, and all further operations through sealing the ampules were carried out in a laminar The ZnNa3DTPA solution vas micro filtered(in portions of approximately one liter,as needed) using an all - glass succ ion filtration apparatus and 47 mm diameter, 0.45 urn pore size filter discs(both from PI ill i pore Corporation,Bedford, Mass.). The filtration apparatus had previously been heated in a28OOC oven for 30 minutes. The filtered solution was transferred to the 40-ounce glass bottle of a n Oxford Model 20 dil ut or (which had also been previously heated at 28OoC for 30 minutes). The dil ut or was operated in the dispensing mode only and was equipped with a specially - built elevator assembly to enable the operator to precisely raise the ampule for filling and prevent Contamination of the neck o f the ampule with the ZnNa3L)TPA solution (where the ZnNa3DT1'A might b e decomposed during the sealing process). The dil ut or was set to dispense 4.40 ml to each ampule so <is to allow delivery of adose of 4.0 in1 t o each patient.Ina series of 10 deliveries made using this pi petting device,the difference in weight between highest and lowest was less than 1%O E the to t31 sample weight. The filled ampules were then sealed Company, Gardiner,New York) which had been modified by the manufacturer t o accept the Whearon 5-ml ampules (see above). The sealed ampules were left upright until they had cooled to room temperature. l'he sealed ampules were visually cliecked against both a white and black background using alighted magnifying glass.thy ampules containing * particulate matter were rejected. l'he ampules o f ZnNa3UTl'A were t:hen ste an sterilized at 121'C and about 15 psi steam pressure for 30 minutes. Included with each batch o € Troy,Michigan)., The autoclave was a1lol;ed to cool at the liquid cool setting for at least 30 minutes before the door was opened. 'The Attest

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indicators were incubated at 56OC for 48 hours as required by the directions and observed for growth. Control indicators, which had not been sterilized, were incubated with the sterilized mpu les and immediately after sterilization for evidence that the desired 121OC steam temperature had been achieved. The Dia ck autoclave controls were visually checked Six randomly - selected ampules were analyzed for sterility and pyrogeni city by standard United States Pharmacopeia techniques.All results were negative.In addition,six ampules were randomly chosen and analyzed for DTPA content by the modification of the method of Doan, Parks, and Lindenbaum [Do75], giving a DTPA concentration of ampules weighed before and after steam sterilization showed no weight A brief toxicity study was done to look for any major differences between the toxicity of the packaged ZnNa3DTPA and the published The LD50 for intra peritoneal ly administered ZnNa3DTPA in the adult HAIICRmice. Controls were given an intra peritoneal injection of dosage levels of ZnNa3DTPR (from randomly selected ampules of the drug) : 15,17,19,23,27, and 3 1 mmol/kg. The results, which are tabulated approximately 600 times the human intravenous dose. The test mice were administered six intra peritoneal Number of deaths Dr. C . Id. Mays arid co-workers at the University of Utah conducted a mouse fetal toxicity study using the same batch of Sigma ZnNa DTPA ,that we packaged for human use.At a daily dose of 11.5 mmol?kg (400 times the human dose),the only fetal effect observed was as light reduction in the average birth weight (see Appendices A and B). Because of the Long-term stability which has been observed for aqueous solutions of CaNa3DTPA (Calcium Chel 330), no decomposition of the ZnNa3DTPA solution is expected. llowever, 3s a precautionary measure, randomly - selected ampules of ZnNa3DTPA will be assayed for DTPA content, pfl, sterility, and pyro geni city quarterly during the first

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'l'lie Food and Drug Ad in iiii st ration will be no tiLled should Any significant alter at lons be observed. Recciuse of tile expected long-term sts bill ty of tlic drug aiid the precautionary as says which will be performed, no expiration date is proposed for ZnNapTPA. Throughout the following discussion, Zn-DTPA refers to ZnNa3DTPA, I n much of the cited literature che late doses are given in moleslkg. Reference mmol/kg, mg/kg, and the relation to the usually employed dose in man for Zn-DTPA and Ca-DTPA are compared in the table below. For the 70 kg standard man the human intravenous dose,H.I.D., is ona molar basis. The dose for Zn-DTPA i s equivalent Mode of action.As with Ca-DTPA, Zn-DTPA functions to remove toxic metals by exchanging its cations for metals that form more stable complexes with the DTPA ligand. The log stability constant for Zn-DTPA and the DTPA complexes with several transuranium(actinide)cations is given in the table below [Mo69]. The stability constants for the Cat ion Log K actinide ch elates are greater by factors of approximately LO6 - 10, which favors the exchange of the actinide for Zn and the for s ation of

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chclatcs resist ex hari g in ; : their actinide io:is vit!l body ligands and are rapidly excreted €rom thz body primarily in urine [Pa71]. Thus, onc2the act in id2 DTPA c ' nel zte is formed, it prevent sac qui - s it ion oE that actinide by body tissues and by hastening excretion of the radioactive actinide fron ihe body decreases the rdi ation Rationale for use of Zn-DTFh. hlherens Ca-DTPX, already available under IiW 4041, can be used for ch elation therapy of internally deposited actinide con tani nation,it has been shown to cause excretion transient and of insufficient magnitude under the usual treat nen t protocols to cause harm. However, under cond i rions of,or approaching, constantin fu sio a the effect becomes al nost additive [ Ca68a,b, Na711 and has caused severely toxic,even lethal,effects in a few days in animal studies 151174, Ta74, P175]. Zn-DTPA is some 30 times less toxic tissues, Ca-DTPA enhances the actinide excretion rate considerably nqre than equivalent a aou nt so € Zn-UTPA; however, after approximately one day Za-DTPA is for practical purposes as effective as the Ca salt multiple protracted t rearm nt,switching from Ca-DTPA t o Zn-DTPA alter the first day decreases the possibility of toxic effects due to trace net al depletion without affecting the efficacy of decontamination. Zg-DTPA can also be used in certain cases i n which the use of Ca - DTPA is contra indicated. Thus in those cases which require Zn-DTPA treat iw nt,it is first necessary to summarize the major poin:s of ch elation therapy with Ca - DTPA,since the two agents are i n many respects very sinilar. At present, Ca-DTPA (available under IN D 4041) is the only available a gz nt for tile removal of internally deposited trn n sura niu in elements in man [Ca76J. Ca-DTPA has been used success € ully in man for dc corporation of internally deposited americium CSm72, Wr72, recent usage of Ca-DTPA € or ch elation therapy in the United States (including records on one patient who rc ce i ved Zn-UPh o n an emergency basis) is given in the table belcir. To ta Is 132 s90 658 2 32 Aver age /Y ear 31 148 110 39 One patient received 299 grams Zn-DTPA and 2 0 grams Ca-D-L'PA.

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The efficacy of Ca-D'SPA is quite good in the case of soluble actinide compounds but is extremely poor o r even nil in the case of polymeric or highly insoluble compounds of che radio nuclides. For example, Ca-DTPA, administered either by systemic or local methods, is totally ineffective in removing PuO2 from an intra muscular depositor from the lung.In sucli cases, surgical excision of the contaminated tissue and lung lava ge,respectively, are the only successful therapeutic methods [Ca76 3 . The fraction of radio nuclide contamination removable with CaDTPA becomes progressively smaller as the time interval between incorporation and administration of Ca-DTPA increases. The various actinides show quite different translocation patterns ; for example, plutonium is trans located largely to bone whereas americium shows a n affinity for liver. The fraction of the radio nuclide removable by Ca-DTPA from the skeleton is generally markedly lower than that from the liver.Therefore,because of this effect and the fact that plutonium compounds are generally much more insoluble than those of americium, Ca-DTP.4 therapy is usually more useful for removal o f americium than plutonium,especially if the initiation of therapy is delayed to the extent that the plutonium is largely trans located to bone ICa761. Finally, Ca-DTPA ch elation therapy is not recommended for contamination with uranium o r neptunium isotopes.In fact,use of Ca-DTPA therapy in these cases can result in greater uptake by kidney and bone respectively, with concomitant greater toxicity to these tissues,than if no ch elation therapy had been used. The overall efficacy patterns for Zn-DTPA are expected to be quite similar to those described above for Ca-DTPA. However, Ca-DTPA hasa number of contra indications associated with its use (because of its toxicity through trace metal depletion, see Rationale section). Ca-DTPA is contra indicated for minors and for such conditions as pregnancy, ne ph ros is, and depressed my elo poi e tic activity,e.g.,leukopenia, thrombocytopenia, etc. ICa761. These conditions are not contra - indications for the use of Zn-DTPA. Perhaps more important is the fact that the toxicity of Ca-DTPA, but not that of Zn-DTPA, is dr asti - call y increased with a highly prolonged or fraction a ted treatment The toxicity of Ca-DTPA for protracted administration,coupled with the other contra indications to its use as stated above, form the basis for this application for use of Zn-DTPA i n humans. Zn-DTPA has been shown to effectively remove 241Am from the rat (Se72, and the baboon [Co76a,b]. The agent has also been used effectively for removal o f 239Pu from the rat [Se71,72 [Se76] from the rat. id it hall actinides studied, comparison of the efficacy of Zn-DTPA with that of Ca-DTPA gives similar results. For prompt treatment with the chel sting agent (<24 hours after administraci on of the isotope),Ca - DTPA is significantly more effective than Zn-DTPtZ i n removing internally