Thursday, April 19, 2012

How Does the New Generic Cosyntropin Compare to Cortrosyn for ACTH Stimulation Testing?


PAPER REVIEW

Comparison of IV and IM Formulations of Synthetic ACTH
for ACTH Stimulation Tests in Healthy Dogs
by T.A. Cohen, and E.C. Feldman
Journal of Veterinary Internal Medicine 2012;26:412-414.

Background

Corticotropin (adrenocorticotropic hormone or ACTH) stimulation testing is widely accepted as the gold standard for confirming a diagnosis of hypoadrenocorticism in dogs and cats. The test is also commonly used as as a screening test for hyperadrenocorticism (Cushing's syndrome). Finally, the ACTH stimulation test is widely accepted as the best means of monitoring medical therapy for hyperadrenocorticism with either mitotane or trilostane (1).

Natural ACTH is a single-chain 39-amino acid peptide hormone synthesized in the corticotrophs of the anterior lobe (pars distalis) of the pituitary gland. Although the amino acid sequence of ACTH varies among species, the first 24 amino acids are identical among all species studied (2). Canine ACTH differs from human ACTH by only one amino acid residue, at position 37, although the amino terminal end of the ACTH molecule (amino acids 1-18) is responsible for its biologic activity.

Cosyntropin is a synthetic form of ACTH, which was created by isolating the first 24 amino acids from the 39-amino acid ACTH peptide. Since the introduction of cosyntropin to the veterinary literature 3 decades ago (3), this synthetic ACTH preparation (marketed as Cortrosyn, Amphastar Pharmaceuticals) has gained popularity and is currently recommended as the ACTH preparation of choice for use in dogs and cats (1).

Cortrosyn is available  as a sterile lyophilized powder in vials containing 0.25 mg of cosyntropin (4).  Once the lyophilized powder is reconstituted with 0.9% sodium chloride, the ACTH solution can be administered either by IV or IM injection with similar cortisol responses.

Recently, a 1-ml liquid form of generic cosyntropin that does not require reconstitution has become commercially available through Sandoz, Inc (5). This sterile solution contains 0.25 mg of cosyntropin.  The amino acid sequence of this generic cosyntropin product is identical to Cortrosyn, suggesting that the biologic activity of the generic product should be similar to that of the brand name Cortrosyn preparation. However, the manufacturer recommends that this generic liquid form of synthetic ACTH be given by the IV route only, and that any unused portion of the vial be discarded (5).

When considering use of one of these cosyntropin products versus the other, the question that can be raised is whether or not their biologic activities are comparable. If each testing agent causes maximal stimulation of cortisol from the canine and feline adrenal cortex, then these diagnostic testing products could be used interchangeably.  That is the question that was addressed in this study by Cohen and Feldman (6).

Objectives of study
To compare the biologic activity of the liquid and lyophilized forms of cosyntropin.

Methods
Eighteen privately owned healthy dogs were studied. Dogs were assigned to one of 2 groups of 9 dogs each. Group 1 dogs were tested with the lyophilized product first and the liquid solution 30 to 60 days later. The Group 2 dogs were tested with the liquid solution first and then tested with the lyophilized drug 30 to 60 days later.

For the ACTH stimulation tests, serum samples were collected before and 1 hour after IM administration of 0.25 mg reconstituted lyophilized product, or 1 hour after IV administration of 0.25 mg of liquid solution. Cortisol concentrations of all serum samples were measured by use of a commercial cortisol radioimmunoassay.

Results
Serum cortisol concentrations before and after ACTH stimulation did not differ significantly between groups (P = .57). In addition, no individual dog had as much as a 20% difference in serum cortisol concentrations after administration of either ACTH formulation.

Conclusions of study
Given the lack of significant differences of the ACTH stimulation test results, the lyophilized and liquid solution products can be used interchangeably.

My Bottom Line:

The results of this study suggest that injection of generic cosyntropin (liquid solution) stimulates adrenocortical secretion to an equivalent degree, as compared with Cortrosyn (lyophilized product). However, many questions about this generic cosyntropin product still need to be answered before it can be strongly recommended for use in dogs and cats.
  1. First of all, only 18 clinically normal dogs were tested in this study (6). It would be very important to repeat the study in dogs with known adrenal disease to verify that both diagnostic testing preparations were truly equivalent for diagnosis of hypo- and hyperadrenocorticism.
  2. Secondly, with Cortrosyn, it has been clearly shown that this product can be administered to dogs by either the intravenous or intramuscular routes with comparable results. Since IM administration can be more convenient in some cases, it would be of interest to investigate if the generic product could be given by that route or if it must be administered IV, as the insert states.
  3. Thirdly, with Cortrosyn, it is common practice to dilute the product and administer lower doses (e.g., 5 μg/kg) of the cosyntropin to dogs (1, 7-9).  Since only a portion of the vial would be used in most dogs, the remaining cosyntropin is divided into aliquots and stored frozen for up to 6 months.  Can the generic product be diluted? And if so, will it maintain its potency when stored for months for later use? We simply don't know — the product insert states that "cosyntropin injection is intended as a single dose injection and contains no antimicrobial preservative; any unused portion should be discarded."
  4. Finally, for reasons that are unclear to me, the current cost of a single vial of this generic preparation (≈$99 per vial) is about 30% more than the cost of an identical amount of Cortosyn.  Why would a generic product cost more than a time-honored brand-name product?
For all of the reasons listed above, I plan to continue using the lyophilized Cortosyn® preparation for  ACTH stimulation testing. 

References:
  1. Melián C, M. Pérez-Alenza, D, Peterson ME. Hyperadrenocorticism in dogs, In: Ettinger SJ (ed): Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat (Seventh Edition). Philadelphia, Saunders Elsevier, 2010;1816-1840.
  2. Eipper BA, Mains RE. Structure and biosynthesis of pro-adrenocorticotropin/endorphin and related peptides. Endocrine Reviews 1980;1:1-27. 
  3. Feldman EC, Stabenfeldt GH, Farver TB, et al. Comparison of aqueous porcine ACTH with synthetic ACTH in adrenal stimulation tests of the female dog. American Journal of Veterinary Research 1982;43:522-524.
  4. Cortrosyn Injection, package insert. Rancho Cucamonga, CA: Amphastar Pharmaceuticals, Inc.  
  5. Cosyntropin Injection (Generic), package insert. Princeton, NJ: Sandoz Inc.
  6. Cohen TA, Feldman EC. Comparison of IV and IM formulations of synthetic ACTH for ACTH stimulation tests in healthy dogs. Journal of Veterinary Internal Medicine 2012;26:412-414. 
  7. Frank LA, Oliver JW. Comparison of serum cortisol concentrations in clinically normal dogs after administration of freshly reconstituted versus reconstituted and stored frozen cosyntropin. Journal of the American Veterinary Medical Association 1998;212:1569-1571. 
  8. Kerl ME, Peterson ME, Wallace MS, et al. Evaluation of a low-dose synthetic adrenocorticotropic hormone stimulation test in clinically normal dogs and dogs with naturally developing hyperadrenocorticism. Journal of the American Veterinary Medical Association 1999;214:1497-1501. 
  9. Martin LG, Behrend EN, Mealey KL, et al. Effect of low doses of cosyntropin on serum cortisol concentrations in clinically normal dogs. American Journal of Veterinary Research 2007;68:555-60. 
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