Prednisolone

Bioavailability Monograph

As research and study regarding the bioavailabiJity of drug products continue, additional information will be made available adding to and/or altering the information and conclusions contained in this monograph. Drug manufacturers and others who conduct bioavailability studies of drug products are encouraged to submit their results immediately to APhA. Monographs will be revised and updated periodically to reflect new information, and where necessary special announcements regarding new data will appear in this journal.

Prednisolone is a potent corticosteroid which possesses about four times the anti-inflammatory activity of hydrocortisone while causing less salt and water retention. Close supervision is recommended for patients receiving the agent. Doses should be individualized according to the severity and prognosis of the disorder, patient response and the anticipated duration of therapy. Furthermore, the dosage should be minimized to balance control of specific symptoms with reduction of undesirable effects. Prednisolone has been included in a list of substances susceptible to bioavailability problems.1.2 Its inclusion may have been a result of its chemical similarity to prednisone for which inequivalence in absorption has been reported 3 or because prednisolone has a low solubility in water. Biological inequivalence of prednisolone tablets has not been demonstrated. To maximize therapy, prednisolone products should exhibit optimum bioavailability characteristics consistently . Unless bioequivalence has been demonstrated, brand interchange with this agent is not advisable. The Drug Entity

General Characteristics-Prednisolone is reported to be completely absorbed, based upon urinary recovery of radioactivity exceeding 98 percent of the dose after oral administration of 414C-prednisolone in dilute ethanol. 4 Further confirmation of the extent of absorption is not available. Urinary quantitation is difficult in the absence of radioactivity since only about 10 percent of the dose is excreted unchanged 5 while the remainder consists largely of qualitatively identified metabolites. Various specific and nonspecific an-

Vo1. NS 16, No. 3, March 1976

Prednisolone

alytical methods have been used to define the vascular prednisolone concentration-time profile after dosing. Prednisolone reportedly reaches maximum plasma concentrations from 1 to 3 hours following oral administration.5- 9 Mean half-lives of 2.5-3 .3 hours were reported for healthy fasted subjects receiving 10-20 mg of prednisolone. 6.7 . 1o After administering prednisolone (0.5 mg/kg IV) to eight normal young adults, a mean half-life of 3.2 hours was observed. 11 Changes in half-lives in diseased subjects have not been large. Prednisolone half-lives of 3.3-4 .2 hours were observed in three patients with chronic liver disease after intravenous administration of 20 mg of prednisolone disodium phosphate. 12 By using 3H_ prednisolone intravenously, a half-life of 3.7 ± 0.2 hours (mean ± SE) was found in seven patients with chronic aggressive hepatitis. 13 Eight patients with respiratory disease exhibited a half-life of 2.2 ± 0.7 hours (mean ± SE) after receiving 20 mg of prednisolone oralIy.s Large intersubject variations in the peak prednisolone level and the area under the plasma concentration-time curve were noted, suggesting that prednisolone may be prone to bioavailability problems. Finally, a mean half-life of 2.6 hours was observed in three patients with liver cirrhosis after receiving 40 mg of prednisolone phosphate intravenously, compared to the mean halflife of 1.9 hours in six normal subjects .14 Prolonged synthetic corticosteroid administration resulted in a decrease of prednisolone 's half-life to a mean of 1.4 hours in 10 patients. It has been inferred 15.16 that prednisolone binds to the corticosteroid binding globulin with a binding capacity of approximately 0.7 J..I.M (250 ng/ml).16 In addition, prednisolone binds to albumin 15.16 with the result that at a concentration of 0.5 J..I.M (180 ng/ml) it is reportedly16 bound about 90 percent in pooled normal human plasma at 37° using gel filtration. However, only about 65 percent was bound at 0.5 J..I.M using pooled normal plasma and equilibrium dialysis at 20° .12 Despite this discrepancy, both reports 12.16 noted a marked decrease in prednisolone binding in the presence of hypoalbuminemia. Dosage Forms

Physical Properties-Prednisolone as the C-21-alcohol is used in tablet formulations. In this form, its water sol-

ubility at 25° is 6 .74 X 10- 4 M (243 J..I.g/ml) 17 indicating a potential for bioavailability problems. As a result, the USP requires a minimum dissolution rate for prednisolone tablets. Analytical Methods for Bioavailability Testing Recent analytical efforts have utilized competitive protein-binding or radioimmunoassay techniques to develop a specific and sensitive prednisolone assay. Most of these methods use chromatographic procedures to separate prednisolone from endogenous steroids followed by competitive protein binding employing a natural endogenous sterOid-binding protein.10.1s.19 The best available method, a radioimmunoassay procedure,20 requires no prior separation , utilizes an antibody obtained from rabbits treated with a prednisolone-protein antigen and makes use of the double antibody technique . Although serum samples are normally diluted, the method is capable of detecting 1 ng in 0.1 ml of undiluted serum . Over the assay concentration range of 4-32 ng/ml, the coefficient of variation reportedly does not exceed 8.8 percent. This method was modified 7 to include a pre-extraction step followed by a single antibody, final charcoal separation procedure. A 1-14 calibration curve with a range ng of prednisolone was given. The development of a specific and sufficiently sensitive radioimmunoassay makes it possible to conduct bioavailability studies on single 5 mg prednisolone tablets .

0"

Bioavailability

Literature Survey and EvaluationVery little published information on prednisolone bioavailability is available . It has been reported 21 that, in an aqueous medium at 37 .5°, magnesium trisilicate adsorbs prednisolone while magnesium oxide leads to chemical degradation. The presence of aluminum hydroxide, calcium carbonate or magnesium carbonate results in no effects. The applicability of this information to prednisolone bioavailability is not known . The in vitro drug availability of prednisolone powder and preqnisolone tablets from six different manufacturers was assessed using a two-compartment dissolution-dialysis system .22 In 600 ml of 0. 1 N hydrochloric acid at room temperature, less than 40 percent

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Prednisolone

of the prednisolone powder and the drug in the tablets from three manufacturers dissolved after 20 minutes. Despite marked dissolution differences, the dialysis profiles (passage of prednisolone across a cellulose membrane) of the six tablet products and the powder were similar. While excipients may have been responsible for differences in dialysis profiles, no evidence was presented concerning the possibility that the membrane was limiting the rate of prednisolone's dialysis. Furthermore, no in vivo experiments were conducted to evaluate the in vitro method as a predictor of bioavailability performance . Plasma steroid levels were determined in 10 normal volunteers receiving two different prednisolone preparations as a 50-mg dose in a crossover study.9 By using a nonspecific colorimetric assay (for 17,21 -dihydroxy-20ketosteroids), no differences were found in availability by evaluating plasma concentrations at four time points. The equimolar absorption of prednisolone (20 mg) and prednisolone-21stearolglycolate (38 mg) was investigated in a partial crossover study in 10 normal volunteers, 20-37 years of age. 6 The nonspecific assay used for 17,21-dihydroxy-20-ketosteroids led to the conclusion that the plasma levels after administration of the ester were significantly higher than after prednisolone and the half-life was significantly longer. In view of the study design, these conclusions must be considered tenuous. A few studies 5 ,23-25 dealt with the ' absorption of enteric-coated or sustained-release prednisolone preparations . Generally, these preparations resulted in a decrease in the maximum plasma prednisolone concentration and the rate of absorption, accompanied by some prolonged maintenance of the levels when compared to conventional compressed tablets, In view of the moderately long duration of action of the steroid and the advocated importance of alternate day therapy, these preparations have no therapeutic rationale. The in vitro and in vivo availability of some commercial prednisolone tablets was reported recently using an extraction radioimmunoassay J The 5-mg preparations tested were from Schering Corporation (lot 1ACC1P35944), Pfizer (lot 14424), Fellows Testagar (lot 71628), The Upjohn Company (lot

144

301AR-A2) and USV Pharmaceutical Corporation (lot 50492). The dissolution of all preparations was tested at 37° in deionized water using a special apparatus equipped with a stirrer. Based upon the results of four tablets, the Schering and Pfizer products provided the extremes in dissolution rates with 50 percent dissolved in 3 .0 ± 0.5 (mean ± SD) and 39 .9 ± 11.4 minutes, respectively. Their bioavailability was then tested in 12 normal male volunteers (23-39 years old, 65.4-99.4 kg) in a crossover design. At 11 p.m. on the day prior to the study, each subject received 1 mg of dexamethasone to suppress endogenous secretion of hydrocortisone which interferes with the plasma assay of prednisolone . The dose along with 240 ml of water was administered to subjects who were fasted overnight and for 4 hours after drug ingestion. The averaged results are summarized in Table I. Analysis of variance using the individual plasma levels produced by the Schering and Pfizer products revealed no difference in the mean peak plasma concentrations (248 and 243 ng/ml, respectively) nor in the mean 0-24 hour areas under the curve (1363 and 1405 ng/ml hour, respectively). These results indicate that the in vitro procedure used was a poor predictor of in vivo performance . Regulatory and Compendia I ActivityPrednisolone tablets became official in USP XV (Second Supplement, April 1, 1959). The content uniformity requirement was specified for prednisolone tablets in USP XVII. USP XVIII included a dissolution test in which 60 percent of labeled prednisolone in the tablets was required to dissolve in not more than 20 minutes. The apparatus was specifically defined with the monograph requiring de-aerated water as the dissolution medium employing a stirrer speed of 100 rpm .26 These requirements also are specified in USP XIX. Since the introduction of compendial dissolution requirements, prednisolone tablets have been recalled once for failing the test. 27 Clinical Significance Reports of therapeutic response related to vascular prednisolone concentrations are not available. The dose employed is the one necessary to control the condition being treated. It is imperative then that bioavailability be ensured in the initiation of prednisolone therapy.

Table I

Summary of Averaged Bioavailability Results for Schering and Pf izer Prednisolone Tabletsa Plasma Prednisolone Level, ng/ml

Ho urs

Scheringb

0.25 0.5

63.4 154 230 207 188 154 86.6 46.7 20.0 3.63 248

I

2 3 4 6 8 12 24 Peak plasma co nccn tra lio n Area under the curve (0 - 24 hours), ng/ml hour

1363

Pfizer c 33.1 134 199 211 210 164 90.0 52.6 19.2 6.5 4 243

1405

g'Lot Data from Reference 7 1 ACC 1 P359 44 CLot 1 442 4

Also, it is important to obtain constancy in bioavailability performance after an effective dose has been reached . Criteria for Bioavailability Tests In view of the limited information available on the in vivo performance of prednisolone tablets, no reference standard can be identified. The following criteria serve as guidelines for future bioavailability investigations and will permit an evaluation of reports on various products. 1. A complete crossover study design should be used, commensurate with the number of products investigated, employing an aqueous or dilute ethanolic solution of prednisolone as the reference standard . 2. Although the number of subjects requ ired to determine differences between products is influenced by such variables as the variance within the group of subjects for a product and the magnitude of product differences, a minimum of 10 subjects would appear reasonab le. 3. Volunteers should undergo adequate physical examination and

Journal of the Amer ican Pharmaceutical Association

Prednisolone

Table II

Average Serum Levels of 5 mg Upjohn Prednisolone Tablets a

Ho urs

Average Ser um Prednisolo ne Level, ng/ ml

0.0 0.5 1.0 2.0 3.0 4.0 6.0 8.0 12.0 24.0

0.00 157.13 163.00 142.25 90.25 62.25 26.50 16. 38 3.25 0.1 3

Ave rage o f indiv idua l peak seru m co ncen tra tion

185.75

Av e rage of the individual peak timcs, hou rs Av e rage of th e areas und er t he individu al sc rum concentrat ion - tim e curves (0-- 24 hours), ng/ ml hour

1. 06

656

a Lot 29 1BE

4.

5.

6. 7.

8.

9.

laboratory screening, with only normals included in the study. Subjects should be between 18 and 55 years of age having a weight within 10 percent of the ideal weight recommended for their height and frame . Steroids should be withheld for 30 days pr ior to the study and other medications should not be taken within 7 days of the study . One week should separate phases of the crossover study. The preparations should be administered with a constant volume of 240 ml of water after an overnight fast, and food and water should be withheld for 4 hours after ingestion . Sufficient blood samples should be collected up to 12 and preferably 24 hours after administration to permit an adequate characterization of the absorption , peak and elimination profile in serum or plasma. Any analytical method employed should be specific for prednisolone. If hydrocortisone interferes in the radioimmunoassay, a preliminary separation of the two steroids should be carried out.

Vol. NS 16, No. 3, March 1976

10. Analysis of variance should be performed to evaluate differences between preparations, peak concentration, time for peak concentration and area under the plasma or serum concentration - time curve. Information Available from Suppliers

Bioavailability information was requested by letter from 68 suppliers and/ or manufacturers of prednisolone tablets. The following companies did not respondApproved Pharmaceutical Arcum Pharmaceutical Barre Drug Company Barry Martin Pharmaceuticals Bell Pharmacal Corp . Bell Pharmacal Company Texas Blaine Company Burgin-Arden C.R. Canfield & Company Carr Drug H.R. Cenci Laboratories Central Consolidated Midland Cord Laboratories Dome Faraday Laboratories FellowsTestagar Ferndale First Texas Pharmaceuticals Generic Phar)11aceutical Geneva Drugs Gotham Pharmaceutical Harvey Laboratories ICN Pharma ceuticals Jenkins Laboratories Kirkman Lannett Len-Tag

McKesson Laboratories Panray Division, Ormount Drug & Chemical Pfizer Laboratories Pharma-Tek Pharmecon Pharmex Premo Pharmaceutical Pure pac Pharmaceuticals Purity Organics Richlyn Laboratories Robinson Laboratory Rocky Mountain Pharmacal Schlicksup Scrip Sheraton Laboratories Sherry Pharmaceutical Sheryl Stanlabs Truxton Ulmer Pharmacal USV Pharmaceuticals Vangard Laboratories Vita-Fore Products Vitarine Company West-Ward Winsale Drug Company Wolins Pharmacal Zenith Laboratories

The following companies indicated that they were only distributors of prednisolone tablets manufactured by another company and, therefore, could not provide any bioavailability informationColumbia Medical Corvit Pharmaceuticals Geneva Generics H.L. Moore Drug Exchange The following companies indicated that no bioavailability information was available for their productsPhilips Roxane Laboratories Stayner Schering Corporation indicated that it no longer markets prednisolone. The following companies did not provide bioavailability data but supplied information on the dissolution characteristics of their products using the USP method-

Halsey Drug Company- The mean amount of predn isolone dissolved after testing six individual 5-mg tablets (lot number not given) was 89 .3 percent. Lemmon- The mean amounts of prednisolone dissolved after testing six individual 5-mg tablets of lots 2253, 9914 and 1805 were 94.8, 89.0 and 101 .9 percent, respectively. Merck Sharp & Dohme- This company stated that its product fully met compendial dissolution requirements. Towne, Paulsen and Company-A laboratory assay report of typical results found for its product was supplied, which indicated that greater than 90 percent of its product dissolved in 20 minutes according to the USP XVIII procedure .

Companies Providing Bioavailability Information

Of the 68 companies, only The Upjohn Company supplied bioavailability information. The data (Table If) were obtained using eight fasting normal adult volunteers (four females and four males) after oral administration of 5 mg of prednisolone (Upjohn, lot 291BE). This monograph contains data submitted as of September 10, 1975.

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Prednisolone

Monograph AuthorJake J. Thiessen, assistant professor, faculty of pharmacy, University of Toronto Monograph Col/aboratorsPeter D. Bernardo, senior investigator, Smith, Kline and French Laboratories

References 1. Schneller, G.H., JAPhA , NS9, 455 (1969) 2. JAPhA. NS13, 279 (1973) 3. Campagna, F.A. , Cureton , G., Mirigian. RA .. and Nelson, E., J. Pharm. Sci.. 52, 605 (1963) 4. Vermeulen. A ., J. Endocrinol., 18,278 (1959) 5. English, J., Chakraborty, J ., Marks, V .• Trigger, D.J., and Thomson , A .G.. Br. J. Clin. Pharmacol., 2, 3 27 (1975) 6. Tommasini , R. . Mandelli, V " Passerini, N., and Tosolini. G.• Arzneim.-Forsch.. 16, 172 (1966) 7. Sullivan, T.J .• Stoll. RG .• Sakmar. E.• Blair. D.C.• and Wagner, J.G.. J. Pharmacokin. Biopharm .. 2, 29 (1974) 8. Wilson. C.G.. Sendagire. R .. May. C.S., and Patterson, J.W., Br. J. Clin. Pharmacol., 2, 321 (1975) 9. Isbister, J.P., Speros, J .. and Steinbeck. AW., Med.

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James Seitz, manager, Pharmaceutical Research and Development Services Division, Abbott Laboratories

Published by American Pharmaceutical Association 2215 Constitution Ave ., NW Washington, DC 20037

William J. Jusko, associate professor of pharmaceutics, school of pharmacy, State University of New York at Buffalo

J. Aust., 56(1), 1135 (1969) 10. English, J .. Chakraborty, J., and Marks, V., Ann. Clin. Biochem.. 11, 11 (1974) 11 . Ely, R.S., Done, A.K., and Kelley, V.C., Proc. Soc. Exp. Bioi. Med., 91, 503 (1956) 12. Powell, loW., and Axelsen, E., Gut, 13,690 (1972) 13. Kozower, M., Veatch, lo, and Kaplan, M.M .. J. Clin. Endocrinol. Metab .. 38, 407 (1974) 14. Araki, Y., Yokota, 0 .. Kato, T., Kashima, M., and Miyazaki, T .. in Steroid Dynamics, Pincu s. G., Nakao, T., and Tait. J.F., ads .• Academic Press, New York (1966) 15. Chem, P.S., Mills, I.H., and Bartler, F.C., J. Endocrinol., 23,129 (1961) 16. Lewi s, G.P., Jusko, W.J .. Burke, C.W., and Graves, L .. Lancet, 2, 778 (1971) 17. Hayton, W.L., Guttman, D.E .. and Levy, G., J. Pharm. Sci., 61, 356 (1972) 18. Sandberg , D.H., Bacallao, C.Z .. and Cleveland ,

WW., Biochem. Med.. 4, 383 (1970) 19. Turner, A.K., Carroll, C.J., Pinkus, J.lo, Charles, D., and Chattoraj, S.C., Clin. Chem .. 19,731 (1973) 20 . Colburn, W.A ., and Buller, RH., Steroids, 21, 833 (1973) 21 . Chulski, T., and Fori st, A .A ., JAPhA , Sci. Ed., 47 , 553 (1958) 22. Northern, E., Lach, J.L., and Fincher, J.H., Am. J . Hasp. Pharm., 30, 622 (1973) 23. Hulme, B .. James, V.H.T., and Rault, R , Br. J. Clin. Pharmacal.. 2, 317 (1975) 24. Wagner, J.G., Carpenter, O.S., and Collins, E.J., J. Pharmacal. Exp. Ther., 129, 101 ( 1960) 25. D'Arcy, P.F., Grittin, J.P., Jenkins, J.S., Kirk, W.F., and Peacock, AW.C., J. Pharm. Sci .. 60, 1028 (1971) 26 . The United States Pharmacopeia, 18th rev ., Mack Publi shing Co., Easton, Pa. (1970) 27. JAPhA . NS11, 567 (1971)

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