Not All Protein Drugs And Vaccines Of The Same Name Are Identical

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A slight chemical modification in a small molecule can dramatically change biologic activity. For example, the addition of methyl groups at position 1,3, and 7 of the natural substance xanthine produces the widely consumed compound caffeine; the addition of methyl groups at position 1 and 3 or 3 and 7 produces the bron-chodilator theophylline or a related compound, theobromine. By the same token, the addition of a hydroxy-methyl group to the anti-herpes simplex drug acyclovir results in ganciclovir, which has anti-cytomegalovirus activity.

Xanthine h3c

CH I

CH I

CH Caffeine

Xanthine

CH Caffeine

Theophylline

CH I

CH I

Theobromine ch3

Theophylline

Theobromine

Acyclovir

CH2OCH2CH2OH

Acyclovir

|CH2OH

H CH2OCH

Gancyclovir CH2OH

Fexofenadine

Fexofenadine

Terfenadine

Terfenadine

One can find many more examples where a subtle modification in a side chain leads to a new drug that produces a drastically different therapeutic or toxicological outcome. This is clearly illustrated by the nonsedating antihistamine terfenadine (Seldane), which produces cardiotoxicity when given with certain drugs that inhibits its metabolism. This product is no longer marketed. It has been replaced by its safer but no less effective carboxylic oxidative metabolite fexofenadine (Allegra).

Biopharmaceuticals based on natural proteins and peptides are often called by the same name as the biologic natural material despite differences in one or more amino-acid residues. For example, insulin, which regulates blood glucose and is used clinically to treat type 1 diabetes and some cases of type 2 diabetes, has several variants that are approved for human use. Insulin contains two polypeptides, A and B chains (Figure 1.2), that are linked together by two disulfide bridges to assume a biologically active conformation. Compared with human insulin, insulin extracted from beef tissue exhibits threonine ^ alanine and isoleucine ^ valine substitutions at posi tion 8 and 10 of the insulin A chain, while insulin extracted from pork tissue contains a threonine ^ alanine substitution at position 30 of the insulin B chain (Table 1.3). Yet both pork and beef insulins have been used successfully to treat diabetes. While trade names may differ, all the insulins, including those that are modified to produce more desirable pharmacokinetic and disposition profiles such as insulin lispro, insulin glargine, and insulin aspart, are still known as and called insulins by physician, and researchers alike. All of

Pork Insulin

-Cys-Cys-Thr-Ser-lle-Cys-Ser-Leu-Tyr-Gln-Leu-| 6 /7 8 9 10 11 12 13 14 15 16 / Chain A HO-Asn-Cys-Tyr-Asn-Glu 21 20 19 18 17

-Cys-Gly-Ser-His-Leu-Val-Glu-Ala-Leu-Tyr-Leu-Val-Cys 7 8 9 10 11 12 13 14 15 16 17 18 19 -Leu-His-Gln-Asn-Val-Phe-H -Phe-Gly-Arg-Glu-Gly 6 5 4 3 2 1 Chain B

24 23 22 21 20

LPhe-Tyr-Thr-Pro-Lys-Ala-OH 25 26 27 28 29 30

Figure 1.2. Schematic presentation of insulin A and B chains and their amino-acid sequences based on insulin extracted from pork.

■TABLE 1.3. Sequence variation among insulins available for human administration

A Chain B Chain

Insulin Amino Acid, 20 & 21

aa Position 8 10 21 Insertion 28 29 30

Insulin Amino Acid, 20 & 21

aa Position 8 10 21 Insertion 28 29 30

Insulin—beef

Ala

Val

Asn

None

Pro

Lys

Ala

Insulin—pork

Thr

Ile

Asn

None

Pro

Lys

Ala

Insulin—human

Thr

Ile

Asn

None

Pro

Lys

Thr

Insulin—lispro

Thr

Ile

Asn

None

Lys

Pro

Thr

(Humalog)

Insulin—asp

Thr

Ile

Asn

None

Asp

Lys

Thr

(Novolog)

Insulin—glargine

Thr

Ile

Gly

Arg & Arg

Pro

Lys

Thr

■TABLE 1.4. Comparison of recombinant hepatitis B vaccines dose recommendations

Group of Patients

Recombivax HB

Engerix-B

Dose (mg)

Volume (ml)

Dose (mg)

Volume (ml)

Infants (HB-), children

2.5

0.25

10

0.5

Infants (HB+)

5

0.5

10

0.5

Children, 11-19

5

0.5

20

1.0

Adult >20

10

1.0

20

1.0

Dialysis/immune-

40

1.0"

40

2.0

compromised patients

"Special formulation.

"Special formulation.

these variants of insulin are used for the same treatment indication—to control blood glucose—and are efficacious as long as the dose and dosing frequency are determined on a product-by-product basis.

The same name is also being used for some vaccines that differ in potency. As shown in Table 1.4, the two approved vaccines against hepatitis B, Recombivax HB and Engerix-B, both known as Hepatitis B Vaccine (Recombinant), when used as directed, are therapeutically equivalent in terms of their ability to induce antibodies that protect vaccinated individuals from hepatitis B virus infection. However, the dose and volume required to produce a satisfactory immune response are different for each product and for each age group.

Despite these differences, physicians use the insulins interchangeably (Table 1.4). The difference in dose between the two vaccines may be due to sequence and production variations of the recombinant proteins that constitute the preparation.

REFERENCES

Moses, V., and R.E. Cape, Biotechnology: the science and business. 1991, Harwood Academic Publishers, Chur Switzerland.

Ernst & Young LLP, Convergence: the biotechnology industry report, 2000, NY.

A timeline of biotechnology .Accessed August 2001, http://www.bio.org/timeline/timeline.html.

COMPARATIVE DRUG DEVELOPMENT OF PROTEINS AND GENES VERSUS SMALL MOLECULES

2.1. TRANSFORMING NEW MOLECULAR ENTITIES INTO DRUGS

2.2. DIFFERENCES BETWEEN DEVELOPMENT OF

BIOTECHNOLOGY PRODUCTS OF MACROMOLECULES AND CHEMICAL PRODUCTS 2.3. CURRENT TRENDS IN DRUG DEVELOPMENT

The US government allocates billons of dollars every year through the Department of Health and Human Services (HHS), the Public Health Service (PHS), and the National Institutes of Health (NIH) to support research aimed at understanding disease mechanisms and finding therapeutic solutions. The drug industry also spends several billon dollars each year in pharmaceutical research to transform novel chemicals and biologics into medicinals that are safe and effective for human use. To ensure that a new drug candidate is proved effective and safe before it reaches the US market, all of the information that has been gathered about the new drug candidate is rigorously scrutinized by the Food and Drug Administration and by independent experts called upon to assist the agency in its evaluation. Whether a drug candidate is a protein, nucleic acid, or small molecule, manufactured in the United States or abroad, the same regulations apply.

In general, traditional drugs (i.e., small organic molecules) are reviewed through the new drug application (NDA) process, while macromolecules (biopharmaceuti-cals), including proteins, peptides, genes, and recombinant products are reviewed under the biologic license application

Biotechnology and Biopharmaceuticals, by Rodney J. Y. Ho and Milo Gibaldi ISBN 0-471-20690-3 Copyright © 2003 by John Wiley & Sons, Inc.

(BLA) process [1]. The Center for Drug Evaluation and Research (CDER) and the Center for Biologies Evaluation and Research (CBER), within the FDA, have been responsible for the review of NDAs and BLAs, respectively. A tripartite organization, known as the International Conference on Harmonization (ICH), which includes the FDA and its counterpart agencies in the European Union and Japan, was established in 1991 with the goal of increasing the efficiency of the drug approval process for the international marketplace. The guidelines developed by the ICH, however, have yet to be fully accepted in most nations. While we recognize the importance of international licensing of drugs and biologics, we will focus on the drug development and approval process elaborated by the FDA for new molecular entities (NMEs), emphasizing the differences between traditional drugs and biopharmaceuticals.

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