MAY 1998

COMMENTARY

What are narrow therapeutic index drugs? Gerhard Levy, PharmD Amherst, 2V.T

Ask any layperson why some oral medications are marketed in many strengths (e.g., levothyroxine sodium tablets, which are available in 12 strengths: 12.5, 25, 50, 75, 88, 100, 112, 125, 150, 175, 200, and 300 pg), whereas many others are marketed in only one strength, and the likely answer will be that the former drugs require precise dosage adjustment, whereas the latter drugs apparently do not need such precision. A young mother may suggest that medications available in a wide range of doses are intended for infants and chil- dren and for adults, whereas the other drug products are indicated only for adult use. However, one could point out that aspirin, taken by both children and adults, was marketed for many years in only two strengths: 81 and 325 mg tablets. Ask a physician or pharmacist why some drugs require greater precision of dosage than others, and the term narrow therapeutic index (or nar- row therapeutic ratio or narrow therapeutic window)

From the Department of Pharmaceutics, School of Pharmacy, State University of New York.

Received for publication Dec. 22, 1997; accepted Jan. 20, 1998. Reprint requests: Gerhard Levy, PharmD, Department of Pharmaceu-

tics, School of Pharmacy, State University of New York at Buffalo, Amherst, NY 14260.

Clin Pharrnacol Ther 1998;63:501-5. Copyright 0 1998 by Mosby, Inc. 0009-9236/98/$5.00 + 0 13/1/WO28

is likely to emerge. Ask for a definition of any one of those terms, and substantial differences in emphasis and comprehensiveness will become apparent. It is time to seek greater understanding of those terms and of the concepts they represent because we are currently fac- ing a question of considerable regulatory and legisla- tive interest1-5: Are there systemically active medica- tions that should be classified as narrow therapeutic index drugs and therefore require stricter bioequiva- lence standards than those currently mandated?

To a clinician familiar with current bioequivalence requirements, a definition of narrow therapeutic index drugs may appear to be quite simple and straightfor- ward: Any drug for which a 20% or smaller change in dosage, with bioavailability remaining constant, pro- duces clinically significant and undesirable pharma- codynamic alterations-that is, increased adverse effects, decreased therapeutic efficacy, or excessive therapeutic effects. The 20% figure is based on cur- rent bioequivalency standards for systemic drugs that require, among other things, that the 90% confidence interval of the extent of absorption, as reflected by the area under the plasma concentration versus time curve, be within 80% to 125% of the reference product (a logarithmically symmetrical range). Like most simple definitions, this necessitates drug-specific interpreta- tions by experts to establish the magnitude and types of increased adverse effects and altered therapeutic

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502 Levy CLINICAL I’ HARMACOLOGY & THERAPEUTICS

MAY 1998

effect intensity that would trigger the narrow thera- peutic index designation. Arbitrary and poorly docu- mented designations would not be defensible scientif- ically or legally and would raise suspicion about their motivation because the strongest advocates of the nar- row therapeutic index classification are pharmaceuti- cal companies with brand-name products facing generic competition. An additional and potentially very complicated problem arises from the pronounced interindividual variation in the pharmacokinetics and pharmacodynamics of many drugs.6,7 Much of what follows focuses on that problem.

Nonlinear Michaelis-Menten-type pharmacokinetics, in which the concentration versus dose relationship is nearly linear at low concentrations but increases more than proportionally and relatively abruptly at concen- trations above the Michaelis constant (KM), is one rea- son narrow therapeutic index definitions should be based on dose rather than drug concentration. Depend- ing on the parameter values and the dose, as little as a 5% or 10% change in bioavailability can result in a sev- eralfold greater change in plasma concentrations.839 Thus even a drug with a fairly shallow concentration- effect intensity relationship could be pharmacodynami- tally sensitive to relatively small changes in extent of absorption. Large interindividual differences in the Michaelis constant, such as those that occur with pheny- toin,’ perhaps combined with similar differences in effective plasma concentration, could confer narrow therapeutic index characteristics on a drug in some indi- viduals (low K, or high effective plasma concentra- tions) and non-narrow therapeutic index characteristics in others (high KIM or low effective plasma concentra- tions). What percentage of the former subpopulation should it take to classify the drug as narrow therapeutic index? Fifty percent? Five percent?

Another aspect of pharmacokinetic nonlinearity has to do with the therapeutic indications. Most readers would not consider aspirin or another salicylate as a nar- row therapeutic index drug. However, when used in large doses to treat inflammatory disease, it is a narrow thera- peutic index drug because of its nonlinear elimination kinetics in humans.ll As little as a 20% change in aspirin dosage can make the difference between no effect or effi- cacy in the treatment of rheumatic fever.‘* No such all- or-none effect is observed when aspirin in much lower doses is used for the relief of minor pain. Should a drug be classified as having a narrow therapeutic index for one (or some) indication(s) and not for others?

The typically nonlinear relationship between drug concentration and pharmacologic effect intensity gives rise to other problems. If the relationship is sigmoidal,

a fixed percentage change in extent of absorption will produce a much greater change in effect intensity at low drug concentrations than at high concentrations.13 On that basis, drugs whose effect intensity target is in the low concentration range of the log concentra- tion-effect curve can be expected to be more sensitive to bioavailability problems. For example, the differ- ence in the average dose of phenobarbital for the suc- cessful and unsuccessful management of neonatal seizures was only about 24% (12.3 + 3.3 versus 16.2 f 2.6 mg/kg [mean f SD], with plasma concentrations of 14.3 + 5.1 and 19.8 + 2.7 pg/ml, respectively).14 Should phenobarbital be designated as a narrow thera- peutic index drug?

The steepness of the drug concentration versus response relationship is frequently mentioned as a nar- row therapeutic index criterion. This is certainly rea- sonable in principle but vastly complicated by pro- nounced interindividual differences in this metric. The literature contains reports of more than loo-fold differ- ences in estimated y values of the sigmoid E,,, equa- tion, but these are probably artifacts that result from poor data. However, even the highly reliable results derived from electroencephalogram monitoring com- bined with intensive plasma concentration measure- ments have revealed large interindividual differences of y values. For example, the y values for the effect of midazolam on the electroencephalographic pharmaco- dynamics ranged from 1.4 (a relatively shallow slope) to 3.5 (approaching an almost all-or-none relationship) in only nine healthy men. l5 A larger study of a more heterogeneous population would have undoubtedly revealed even greater differences between subjects. Large and reproducible differences have also been observed in the slope of the anticoagulant effect versus log-plasma concentration relationship of coumarin anti- coagulants. In the case of dicumarol (INN, dicoumarol), the slope ranged over one order of magnitude in only 11 subjects. l6 It is not unlikely that some of the “steep responders” to coumarin anticoagulants are classified by some clinicians as individuals who, for one reason or another, cannot handle this type of drug. Unaccept- ably large fluctuations of prothrombin time are typi- cally attributed to poor compliance or dietary indiscre- tions when in fact a very steep concentration-effect relationship may be primarily responsible in some cases. Thus coumarin anticoagulants may be narrow therapeutic index drugs for some patients but not for others. Again, what proportion of patients must be steep responders to designate such drugs as narrow therapeu- tic index products for regulatory purposes? This ques- tion becomes even more complex if the surrogate effect

CLINICAL PHARMACOLOGY & THERAPEUTICS VOLUME 63, NUMBER 5 Levy 503

measure, prothrombin time for the coumarin anticoag- ulants, and activated partial thromboplastin time for high molecular weight heparin (which exhibits similar large and highly reproducible intersubject slope differ- ences17) are to be translated into incidence and sever- ity of bleeding episodes or the reduction in the inci- dence and severity of thrombotic events.

There are three conditions that demand particular attention to dose titration to minimize concentration- dependent adverse effects. One condition is nonlinear kinetics, referred to above. Another is a condition in which the adverse effect is an extension of the drug’s therapeutic effect, the concentration-effect relation- ship is steep, and/or the therapeutic concentrations are near the concentrations associated with adverse effects. The third condition is a situation in which a drug acts on different biologic targets to elicit its desirable and undesirable effects, respectively. In the latter case, one hopes for well-separated concentration versus effect curves to obtain the desired selectivity; however, phar- macodynamic variability can again complicate matters. Strictly as a hypothetical illustration, the ratio of the EC,, for heart rate to the EC,, for systolic blood pres- sure reduction of oxprenolol in as few as six healthy men ranged from 0.23 to 4.5.t8 If one were to avoid the bradycardic effect, one would look for a drug with a ratio well above unity in all patients. Absent the avail- ability of such a drug, one would recognize clinically that oxprenolol is unsuitable for some patients (those with EC,, ratio values less than or equal to unity) and requires strict dose (concentration) control for patients with EC,, values from 1 to 2. How does one classify, for regulatory purposes, drugs that are unsuitable for some patients, narrow therapeutic index (with all that it implies) for others, and quite benign (selective) for a third subpopulation?

How have others, including federal regulatory agency scientists and state legislators, approached these problems-particularly the definition of narrow thera- peutic index? Benet and Goyant refer to narrow thera- peutic index drugs as those “for which relatively small changes in systemic concentrations lead to marked changes in pharmacodynamic response.“A descriptively similar definition is offered by Patnaik et al.? they refer to drugs with a narrow therapeutic window and define the window as “the difference between the minimum effective exposure and the maximum tolerable exposure to a drug.” In a recent letter to the National Association of Boards of Pharmacy,3 Roger L. Williams, MD, of the Center for Drug Evaluation and Research of the U.S. Food and Drug Administration (FDA) points out that the narrow therapeutic index designation is not a for-

mal designation by the FDA; however, narrow thera- peutic ratio as a term of art is defined in the FDA reg- ulations as follows:

1. There is a less than twofold difference in median lethal dose (LDso) and median effective dose (ED,,) values, or

2. There is less than a twofold difference in the mini- mum toxic concentrations and minimum effective concentrations in the blood, and

3. Safe and effective use of the drug products require careful titration and patient monitoring.

Legislation proposed in 1997 in New Jersey4 extends this definition:

The drug formulation shall meet at least three of the following criteria: that the drug formulation meets the federal Food and Drug Administration cri- teria for narrow therapeutic range as provided in 21 C.F.R. 320.33 unless the drug formulation was approved for marketing by the federal Food and Drug Administration before 1938; that the drug formula- tion is used to treat a critical acute or chronic condi- tion; that the drug formulation is associated with the risk of toxic reactions, complex drug-drug interac- tions, or steep dose response curves; that the drug formulation has highly individualized dosing requir- ing continuing dose supervision by the prescriber to ensure its safe use; or that there is a competent med- ical determination that a lack of bioequivalency could have a serious adverse effect in the treatment or pre- vention of a serious disease or medical condition.

The Drug Utilization Review Council of New Jersey would be given the responsibility to determine which drug products are to be included in this category.4

Proposed legislation in New York State specifies 24 narrow therapeutic range drugs, including carba- mazepine, clonidine, minoxidil, phenytoin, quinidine, theophylline, valproic acid, and warfarin sodium.5 The dosage forms include tablets, capsules, oral suspension, transdermal patches, extended release capsules and tablets, syrup, and inhalation aerosol. No general defini- tion of narrow therapeutic range is given; reference is made to “drugs that meet the FDA regulatory definition of narrow therapeutic range.” No specific rationale or data are offered to justify the inclusion of any one of those drugs in the list.

The FDA is presently taking the position that “drugs do not fall into discrete groups that would allow one to consider narrow therapeutic index drugs as being

504 Levy

clearly different from other drugs for purposes of ther- apeutic substitution.“3 Because this position is now being reexamined by the scientific community, it may be that despite the difficulties outlined in this commen- tary, a consensus will be reached that some drugs can definitely be assigned to the narrow therapeutic index category. What should be the regulatory requirements to ensure the bioequivalence of such products? In the first instance it should be recognized that the concept of bioequivalence applies not only to products of dif- ferent manufacturers but also to different lots of any one product. It is clearly inadequate to rely on a bioavailability study performed 10 or more years ago and subsequent in vitro dissolution tests to ensure the consistent bioequivalence of narrow therapeutic index drugs.19 The innovator companies must be required to confirm the continuing bioequivalence of their product by periodic testing. The same requirements apply, of course, to generic manufacturers. There still remains that matter of numbers; how much stricter should the bioequivalence standards be for narrow therapeutic index drugs? Ideally, this decision should be based on the population pharmacokinetics and pharmacodynam- its of the drug and on expert clinical judgment; however, it is unlikely that the required database exists. In that case, relative bioavailability determinations on several different lots of the innovator’s product, perhaps selected to represent a range of in vitro dissolution rates (but all within quality control specifications), can establish the relative bioavailability range of that product and thereby the range to be required for generic equivalence. This will result at least in consistent and equal bioavailability standards for the drug, irrespective of manufacturer. If any one manufacturer can produce a biopharmaceutically improved narrow therapeutic index product in the future (i.e., a product with a very narrow and reproducible bioavailability range) and demonstrate consequent ther- apeutic superiority, it may well be rewarded economi- cally, provided that it can obtain regulatory approval of the superiority claim, and patients will benefit from the improved pharmaceutical formulation. Although this may be a utopian view, it should not be discounted.

A more realistic and practical approach to the assur- ance of bioequivalency may be to tighten present stan- dards somewhat (with special consideration for highly variable drugs20) to obviate the need for separate stan- dards for narrow therapeutic index drugs. Progress in pharmaceutical formulation and manufacturing tech- nology justifies a change of the present 90% confidence interval of 80% to 125 % of the bioavailability reference product to a tighter range such as 90% to 112% for most drugs that are not subject to variable first-pass effects.

CLINICAL PHARMACOLOGY &THERAPEUTICS MAY 1998

Even more important than the tightening of bioequiva- lence standards will be the removal of the “clay feet” of bioequivalence testing,lg including the introduction of meaningful product sampling methods, the required reporting of failed bioequivalence tests, periodic bioe- quivalence retesting of marketed products, and proper validation of the upper and lower limits of in vitro dis- solution standards. This would result in enhancing the biopharmaceutical quality of all oral dosage forms intended for systemic pharmacotherapy.

References

1. Benet LZ, Goyan JE. Bioequivalence and narrow thera- peutic index drugs. Pharmacotherapy 1995;15:433-40.

2. Patnaik RN, Lesko LJ, Chen ML, Williams RL, FDA Indi- vidual Bioequivalence Working Group. Individual bioequiv- alence: new concepts in the statistical assessment of bioe- quivalence metrics. Clin Phannacokinet 1997;33:1-6.

3. Williams RL. FDA position on product selection for “nar- row therapeutic index” drugs. Am J Health Syst Pharm 1997;54:1630-2.

4. State of New Jersey Assembly bill No. 2926, May 5, 1997.

5. New York State Assembly bill A8087, May 27, 1997. 6. Rowland M, Sheiner LB, Steimer JL, editors. Variability

in drug therapy: description, estimation, and control. New York: Raven Press; 1985.

7. Levy G, Ebling WF, Forrest A. Concentration- or effect- controlled clinical trials with sparse data. Clin Pharma- co1 Ther 1994;56:1-8.

8. Ludden TM, Allerheiligen RB, Browne TR, Koup JR. Sensitivity analysis of the effect of bioavailability or dosage form content on mean steady state phenytoin con- centration. Ther Drug Monit 1991;13:120-5.

9. Tsuchiya T, Levy G. Relationship between dose and plateau levels of drugs eliminated by parallel first-order and capac- ity-limited kinetics. J Pharm Sci 1972;61:541-4.

10. Jusko WJ. Bioavailability and disposition kinetics of phenytoin in man. In: Kellaway P, Petersen I, editors. Quantitative analysis studies in epilepsy. New York: Raven Press; 1976. p. 115-36.

11. Levy G, Tsuchiya T. Salicylate accumulation kinetics in man. N Engl J Med 1972;287:430-2.

12. Calabro JJ, Marchesano JM. Fever associated with juve- nile rheumatoid arthritis. N Engl J Med 1967;276: 1 l-8.

13. Levy G. Bioavailability, clinical effectiveness, and the public interest. Pharmacology 1972;8:33-43.

14. Lockman LA, Kriel R, Zaske D, Thompson T, Vimig N. Phenobarbital dosage for control of neonatal seizures. Neurology 1979;29:1445-9.

15. Fiset P, Lemmens HLM, Egan TE, Shafer SL, Stanski DR. Pharmacodynamic modeling of the electroen- cephalographic effects of flumazenil in healthy volun- teers sedated with midazolam. Clin Pharmacol Ther 1995;58:562-82.

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16. Levy G. Variability in animal and human pharmacody- namic studies. In: Rowland M, Sheiner LB, Steimer JL, editors. Variability in drug therapy: description, estimation and control. New York: Raven Press; 1985. p. 125-38.

17. Whitfield LR, Levy G. Relationship between concen- tration and anticoagulant effect of heparin in plasma of normal subjects: magnitude and predictability of interindividual differences. Clin Pharmacol Ther 1980;28:509-615.

18. Koopmans R, Oosterhuis B, Karemaker JM, Werner J, Van Boxtel CJ. Pharmacokinetic pharmacodynamic modelling of oxprenolol in man using continuous non-invasive blood pressure monitoring. Eur J Clin Pharmacol1988;34:395-400.

19. Levy G. The clay feet of bioequivalence testing. J Pharm Pharmacol 1995;47:975-7.

20. Shah VP, Yacobi A, Barr WH, Benet LZ, Breimer D, Dobrinska MR, et al. Evaluation of orally administered highly variable drugs and drug formulations. Pharm Res 1996;13:1590-4.

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