CHIRALITY 3:161- 164 (1991)
Drug Chirality: Impact on Pharmaceutical Regulation ANDREW J. HUTT Chelsea Department of Pharmacy, King’s College London, London S W 3 6LX, United Kingdom
The Regulatory Affairs Division of IBC Legal Studies and Services Limited recently (October, 1990) organised a 2-day seminar, with the above title, at the London Press Centre with the object of providing a summary of the basic science underlying drug chirality and its significance on pharmaceutical development and regulation. The seminar attracted an audience of some 200 delegates, predominantly European but with representation from the United States, Japan, and South Africa, reflecting the ever increasing interest in the area of the stereochemistry of drug molecules. The first day of the meeting was chaired by Anthony Cartwright (London) and opened with a presentation on the methodological aspects of chiral analysis by Professor A.F. Fell (Bradford). Fell began his presentation with some introductory remarks concerning the significance of stereochemical considerations in pharmacology and made the comment that the current interest in this area has been due to the recent rapid developments in the technology available for the analytical determination of drug enantiomers. The majority of the presentation involved a discussion of the chiral stationary phases (CSPs) available for liquid chromatography (ca 50 being currently available), and it was pointed out that apart from the Pirkle and cyclodextrin CSPs, column selection for a given analysis still relies very much on a n intuitive approach. The difficulties associated with chiral drug bioanalysis were illustrated with reference to the enantiomeric resolution of a chiral drug, the enantiomers of the two major metabolites of which could not be resolved using the same system. Fell also discussed various optimization methods as a n aid for enantiomeric resolution and presented some impressive results obtained with a p-cyclodextrin CSP with which, following a number of preliminary experiments, he was able to predict both analyte retention and resolution values with a remarkable degree of accuracy. The second presentation of the morning was a typically challenging t a l k by Professor E . J . Ariens (Nijmegen). Ariens opened with some comments concerning stereochemical awareness-or lack of itwith respect to several standard texts and journals in the areas of pharmacology and toxicology, describing the lack of relevant information as a stereophobia. This was followed by a consideration of the extent of drug chirality in terms of the pharmaceutical market place with the majority of synthetic chiral agents being marketed as racemates rather than as pure enantiomers. 0 1991 Wiley-Liss, Inc
This theme was continued with a plea for “clean water, clean air, clean food and tomorrow, clean drugs free from isomeric ballast.” Ariens pointed out that chirality was not a n essential feature for biological activity and illustrated his argument with several examples of nonchiral endogenous transmitter agents and potent analgesics. Moving on to examine drug disposition, Ariens commented that only exceptionally will the ratio of enantiomers in plasma be 1:l following administration of a racemic drug. In fact, the enantiomeric ratio in plasma changes continuously until steady state is reached for both isomers, and thus the development of highly complex pharmacokinetic models is of little use if the enantiomeric composition of the circulating material is not taken into account. Ariens made the point that with regard to the complexity of obtaining enantiomer pharmacokinetic data following the administration of a racemate that the “notion of the impossibility or inability to do things the proper way is no excuse to do them the wrong way.” Stereochemical considerations in drug disposition, pharmacokinetics, and toxicology were examined in the following two presentations by A.J. Hutt (London) and Joachim Mayer (Lousanne). Hutt presented a n overview of enantioselectivity in absorption, distribution, and excretion and examined in detail the possible metabolic fates of both chiral and prochiral compounds in stereochemical terms. The importance of “true” pharmacokinetic parameters was emphasized in the presentation, which was illustrated by several examples, verapamil, disopyramide, and propranolol, where stereochemical considerations has helped to clarify the complex disposition of these agents. In discussing toxicity in relation to changing from racemates to single isomer drugs, Mayer divided compounds into groups relating stereoselectivity in terms of pharmacological activity to their possible stereoselectivity in toxicology. At meetings of this type, and the present one was no exception, thalidomide is frequently cited as a n agent where stereochemical considerations may have prevented the tragedy of the early 1960s, recent studies indicating that the R-enantiomer is a sedative hypnotic, whereas the S-isomer is a teratogen. Mayer put this situation in some perspective Received for publication November 26, 1990; accepted December 20, 1990. Address reprint requests to the author at the address given above.
162
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by referring to some earlier findings in which it was shown that there is no difference in teratogenic activity between the enantiomers on administration to New Zealand white rabbits, a species known to be highly sensitive to the teratogenic effects of the drug. The situation with this compound is by no means as clear a s some of the present literature would indicate. It is also of interest to note that within the extensive number of examples cited by Mayer, two compounds th a t had been developed as single isomer drugs, namely Dpenicillamine and L-dopa, had resulted in decreased toxicity compared to their racemates. As both these compounds are relatively “old,” the decision to use single isomers must surely relate to the technology available at the time of their development, both being based on amino acid chemistry, and hence adds to the argument that with 1990s technology single isomer drugs should become the norm rather than the exception. Mayer concluded a useful presentation by suggesting that stereochemical differences in pharmacology and toxicology should be examined for early on in drug development so that a rational decision could be taken at that stage on the material to be finally developed and marketed. A clinicians view of stereochemistry was presented by Andrew Scott (Liverpool), who pointed out that, whereas there is a considerable amount of information concerning the significance of stereochemistry in pharmacology, remarkably little is known concerning the value of single isomer drugs in terms of clinical activity. Here again the lack of readily available information is a problem, the majority of prescribers being unaware which drugs are used as racemates, single enantiomers, or are achiral. In terms of adverse drug effects, Scott commented that those associated with the pharmacological activity of the compound were unlikely to be reduced greatly if a switch was made from a racemate to a single isomer; however, the incidence of idiosyncratic reactions may well be reduced. If such advances resulted in greatly increased drug costs, then Scott suggested that a major improvement in the risubenefit ratio would be required. In extending this argument with a consideration of labetalol, it is of interest to note that the use of t h e P - bl oc ki ng iso m er of t h e d r u g , t h e R,Rstereoisomer, dilevalol has resulted in several reports of hepatic reactions a n adverse effect only rarely observed with the mixture of isomers. The reason for this increased toxicity is at present unknown but may be associated with higher tissue concentrations of the drug and/or metabolites or one of the other stereoisomers present in labetalol may provide some protection, by, for example, limiting the metabolism of dilevalol to a toxic metabolite. In discussing the adverse effects of t h e nonsteroidal anti-inflammatory drugs, Scott pointed out that naproxen, marketed as the pure Senantiomer, is one of the less toxic agents in this group. Whether this is cause and effect, however, is by no means clear. In concluding, Scott stressed the importance of stereochemical considerations in therapeutic
drug monitoring, pharmacokinetics, a n examination of drug interactions, and the influence of disease and age on drug isomer disposition. The problem of patentability of pure enantiomers once the racemate is “known to the art” was addressed by Alan Walls (London) in a presentation entitled “Chirality and Intellectual Property.” Walls commented that historically racemates are generally produced and a n initial assessment of the properties of the compound made well before the individual isomers are resolved. The result of this being that single isomer development lags well behind that of the racemate. The critical question concerning racemates and enantiomers a s far as patent law is concerned is one of novelty. As the structure of the compound is “known to the art,” then any school chemistry student may see that the compound has asymmetric centre(s) and therefore that the isomer exists. Also, as the compound is known, then the isomer has been used even though it is mixed with other stereoisomers. The question then arises is the stereoisomer novel? Walls pointed out that the answer to this question is often yes and illustrated the point with a number of examples describing the basis on which such decisions may be made. There are, however, a number of cases where patent claims for particular stereoisomers have been rejected, mainly due to the predictability of the superior properties of one stereoisomer over that of a mixture and therefore that the invention was obvious. The patent would therefore be rejected on the classic grounds of lack of novelty. The requirement for patenting a stereoisomer would appear to be that there is evidence for unexpected and advantageous properties for that compound when compared to the racemate. A potential commercial problem could arise if a single isomer of a previously marketed racemate could be patented but by a company other than the compounds’ originator. In this situation, obviously the competitive position of the originator in the marketplace would be difficult, to put it mildly. The significance of chirality in the assessment of human and veterinary marketing authorisations was addressed, in the final presentation of the day, by Professor J.R. Brown (Sunderland). In briefly reviewing stereochemistry Brown made the point that in all cases stereoisomers are different compounds rather than different forms of the same compound. At one point in his presentation when discussing the difference between achiral and chiral environments, Brown suggested that he could illustrate the situation by taking his shoes and socks off. Possibly in the future we may refer to footedness rather than handedness in this journal! In addressing the regulatory implications for mixtures of stereoisomers, Brown took the view that all the components present in a formulation should be justified, in the same way a s any other combination products and that the use of racemates is essentially polypharmacy with the proportions of materials present in the mixture being based on chemical rather then clinical considerations. Brown acknowledged th a t the reg-
DRUG CHIRALITY
ulatory approach adopted for a chiral drug would vary depending on the “age” of the compound and that a pragmatic rather than a n idealistic view would be required. However, for “new” compounds one would need to consider what is technically achievable in the 1990s in terms of selective synthesis and analysis of stereoisomers and in many cases a change in working practices is required with a move away from a n achiral to a chiral “working” environment. Brown concluded by making the point that in the future single isomer products will be the norm a s technology advances and that, whereas racemates, and other isomeric mixtures, would not be “outlawed“ by regulatory authorities, they would need to be rigorously justified on the basis of differential activity, disposition, and therapeutic need. The second morning of the meeting, chaired by Professor Ariens, was concerned with the regulatory aspects of stereoisomerism. Ariens opened the session by pointing out that the audience had previously heard what could happen to drug enantiomers and that now we would hear what will happen. The first presentation, by Anthony Cartwright (London), was concerned with the Regulatory Requirements for Racemates and Enantiomers in the European Community. Cartwright opened by stating that his talk would be a perspective on the regulatory view rather than a final statement as ‘Latpresent the situation is changing.” He made two initial points: (1) that the market size for chiral compounds has been estimated to be $5 billion by the year 2000, and (2) that due to the considerable technical interest in the area of stereoisomerism, enantiospecific synthesis, and analysisthat much of the work with respect to isomerically pure compounds would be carried out and therefore the regulators need to direct the approach taken to the “right” path. Cartwright also commented that in the future i t is likely that it will be cheaper to decide at the “discovery chemistry” stage which isomer possess the desired properties and to concentrate the development work on that compound. In discussing the EC Regulatory Requirements 1989 Notice to Applicants, Cartwright pointed out that the regulations do not require single isomers to be separated or manufactured and enantiomers to be marketed. However, the problem of stereoisomerism is addressed in the section of the document concerned with Expert Reports where the issues to be examined include: toxicological considerations; pharmacological considerations including evidence a s to the pharmacological properties of the isomers; pharmacokinetics, including data on the metabolism of the individual isomers; extrapolation of preclinical animal toxicology data with a particular emphasis on species differences in the handling of the isomers; and the significant clinical issues. An area of considerable interest to the industry is the situation with respect to Bridging Studies. Two questions arise: (1)what additional studies will be required if the racemate has been marketed previously, and (2)
163
what studies are required if some of the initial toxicological and phase I clinical investigations have been carried out using a racemic mixture. The regulatory position with respect to such investigations have not been defined by the authorities; however, each situation will probably be examined on a “case-by-case” basis related to the therapeutic significance of the compound. In view of the current interest in the area of stereoisomerism, the EC Committee for Proprietary Medicinal Products (CPMP) is in the process of producing guidelines that will be issued for consultation in 1991. Such guidelines will probably include the following: definitions of stereoisomers; nomenclature with descriptions of absolute configuration; manufacture of enantiomerically pure drugs; requirements for pharmacodynamic, pharmacokinetic, and toxicity studies together with clinical implications. Cartwright concluded his presentation with a plea for the industry to contribute to the CPMP guidelines when they are issued. The present situation with regard to racemates and enantiomers in the United States was addressed by Alastair Ramsay (Fernandina Beach). He opened with a brief resume of the Pharmaceutical Manufacturers Associations (PMA) comments on stereoisomerism since 1987. The present position of the PMA being that the development of either a racemate or single enantiomer should be made on a “case-by-case” basis depending on pharmacological and toxicological considerations and technical feasibility, together with the view t h a t clinical and preclinical data obtained on racemates may be used to support the development and marketing of a single isomer. With regard to the regulatory position in the United States, Ramsay made reference to the policy statement, to be available shortly, to the effect that racemates are acceptable with appropriate scientific justification and t h a t it would be beneficial to discuss each individual situation with the agency. At present a formal extension of the combination drug policy to racemates has not been proposed. However, Ramsay did suggest that there is a strong recommendation for the development of chiral analytical methods for the analysis of material in plasma. The situation in Japan was the subject of a brief additional presentation by Nigel Ratcliffe (Osaka). Ratcliffe commented that the minimum preclinical requirements with respect to stereoisomers in Japan are a comparison of acute toxicity and pharmacology of both enantiomers and the racemate, together with a pharmacokinetic profile of each enantiomer in animals. Also, it is necessary to establish if inversion of chirality occurs in vivo. The results of such studies influence the nature of subsequent preclinical studies in terms of subacute toxicity and additional pharmacological investigations. Ratcliffe then described the outcome of seminars by the Japanese regulatory authorities with respect to stereoisomers and new product approvals, i n which various instructions a n d t h e
164
HUlT
rationale behind them were explained to applicants. In concluding, Ratcliffe made the point that in Japan, again the use of a racemate rather than a pure enantiomer would need good justification. Following the presentations concerning the regulatory perspectives, the final session of the meeting was devoted to a Round Table discussion, chaired by Professor Ariens and involving the above speakers. The discussion that ensued provided a useful forum for the important issues involved in the enantiomer versus racemate debate, particularly as in such situations a fairly free exchange of ideas and comments may take
place between both industrial and regulatory authority scientists in a form that possibly would not be appropriate in their more normal exposure with one another. It is fairly difficult to summarise the discussion that took place in this session, which was wide ranging, particularly as a number of valuable contributions were made from the floor. However if the level of discussion provoked, both from the delegates to the speakers and between the delegates, is a measure of success, then this meeting was one of the most successful the present reporter has been fortunate enough to attend.
Drug Chirality: Impact on Pharmaceutical Regulation ANDREW J. HUTT Chelsea Department of Pharmacy, King’s College London, London S W 3 6LX, United Kingdom
The Regulatory Affairs Division of IBC Legal Studies and Services Limited recently (October, 1990) organised a 2-day seminar, with the above title, at the London Press Centre with the object of providing a summary of the basic science underlying drug chirality and its significance on pharmaceutical development and regulation. The seminar attracted an audience of some 200 delegates, predominantly European but with representation from the United States, Japan, and South Africa, reflecting the ever increasing interest in the area of the stereochemistry of drug molecules. The first day of the meeting was chaired by Anthony Cartwright (London) and opened with a presentation on the methodological aspects of chiral analysis by Professor A.F. Fell (Bradford). Fell began his presentation with some introductory remarks concerning the significance of stereochemical considerations in pharmacology and made the comment that the current interest in this area has been due to the recent rapid developments in the technology available for the analytical determination of drug enantiomers. The majority of the presentation involved a discussion of the chiral stationary phases (CSPs) available for liquid chromatography (ca 50 being currently available), and it was pointed out that apart from the Pirkle and cyclodextrin CSPs, column selection for a given analysis still relies very much on a n intuitive approach. The difficulties associated with chiral drug bioanalysis were illustrated with reference to the enantiomeric resolution of a chiral drug, the enantiomers of the two major metabolites of which could not be resolved using the same system. Fell also discussed various optimization methods as a n aid for enantiomeric resolution and presented some impressive results obtained with a p-cyclodextrin CSP with which, following a number of preliminary experiments, he was able to predict both analyte retention and resolution values with a remarkable degree of accuracy. The second presentation of the morning was a typically challenging t a l k by Professor E . J . Ariens (Nijmegen). Ariens opened with some comments concerning stereochemical awareness-or lack of itwith respect to several standard texts and journals in the areas of pharmacology and toxicology, describing the lack of relevant information as a stereophobia. This was followed by a consideration of the extent of drug chirality in terms of the pharmaceutical market place with the majority of synthetic chiral agents being marketed as racemates rather than as pure enantiomers. 0 1991 Wiley-Liss, Inc
This theme was continued with a plea for “clean water, clean air, clean food and tomorrow, clean drugs free from isomeric ballast.” Ariens pointed out that chirality was not a n essential feature for biological activity and illustrated his argument with several examples of nonchiral endogenous transmitter agents and potent analgesics. Moving on to examine drug disposition, Ariens commented that only exceptionally will the ratio of enantiomers in plasma be 1:l following administration of a racemic drug. In fact, the enantiomeric ratio in plasma changes continuously until steady state is reached for both isomers, and thus the development of highly complex pharmacokinetic models is of little use if the enantiomeric composition of the circulating material is not taken into account. Ariens made the point that with regard to the complexity of obtaining enantiomer pharmacokinetic data following the administration of a racemate that the “notion of the impossibility or inability to do things the proper way is no excuse to do them the wrong way.” Stereochemical considerations in drug disposition, pharmacokinetics, and toxicology were examined in the following two presentations by A.J. Hutt (London) and Joachim Mayer (Lousanne). Hutt presented a n overview of enantioselectivity in absorption, distribution, and excretion and examined in detail the possible metabolic fates of both chiral and prochiral compounds in stereochemical terms. The importance of “true” pharmacokinetic parameters was emphasized in the presentation, which was illustrated by several examples, verapamil, disopyramide, and propranolol, where stereochemical considerations has helped to clarify the complex disposition of these agents. In discussing toxicity in relation to changing from racemates to single isomer drugs, Mayer divided compounds into groups relating stereoselectivity in terms of pharmacological activity to their possible stereoselectivity in toxicology. At meetings of this type, and the present one was no exception, thalidomide is frequently cited as a n agent where stereochemical considerations may have prevented the tragedy of the early 1960s, recent studies indicating that the R-enantiomer is a sedative hypnotic, whereas the S-isomer is a teratogen. Mayer put this situation in some perspective Received for publication November 26, 1990; accepted December 20, 1990. Address reprint requests to the author at the address given above.
162
HU”
by referring to some earlier findings in which it was shown that there is no difference in teratogenic activity between the enantiomers on administration to New Zealand white rabbits, a species known to be highly sensitive to the teratogenic effects of the drug. The situation with this compound is by no means as clear a s some of the present literature would indicate. It is also of interest to note that within the extensive number of examples cited by Mayer, two compounds th a t had been developed as single isomer drugs, namely Dpenicillamine and L-dopa, had resulted in decreased toxicity compared to their racemates. As both these compounds are relatively “old,” the decision to use single isomers must surely relate to the technology available at the time of their development, both being based on amino acid chemistry, and hence adds to the argument that with 1990s technology single isomer drugs should become the norm rather than the exception. Mayer concluded a useful presentation by suggesting that stereochemical differences in pharmacology and toxicology should be examined for early on in drug development so that a rational decision could be taken at that stage on the material to be finally developed and marketed. A clinicians view of stereochemistry was presented by Andrew Scott (Liverpool), who pointed out that, whereas there is a considerable amount of information concerning the significance of stereochemistry in pharmacology, remarkably little is known concerning the value of single isomer drugs in terms of clinical activity. Here again the lack of readily available information is a problem, the majority of prescribers being unaware which drugs are used as racemates, single enantiomers, or are achiral. In terms of adverse drug effects, Scott commented that those associated with the pharmacological activity of the compound were unlikely to be reduced greatly if a switch was made from a racemate to a single isomer; however, the incidence of idiosyncratic reactions may well be reduced. If such advances resulted in greatly increased drug costs, then Scott suggested that a major improvement in the risubenefit ratio would be required. In extending this argument with a consideration of labetalol, it is of interest to note that the use of t h e P - bl oc ki ng iso m er of t h e d r u g , t h e R,Rstereoisomer, dilevalol has resulted in several reports of hepatic reactions a n adverse effect only rarely observed with the mixture of isomers. The reason for this increased toxicity is at present unknown but may be associated with higher tissue concentrations of the drug and/or metabolites or one of the other stereoisomers present in labetalol may provide some protection, by, for example, limiting the metabolism of dilevalol to a toxic metabolite. In discussing the adverse effects of t h e nonsteroidal anti-inflammatory drugs, Scott pointed out that naproxen, marketed as the pure Senantiomer, is one of the less toxic agents in this group. Whether this is cause and effect, however, is by no means clear. In concluding, Scott stressed the importance of stereochemical considerations in therapeutic
drug monitoring, pharmacokinetics, a n examination of drug interactions, and the influence of disease and age on drug isomer disposition. The problem of patentability of pure enantiomers once the racemate is “known to the art” was addressed by Alan Walls (London) in a presentation entitled “Chirality and Intellectual Property.” Walls commented that historically racemates are generally produced and a n initial assessment of the properties of the compound made well before the individual isomers are resolved. The result of this being that single isomer development lags well behind that of the racemate. The critical question concerning racemates and enantiomers a s far as patent law is concerned is one of novelty. As the structure of the compound is “known to the art,” then any school chemistry student may see that the compound has asymmetric centre(s) and therefore that the isomer exists. Also, as the compound is known, then the isomer has been used even though it is mixed with other stereoisomers. The question then arises is the stereoisomer novel? Walls pointed out that the answer to this question is often yes and illustrated the point with a number of examples describing the basis on which such decisions may be made. There are, however, a number of cases where patent claims for particular stereoisomers have been rejected, mainly due to the predictability of the superior properties of one stereoisomer over that of a mixture and therefore that the invention was obvious. The patent would therefore be rejected on the classic grounds of lack of novelty. The requirement for patenting a stereoisomer would appear to be that there is evidence for unexpected and advantageous properties for that compound when compared to the racemate. A potential commercial problem could arise if a single isomer of a previously marketed racemate could be patented but by a company other than the compounds’ originator. In this situation, obviously the competitive position of the originator in the marketplace would be difficult, to put it mildly. The significance of chirality in the assessment of human and veterinary marketing authorisations was addressed, in the final presentation of the day, by Professor J.R. Brown (Sunderland). In briefly reviewing stereochemistry Brown made the point that in all cases stereoisomers are different compounds rather than different forms of the same compound. At one point in his presentation when discussing the difference between achiral and chiral environments, Brown suggested that he could illustrate the situation by taking his shoes and socks off. Possibly in the future we may refer to footedness rather than handedness in this journal! In addressing the regulatory implications for mixtures of stereoisomers, Brown took the view that all the components present in a formulation should be justified, in the same way a s any other combination products and that the use of racemates is essentially polypharmacy with the proportions of materials present in the mixture being based on chemical rather then clinical considerations. Brown acknowledged th a t the reg-
DRUG CHIRALITY
ulatory approach adopted for a chiral drug would vary depending on the “age” of the compound and that a pragmatic rather than a n idealistic view would be required. However, for “new” compounds one would need to consider what is technically achievable in the 1990s in terms of selective synthesis and analysis of stereoisomers and in many cases a change in working practices is required with a move away from a n achiral to a chiral “working” environment. Brown concluded by making the point that in the future single isomer products will be the norm a s technology advances and that, whereas racemates, and other isomeric mixtures, would not be “outlawed“ by regulatory authorities, they would need to be rigorously justified on the basis of differential activity, disposition, and therapeutic need. The second morning of the meeting, chaired by Professor Ariens, was concerned with the regulatory aspects of stereoisomerism. Ariens opened the session by pointing out that the audience had previously heard what could happen to drug enantiomers and that now we would hear what will happen. The first presentation, by Anthony Cartwright (London), was concerned with the Regulatory Requirements for Racemates and Enantiomers in the European Community. Cartwright opened by stating that his talk would be a perspective on the regulatory view rather than a final statement as ‘Latpresent the situation is changing.” He made two initial points: (1) that the market size for chiral compounds has been estimated to be $5 billion by the year 2000, and (2) that due to the considerable technical interest in the area of stereoisomerism, enantiospecific synthesis, and analysisthat much of the work with respect to isomerically pure compounds would be carried out and therefore the regulators need to direct the approach taken to the “right” path. Cartwright also commented that in the future i t is likely that it will be cheaper to decide at the “discovery chemistry” stage which isomer possess the desired properties and to concentrate the development work on that compound. In discussing the EC Regulatory Requirements 1989 Notice to Applicants, Cartwright pointed out that the regulations do not require single isomers to be separated or manufactured and enantiomers to be marketed. However, the problem of stereoisomerism is addressed in the section of the document concerned with Expert Reports where the issues to be examined include: toxicological considerations; pharmacological considerations including evidence a s to the pharmacological properties of the isomers; pharmacokinetics, including data on the metabolism of the individual isomers; extrapolation of preclinical animal toxicology data with a particular emphasis on species differences in the handling of the isomers; and the significant clinical issues. An area of considerable interest to the industry is the situation with respect to Bridging Studies. Two questions arise: (1)what additional studies will be required if the racemate has been marketed previously, and (2)
163
what studies are required if some of the initial toxicological and phase I clinical investigations have been carried out using a racemic mixture. The regulatory position with respect to such investigations have not been defined by the authorities; however, each situation will probably be examined on a “case-by-case” basis related to the therapeutic significance of the compound. In view of the current interest in the area of stereoisomerism, the EC Committee for Proprietary Medicinal Products (CPMP) is in the process of producing guidelines that will be issued for consultation in 1991. Such guidelines will probably include the following: definitions of stereoisomers; nomenclature with descriptions of absolute configuration; manufacture of enantiomerically pure drugs; requirements for pharmacodynamic, pharmacokinetic, and toxicity studies together with clinical implications. Cartwright concluded his presentation with a plea for the industry to contribute to the CPMP guidelines when they are issued. The present situation with regard to racemates and enantiomers in the United States was addressed by Alastair Ramsay (Fernandina Beach). He opened with a brief resume of the Pharmaceutical Manufacturers Associations (PMA) comments on stereoisomerism since 1987. The present position of the PMA being that the development of either a racemate or single enantiomer should be made on a “case-by-case” basis depending on pharmacological and toxicological considerations and technical feasibility, together with the view t h a t clinical and preclinical data obtained on racemates may be used to support the development and marketing of a single isomer. With regard to the regulatory position in the United States, Ramsay made reference to the policy statement, to be available shortly, to the effect that racemates are acceptable with appropriate scientific justification and t h a t it would be beneficial to discuss each individual situation with the agency. At present a formal extension of the combination drug policy to racemates has not been proposed. However, Ramsay did suggest that there is a strong recommendation for the development of chiral analytical methods for the analysis of material in plasma. The situation in Japan was the subject of a brief additional presentation by Nigel Ratcliffe (Osaka). Ratcliffe commented that the minimum preclinical requirements with respect to stereoisomers in Japan are a comparison of acute toxicity and pharmacology of both enantiomers and the racemate, together with a pharmacokinetic profile of each enantiomer in animals. Also, it is necessary to establish if inversion of chirality occurs in vivo. The results of such studies influence the nature of subsequent preclinical studies in terms of subacute toxicity and additional pharmacological investigations. Ratcliffe then described the outcome of seminars by the Japanese regulatory authorities with respect to stereoisomers and new product approvals, i n which various instructions a n d t h e
164
HUlT
rationale behind them were explained to applicants. In concluding, Ratcliffe made the point that in Japan, again the use of a racemate rather than a pure enantiomer would need good justification. Following the presentations concerning the regulatory perspectives, the final session of the meeting was devoted to a Round Table discussion, chaired by Professor Ariens and involving the above speakers. The discussion that ensued provided a useful forum for the important issues involved in the enantiomer versus racemate debate, particularly as in such situations a fairly free exchange of ideas and comments may take
place between both industrial and regulatory authority scientists in a form that possibly would not be appropriate in their more normal exposure with one another. It is fairly difficult to summarise the discussion that took place in this session, which was wide ranging, particularly as a number of valuable contributions were made from the floor. However if the level of discussion provoked, both from the delegates to the speakers and between the delegates, is a measure of success, then this meeting was one of the most successful the present reporter has been fortunate enough to attend.
