Racemic drugs

RACEMIC DRUGS AND ENANTIOMERS
Identifying the really useful innovations
Many drugs are available as racemic mixtures or
50:50 mixtures of two molecules (enantiomers) that are different merely by one being the non- superimposable mirror image of the other. There are normally two classifications used for en- antiomers: the first one distinguishes the two molecules as a dextrorotatory and levorotatory
enantiomer, the second one distinguishes them an R and S enantiomer (see fly-leaf).
Almost all biological organisms produce only one of the 2 enantiomers, usually the levorotatory one. For this reason, production, experimentation and clinical use of substances of natural origin are
suddenly directed towards single enantiomers (typical examples are levothyroxin and levodopa). On the other hand, enantiomers of non-natural
origin, before the decade of '80-90, had been pre-
dominantly marketed in the form of racemic mix- tures. Some examples are ketoprofen, atenolol, warfarin, omeprazole, fluoxetine. In the last 20 years, technical innovations have made the syn- Among the new drugs marketed from the outset as thesis of single enantiomers more feasible; the single enantiomers there are: simvastatin, ator- regulatory authorities have gradually made it a re- vastatin, pravastatin, paroxetine, clopidogrel, fluti- quirement that, when drugs at the development casone, salmeterol, valsartan, etc. (see table 1). stage are made up of a racemic mixture, the pro-
In some cases, the enantiomers recently
ducer must assess the efficacy of the single enan- brought on to the market are not really new
tiomers and choose, giving reasons, which of the drugs: they are simply the active enantiomer of
two to market. So, in the near future, there will racemic mixtures of proven clinical efficacy whose have to be a gradual reduction in the marketing of expiring patent reduces their commercial value. new drugs made up of racemic mixtures.1
In other cases, the enantiomer is a real improve- ment compared to the racemic mixture in terms of better effectiveness, less toxicity or more advanta- geous pharmaco-kinetic profile. Corresponding single
Finally, it has to be considered that the marketing enantiomers
of a single enantiomer, whose racemic mixture has already been licenced, may be approved on a basis of relatively limited evidence, with few new clinical In this Information Package, the effectiveness and tolerability of some recently marketed enantiomers will be analysed in comparison with the corre- Destroketoprofen sponding racemic mixture, with particular refer- ence to the choices guided by predominantly com- mercial-type reasons. Destrofluoxetine On the following pages.
Racemic drugs
A large number of drugs on the Levofloxacin: the spectrum is changed the enantiomer is market are racemic mixtures, eg: not marketed atenolol, warfarin, disopyramide, Levocetirizine: nothing new but the dose atropine, Ca-antagonists,. Esomeprazole: much ado about nothing Enantiomers
Clopidogrel, atorvastatin, simvastatin, pravastatin, Escitalopram: is it really superior? only as single paroxetine, sertraline, fluticasone, enantiomers salmeterol, valsartan,. Racemic drugs, enantiomers & Co. Table 1. Some examples of racemic mixtures and
enantiomers of non-natural origin Information Packages on Drugs n.3 -
November, 2006 pag 1
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From ofloxacin to levofloxacin: the spectrum is changed
Ofloxacin is a fluoroquinolone, on the market since 1987 as a
Levofloxacin = S (-) ofloxacin
racemic mixture. The antibacterial activity of the racemic drug ofloxacin is due Registered indications: substantially
similar even if more detailed for
mainly to its levorotatory enantiomer (levofloxacin)4,5 From the microbiological point of view, in fact, levofloxacin is up to 128 times more effective than the dextrorotatory enantiomer and up Patents and marketing activities:
to twice as effective than the racemic mixture according to the Ofloxacin: the patent expired in January, Gram positive and Gram negative bacterial stocks assayed.5 The pharmacokinetics of levofloxacin is similar to those of oflox- Levofloxacin: it came on to the market in acin, but its greater microbiological efficacy (represented by lower MIC90 for some pathogens) helps it to reach effective tis- sue concentrations that permit administration of a single daily Of particular clinical interest is the extension of the spectrum IN PRATICE…
with respect to Streptococcus pneumoniae (pneumococcus):in
fact, the main guidelines on treatment of community acquired The introduction on the market of pneumonia mention levofloxacin (and not ofloxacin) among the levofloxacin provided a therapeutic fluoroquinolones with activity against pneumococcus.7,8 choice of greater efficacy compared With regard to tolerability, no clinically significant differences with ofloxacin, in particular in the have been found between the racemic mixture and the pure en- treatment of community acquired 9 it should, however, be remembered that a risk of tendinous lesioning/rupture is associated with the administration Tolerability seems to be substantially of fluoroquinolones.10 Levocetirizine: nothing new but the dose
Levocetirizine = R (-) cetirizine
Quite often in the history of antihistamines, it has been observed the replacement of old drugs - because of frequent (eg. sedation) or Registered indications: similar.
serious side effects (eg. death from arrhythmia) - with analogues, Patents and marketing activities:
usually metabolites, that are better tolerated or less toxic: ter- Cetirizine: the patent will expire in fenadine - for example - was replaced by its active metabolite fexofenadine. This is not the case of levocetirizine, an active enanti- Levocetirizine: it came on to the omer of cetirizine.11,12 market in Italy in 2003. Levocetirizine was compared with cetirizine only in healthy volun- teers in order to assess its effective dose: 2.5 and 5 mg of pure en- antiomer were as effective as 5 and 10 mg respectively of racemic mixture in reducing the response to intranasal11 and cutaneous12 ad- ministration of histamine.
Clinical trials available

Seasonal or permanent allergic rhinitis. The clinical efficacy of
levocetirizine (5 mg/day) was assessed in around 20 RCTs, none of which was versus cetirizine, most against placebo and some versus other antihistamines. In the comparisons available, levocetirizine was more effective than placebo but mostly as effective as the com- parative antistamines (fexofenadine 180 mg, loratadine 10 mg, de- sloratadine* 5 mg) in reducing the symptoms of rhinitis, measured with various scales. The larger published RCT versus another anti- histamine,13 involved 373 patients treated for 2 days with levoceti- rizine (5mg/day), desloratadine* (5mg/day) or placebo: both anti- histamines were shown to be more effective than placebo in reduc- ing the symptoms (rhinorrhea, eye irritation, etc.).
*active metabolite of loratadine

Chronic idiopathic urticaria. In literature there are 7 RCTs (for a to-
tal of less than 200 subjects) of which 5 are on healthy volunteers and IN PRATICE…
only 2 on patients. Of the latter two, the first one14 is in Chinese and cannot be found, the other is versus placebo and has shown the greater On the basis of studies available, effectiveness of levocetirizine (5 mg/day) in reducing the symptoms of levocetirizine does not appear to urticaria (measured as subjective symptoms, daily episodes, etc.).15 provide any advantage over ceti- rizine in terms of effectiveness Tolerability. Data on tolerability of levocetirizine are no different
and tolerability. from those of cetirizine, although with a decidedly lower observation time and number of patients treated. Information Packages on Drugs n.3 -
November, 2006 pag 2
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Esomeprazole: double dose in order to seem more effective
S (-) omeprazole (hence the name esomeprazole) Esomeprazole = S (-) omeprazole
is the levorotatory enantiomer of omeprazole, a Registered indications: similar
50:50 racemic mixture of levo and dextro (or R) Patents and marketing activities:
Both enantiomers are partially inactivated: S- Omeprazole: it has been marketed as a generic drug since omeprazole is inactivated to a lesser extent than R- 2001 in the USA, since 2003 in the EU, but in Italy the va- omeprazole, thus reaching greater blood concentra- lidity of the patent was extended until 2008 tions. At gastric cell level there occurs the transfor- (Supplementary Protection Certificate). mation of both isomers in omeprazole-sulfenamide, Esomeprazole: it came on to the market in Italy in 2002 the active metabolite on the proton pump.16,17
with a mutual recognition procedure. As a result of the different inactivation of the two enantiomers, administration of 20 mg of esomepra- zole makes it possible to obtain blood concentra- tions of the drug (evaluated as area under the curve or AUC) 70-90% higher than those obtained by administering 20 mg of the racemic drug.17,18 Due to the higher serum levels obtained, 20 mg of esomeprazole administered for 5 days cause 90% suppression of gastric acidity, higher than the 79% obtained with 20 mg of omeprazole19 1 Kg vs 1,5 Kg: which one is heavier?
On the basis of these figures, it can be said that 14-16 mg of esomeprazole are able to induce
Clinical data: an uneven comparison
an increase in gastric pH similar to that pro-
duced by 20 mg of omeprazole.
Despite the availability of basic pharmacological data, clinical trials were conducted using mainly In a comparative trial on healthy volunteers, ad- 40 mg of esomeprazole: in practice the choice was
ministration of 40 mg of esomeprazole for 5 days made to compare relatively higher doses of
maintained gastric pH >4 for 14.0 hours: a higher esomeprazole in relation to the standard doses
effect if compared to the 12.1 hours obtained with of the other proton pump inhibitors (PPI).
rabeprazole (20 mg), 11.8 hours with omeprazole (20 mg), 11.5 hours with lansoprazole (30 mg) and An example of this is the greater effectiveness in the 10.1 hours with pantoprazole (40 mg).20 This supe- treatment of reflux esophagitis found in a systematic riority was not confirmed in a trial where healthy review comparing esomeprazole with other PPIs22 volunteers treated with 20 mg of esomeprazole for attributable to the use of esomeprazole in higher 5 days showed a less rapid and prolonged gastric doses than the standard doses of the other PPIs. pH control compared with 20 mg of rabeprazole.21 After 8 weeks of treatment, 40 mg of esomeprazole achieved an endoscopic cure in 4% more patients (88% vs. 84%) compared to those treated with standard doses of the other PPIs. Figure 1. National prescription trend of esomeprazole, ome-
prazole and all the other PPIs (Source: 2005 OsMED Report)
Equivalent doses* Doses on the market Table 2. Equivalent doses and doses on the market for
various PPIs. * Equivalence expressed on the basis of the ability to inhibit gastric acidity What they write from abroad…
IN PRATICE.
Esomeprazole does not provide advan- There are no figures showing the superiority of tages compared with equivalent doses of one PPI over the others if used at equivalent the other proton pump inhibitors.18 doses. The introduction of esomeprazole into clini- cal practice has not provided real advantages, but .Esomeprazole, promoted in order to re- is an example of a commercial initiative designed place omeprazole, does not really have to maintain a market share when the patent of any clinical advantage over it, either in terms of effectiveness or in terms of adverse side effects. drugs belonging to the same class expires. Its raison d'être is purely commercial…24 Information Packages on Drugs n.3 -
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Escitalopram: are there major advantages over citalopram?
Escitalopram, a selective antidepressant inhibitor of the re- Escitalopram = S (+) citalopram
uptake of serotonin (SSRI), is the active enantiomer of the racemic mixture citalopram.
Registered indications: similar
Escitalopram vs. Citalopram: the available evidence Patents and marketing activities:
Citalopram: the patent expired in 2004 The efficacy of escitalopram in the treatment of major depres- (the generic product is also available). sion, panic attacks and anxiety in adults was initially demon- Escitalopram: it came on to the market in strated - in the same way as that of the racemic mixture (citalopram) - in comparison with placebo. RCTs were then carried out versus other antidepressants.
Major depression. There are only four RCTs published
(found in PubMed) that have compared escitalopram Figure 2. Prescription trend of SSRI in Italy:
the rise of escitalopram (Source: 2005 OsMED (10- 20 mg/day) with citalopram (20-40 mg/day) in major depression. Three trials25-27 were over a short period of time Report)23 (8 weeks) and had 280, 469 and 491 patients enrolled, re- spectively, whereas only one trial28 on 357 patients had a clinically relevant follow-up period (24 weeks). Three26-28 out of four of these RCTs showed no differences in the average score on the MADRS depression scale (main indi- cator). Only one RCT25 lasting for 8 weeks showed a statisti- cally significant difference on the MADRS scale in favour of escitalopram: the size of this difference is, however, negligi-
ble from the clinical point of view (2 points on a scale of 60).
In 3 RCTs25,26,28 escitalopram showed an improvement of some secondary indicators (percentages of patients respond- ing to the treatment or patients in remission) compared with the racemic mixture; these results still need confirmation, considering the short study period and the limits of the sta- IN PRACTICE…
tistical analyses made.29 At present there is insufficient evidence that escitalopram is really an innovative Panic attacks. One RCT only30 compared the 2 drugs in the
drug compared to the racemic mixture prevention of panic attacks, evaluating 366 patients over 10 weeks and not showing any differences. Its introduction on the market seems to Side effects: from the trials available, it is unclear whether
be linked to commercial reasons. there are differences in tolerability between the 2 drugs. Conclusions
This publication is quoted as: Maestri E, Maltoni S, Formoso G, Marata AM,
Magrini N. Racemic drugs and enantiomers.
• Ever since the chemical synthesis of single enanti- Identifying really useful innovations. omers has been possible and economically sustain- Information Packages on Drugs, 2006; 3:1-4 able, it has become increasingly frequent to see them being brought out on the market. Information Packages on Drugs no. 3 / 2006
This approach is currently required by international Periodical of medical information of the Local Health Authority of Modena regulatory authorities for new drugs. CeVEAS - Centre for the Evaluation of the Effective-
ness of Health Care - viale Muratori, 201 - 41100 • The use of the pure enantiomer is not justified when Modena - Tel 059 435200 - Fax 059 435222 there are on the market racemic mixtures of the
Editor: Nicola Magrini
same effectiveness and tolerability, shown by trials and prolonged clinical use. Associate editors: Anna Maria Marata, Giulio Formoso • Of the examples given, levocetirizine, esomeprazole Graphic editing: Barbara Paltrinieri and escitalopram have similar effectiveness to the Photographs: Emilio Maestri respective racemic compounds, and their marketing seems, above all, linked to economic reasons (expiry Printing: Premiato Stabilimento Tipografico dei of racemic drug patent). On the other hand, com- Comuni – Santa Sofia (Fo) pared with ofloxacin, levofloxacin has greater micro- The last draft of this copy is dated 3/11/2006 biological activity against some bacteria, in particular Edition: 11,200 copies. Distributed to General Practitio-ners. Available on-line at the following address http://www.
ceveas.it Registration at the Court of Modena nr.1787 dated 27/02/2006 Information Packages on Drugs n.3 -
November, 2006 pag 4
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Racemic drugs, enantiomers, chiral centers & Co.
How to find your way around the definitions
different compounds with same empirical formula, therefore same atoms in the same quantity same atoms and same same atoms in the same bonds but different
quantity but bonded together in same atoms, same bonds, same atoms, same bonds but one molecule is the mirror image of the other a mixture in equal parts WHEN ARE TWO MOLECULES CHIRAL?
If 2 molecules have the same composition and the same
type and quantity of bonds between atoms but are a su-
perimposable mirror image of each other they are
called chiral (from the Greek chiròs, hand).
These molecules contain one or more chiral centers or
asymmetric atoms (usually of carbon) to which other atoms or groups of atoms, all different from each other, are Chiral centers
Molecule of levodopa-mine: the chiral center is indicated Chirality is a necessary condition for the existence of
enantiomers: a compound whose molecule is chiral can
exist in the form of enantiomers.
HOW ARE ENANTIOMERS INDICATED?
There are mainly 2 types of classification: • the one that is based on the direction towards which they rotate a plane of polarized light: if to the right, the enantiomer will be dextrorotatory and will be indi-
cated as (+); if to the left, it is levorotatory and will be
indicated as (-);
• the one that refers to the spatial arrangement of the molecule in relation to the chiral center/s: if the arrange- ment of the atoms or groups of atoms (starting from the heaviest and going towards the lightest) goes clockwise it will be known as enantiomer R (from rectus); if anti-
clockwise it will be known as enantiomer S (from sinis-
ter) (rule of Cahn, Ingold, Prelog).31
The 2 types of classification are independent of each
other: it is impossible to know a priori whether the rota-
tion (+) or (-) corresponds to the R or S configuration.
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1. Caner H, et al. Trends in the development of chiral drugs. Drug Discov Today. 2004;9:105-10. 2. Fda's policy statement for the development of new stereoisomeric 3. Somogyi A, et al. Inside the isomers: the tale of chiral switches. Aust Prescr. 2004;27:47-9 4. New drugs IV. Therapeutics Letter. 1998;26 http://www.ti.ubc.ca/ 5. Hayakawa I, et al. Synthesis and antibacterial activities of optically acti- ve ofloxacin. Antimicrob Agents Chemother. 1986;29:163-4 6. Fish DN, Chow AT. The clinical pharmacokinetics of levofloxacin. Clin Pharmacokinet. 1997;32:101-19 7. Guidelines for the Management of Adults with Community-acquired 8. The British Thoracic Society. Pneumonia Guidelines. http://www.brit- 9. Owens RC, Ambrose PG. Antimicrobial safety: focus on fluoroquinolo- nes. Clin Infect Dis. 2005;41(Suppl 2):S144-57. 10. Ministero della Salute. Dear Doctor Letter 15/03/2002 11. Wang DY, et al. Effect of cetirizine, levocetirizine, and dextrocetirizine on histamine-induced nasal response in healthy adult volunteers. Al-lergy. 2001;56:339-43 12. Devalia JL, et al. A randomized, double-blind, crossover comparison among cetirizine, levocetirizine, and ucb 28557 on histamine-induced cutaneous responses in healthy adult volunteers. Allergy. 2001; 56 :50–7 13. Day JH, et al. Comparative clinical efficacy, onset and duration of action of levocetirizine and desloratadine for symptoms of seasonal allergic rhinitis in subjects evaluated in the Environmental ExposureUnit (EEU). Int J Clin Pract. 2004;58:109–18 14. Yun R, et al. A clinical trial of levocetirizine in the treatment of chronic idio- pathic urticaria. Journal of Clinical Dermatology. 2003;32:477-8 15. Nettis E, et al. Levocetirizine in the treatment of chronic idiopathic urti- caria: a randomized, double-blind, placebo-controlled study. Br J Der-matol. 2006;154:533-8 16. Hassan-Alin M, et al. Eur J Clin Pharmacol. 2005;60:779-84 17. Astra-Zeneca, report drawn up by M. Hassan-Alin, et al. Eur J Clin Pharmacol. 2005;60:779-84 18. Do Single Stereoisomer Drugs Provide Value? Therapeutics Letter. 2002;45 19. Andersson T, et al. Aliment Pharmacol Ther. 2001;15:1563-9 20. Miner P Jr, et al. Acid Control With Esomeprazole Lansoprazole, Ome- prazole, Pantoprazole, and Rabeprazole: A Five-Way Crossover Study. Am J Gastroenterol. 2003;98:2616-20 21. Warrington S, et al. Effects of rabeprazole 20 mg or esomeprazole 20 mg on 24-h intragastric pH and serum gastrin in healthy subjects. Ali-ment Pharmacol Ther. 2002;16:1301–7 22. Edwards SJ et al. Systematic review: proton pump inhibitors for the healing of reflux oesophagitis - a comparison of esomeprazole with o-ther PPIs. Aliment Pharmacol Ther. 2006;24:743-50 23. The use of drugs in Italia. Rapporto OsMED 2005 http://www.
agenziafarmaco.it 24. Redactional. Ésoméprazole et oméprazole: bonnet blanc et blanc bon- net. Prescrire. 2002;227:248-50 25. Moore N, et al. Prospective, multicentre, randomized, double-blind study of the efficacy of escitalopram versus citalopram in outpatient treatment of major depressive disorder. Int Clin Psychopharmacol. 200-5;20:131-7 26. Lepola UM, et al. Escitalopram (10-20 mg/day) is effective and well to- lerated in a placebo-controlled study in depression in primary care. Int Clin Psychopharmacol. 2003;18:211-7 27. Burke WJ, et al. Fixed-dose trial of the single isomer SSRI escitalopram in depressed outpatients. J Clin Psychiatry. 2002;63:331-6 28. Colonna L, et al. A randomized, double-blind, 24-week study of escita- lopram (10 mg/day) versus citalopram (20 mg/day) in primary care patients with major depressive disorder. Curr Med Res Opin. 200-5;21:1659-68 29. Svensson S, Mansfield PR. Escitalopram: superior to citalopram or a chiral chimera? Psychother Psychosom. 2004;73:10-6 30. Stahl SM, et al. Escitalopram in the treatment of panic disorder: a ran- domized, double-blind, placebo-controlled trial. J Clin Psychiatry. 200-3;64:1322-7 31. Morrison RT, Boyd RN. Organic chemistry. Ambrosiana Publishers Milan. 5th edition, 1991 Information Packages on Drugs n.3 -
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Source: http://assr.regione.emilia-romagna.it/it/servizi/pubblicazioni/collane-cessate/archivio-pacchetti/pacc32006eng.pdf/at_download/file/pacc3-2006-eng.pdf