Xenobiotics and Food-Producing Animals - ACS Publications

Chapter 3

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Veterinary Medicines: Regulation in Europe and the Importance of Pharmacokinetic Studies Κ.

N.

Woodward

Veterinary Medicines Directorate, Woodham Lane, New Haw, Addlestone, Surrey KT15 3NB, United Kingdom

There is a comprehensive system of legislation in the European Community for the regulation of veterinary drugs which is superimposed onto the regulatory requirements of Member States. An important aspect of this framework is the requirement for studies designed to ensure consumer safety. Pharmacokinetic studies and the data which they generate are important for the understanding of the results of laboratory toxicology studies and in the design and interpretation of residues depletion investigations. In the European Community (EC), veterinary medicinal products are regulated as two d i s t i n c t groups. The f i r s t of these, and the group which w i l l mainly be featured i n the f i r s t part of t h i s a r t i c l e constitutes what might be regarded as conventional medicines used f o r various therapeutic purposes. The second comprises those medicinal products which are added to feed largely for prophylactic, c o c c i d i o s t a t i c and growth promotion purposes. The former group i s regulated i n the EC under a series of Directives, the most important ones being those often referred to as the veterinary medicines d i r e c t i v e s , 81/851/EEC and 81/852/EEC (1,2). The l a t t e r group i s controlled under the so-called Feed Additives Directive, 70/524/EEC (3), although i t does not cover drugs added to feed f o r therapeutic purposes; these are dealt with by the veterinary medicines directives. Directives and regulations issuing from the EC are incorporated into the national l e g i s l a t i o n of Member States. Thus, i n the United Kingdom, the requirements of 81/851/EEC, 81/852/EEC and 70/524/EEC have been subsumed into regulations made under the Medicines Act 1968, the key l e g i s l a t i v e framework f o r the control of both human and veterinary medicines (4). A key requirement f o r a l l veterinary medicinal products under both EC and UK law i s that they meet exacting standards of quality, e f f i c a c y and safety. Safety here r e f e r s to safety to the animal patient, safety to the environment, safety to users and safety to the consumer. This work w i l l

0097-6156/92/0503-0026$06.00/0 © 1992 American Chemical Society Hutson et al.; Xenobiotics and Food-Producing Animals ACS Symposium Series; American Chemical Society: Washington, DC, 1992.

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WOODWARD

Regulation & Importance of Pharmacokinetic Studies 27

examine t h i s l a t t e r aspect i n terms of what t h i s means i n p r a c t i c e set against the framework of EC, and therefore, national requirements. Moreover, i t w i l l s p e c i f i c a l l y examine the need for and usefulness of pharmacokinetic studies i n safety assessment.


The Veterinary Medicines Directives These two Directives set out the basic rules for the assessment and authorization of veterinary medicinal products i n the EC. Together, they e s t a b l i s h the Committee for Veterinary Medicinal Products (CVMP) and the essentials of l e g i s l a t i o n for multistate l i c e n s i n g of drugs i n the Community, as well as providing guidelines governing q u a l i t y , safety and e f f i c a c y . The main r o l e of the CVMP i s to advise and give opinions on a l l matters concerned with veterinary medicines, including those r e l a t i n g to the multistate applications mentioned above. At the time of writing, the predominant method of gaining marketing authorization i s through national procedures. A company submits an a p p l i c a t i o n to the regulatory authority i n the country i n which i t wishes to market the product. In the case of the United Kingdom, t h i s i s the Veterinary Medicines Directorate (VMD) based at Weybridge i n Surrey (4). I f the a p p l i c a t i o n i s successful i t may market that product but only i n the Member State i n which the a p p l i c a t i o n was made. As suggested i n the previous paragraph, the Veterinary Medicines Directives or more precisely, 81/851/EEC, o f f e r s an a l t e r n a t i v e approach - the so-called multistate procedure. Here, a company which has previously obtained an authorization i n at least one Member State may request the extension of that authorization to at least f i v e of the others. Under t h i s procedure, a complete dossier of the supporting data i s submitted to each Member State and these then have 120 days to assess t h i s and to provide objections to the European Commission. The a p p l i c a t i o n and the objections are considered by the CVMP which then issues an opinion which i s not binding and Member States then have 30 days to decide whether or not to authorize the product (5). To a s s i s t i t i n i t s work, the CVMP has established a number of working groups (6). The Working Group on the Safety of Residues i s the EC committee which examines the data relevant to the assessment of consumer safety and which makes recommendations to the CVMP accordingly. One of the major functions of the Working Group on the Safety of Residues i s the establishment of maximum residue l i m i t s (MRLs) f o r Community-wide adoption. For the l a s t few years and up to the end of 1991, t h i s has been, and i s now a very much ad hoc procedure, the p r i o r i t i e s for MRL s e t t i n g being i d e n t i f i e d by the Working Group. However, from January 1st 1992, a new Council Regulation (EEC No. 2377/90) comes into force (7). This Regulation has two main implications; from January 1992 no Member State may authorize a new pharmacologically active substance for use i n veterinary medicines unless a Community MRL has been established and i n the period 1992-1996, the safety of a l l pharmacologically active ingredients currently used in veterinary medicines must be reviewed, and MRLs established. It w i l l be the function of the Working Group to carry out the safety

Hutson et al.; Xenobiotics and Food-Producing Animals ACS Symposium Series; American Chemical Society: Washington, DC, 1992.


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assessment o f new and e x i s t i n g a c t i v e i n g r e d i e n t s and t o e s t a b l i s h MRLs f o r t h e s e . D i r e c t i v e 87/22/EEC l a y s down a p r o c e d u r e f o r a p p l i c a t i o n s f o r s o - c a l l e d high technology p r o d u c t s i n t h e Community ( 8 ) . These are l a r g e l y products d e r i v e d from recombinant DNA t e c h n o l o g y o r hybridoma and m o n o c l o n a l a n t i b o d y t e c h n i q u e s b u t t h e y a l s o i n c l u d e p r o d u c t s g i v e n by new d e l i v e r y systems, and p r o d u c t s which f e a t u r e s i g n i f i c a n t innovations. This procedure i s of i n t e r e s t i n that i t is a semi-centralised procedure. As soon a s a Member State r e c e i v e s an a p p l i c a t i o n , i t must r e f e r i t t o t h e CVMP f o r an opinion. I t seems l i k e l y t h a t when t h i s i n v o l v e s a new s u b s t a n c e , t h e a p p l i c a t i o n w i l l be p a s s e d by t h e CVMP t o t h e Working Group on t h e S a f e t y o f R e s i d u e s s o t h a t an MRL c a n be e s t a b l i s h e d . Safety

Data

required

European law w i t h r e s p e c t t o v e t e r i n a r y m e d i c i n e s i s somewhat i n a s t a t e o f f l u x a t the present time. The impending implementation o f C o u n c i l R e g u l a t i o n (EEC) 2377/90 has a l r e a d y been r e f e r r e d t o but i n a d d i t i o n amendments a r e b e i n g made t o t h e v e t e r i n a r y m e d i c i n e s D i r e c t i v e s and v a r i o u s g u i d e l i n e s accompanying t h e s e a r e c u r r e n t l y being revised. However, t h e Working Group on t h e S a f e t y of R e s i d u e s h a s p r o d u c e d a d r a f t g u i d a n c e n o t e w h i c h i s v e r y much in a final form. This sets out the requirements for p h a r m a c o l o g i c a l and t o x i c o l o g i c a l s t u d i e s i n what i s r e f e r r e d t o as t h e S a f e t y F i l e , and t h o s e f o r r e s i d u e s and t h e e l a b o r a t i o n o f MRLs i n t h e R e s i d u e s F i l e , f o r the purposes o f 81/851/EEC and C o u n c i l R e g u l a t i o n (EEC) 2377/90 (9,10) As described elsewhere i n this Volume, t h e aim o f t h e toxicological (and m i c r o b i o l o g i c a l ) studies i s t o allow the i d e n t i f i c a t i o n o f a no-observed effect level (NOEL) and t h e c a l c u l a t i o n o f an a c c e p t a b l e d a i l y i n t a k e (ADI) ( 1 1 ) . The s a f e t y f i l e s p e c i f i e s the types of t o x i c o l o g i c a l study that a r e u s u a l l y required t o allow the construction of the t o x i c o l o g i c a l p r o f i l e of a veterinary drug active ingredient and t o i d e n t i f y t h e NEL. These i n c l u d e t h e f o l l o w i n g : s i n g l e dose t o x i c i t y r e p e a t e d dose t o x i c i t y reproductive t o x i c i t y e f f e c t s on r e p r o d u c t i o n e m b r y o / f e t o t o x i c e f f e c t s and t e r a t o g e n i c i t y mutagenicity studies carcinogenicity studies pharmacodynamics i n l a b o r a t o r y s p e c i e s pharmacokinetics i n laboratory species microbiological effects o b s e r v a t i o n s i n humans. The o b j e c t i v e o f t h e R e s i d u e s F i l e i s t o a l l o w t h e e l a b o r a t i o n o f MRLs t a k i n g i n t o a c c o u n t t h e ADI c a l c u l a t e d from t h e t o x i c o l o g y and o t h e r safety data, and t h e p h a r m a c o k i n e t i c s and residues depletion information. These latter two a s p e c t s will now be d i s c u s s e d i n more d e t a i l .


3. WOODWARD

Regulation & Importance of Pharmacokinetic Studies


Pharmacokinetic Requirements: Some Applications and Considerations Pharmacokinetic studies are often referred to using the acronym ADME - absorption, d i s t r i b u t i o n , metabolism and excretion r e f l e c t i n g the four main areas for study. The use of such an acronym i s s i m p l i s t i c i n nature when one considers that each of the four areas i s interdependent on one or more of the others, but nevertheless i t i s a convenient way of d i v i d i n g up the studies that f a l l under the broad heading of pharmacokinetics. The European Communities' guidelines mentioned i n the previous paragraph are notable i n that while they indicate i n some d e t a i l the types of t o x i c o l o g i c a l tests required, pharmacology studies appear under the two broad headings of "pharmacodynamic" and "pharmacokinetic" studies. There i s a good reason for t h i s f o r whereas toxicology studies have evolved into rather rigid investigations i n order to maintain standards and to ensure that chemicals are tested using s i m i l a r models, pharmacodynamic, and e s p e c i a l l y pharmacokinetic studies have remained as ad hoc experimental investigations. The design of each experiment depends very much on the nature of the chemical agent and on i t s i n t e r a c t i o n (and vice versa) with the animal i n which the experiments are being c a r r i e d out. Consequently, each experiment i s usually designed de novo depending on the drug being tested, the e f f e c t being investigated and the animal being used. For these reasons there are no s t r i c t pharmacological testing guidelines comparable with those (e.g. the OECD Guidelines) developed for t o x i c o l o g i c a l testing. For veterinary drugs, intended for use i n food producing animals, pharmacokinetic studies are c a r r i e d out f o r several reasons and they can be divided into investigations with laboratory animals (mice, rats and dogs f o r example) and those with target animals (pigs, sheep, c a t t l e e t c ) . In the i n t e r p r e t a t i o n of the r e s u l t s of t o x i c o l o g i c a l studies i n general, pharmacokinetic studies i n laboratory species provide information not only on absorption, d i s t r i b u t i o n , metabolism and excretion per se, but they y i e l d i n addition much more s p e c i f i c information on the r e l a t i o n s h i p of target organs f o r d i s t r i b u t i o n with s i t e specific toxicity, data on major metabolites, biochemical mechanisms of t o x i c i t y , and they i d e n t i f y routes of excretion, a l l of which may help i n the interpretation of t o x i c i t y studies. They also a i d i n cross species extrapolation of the r e s u l t s of t o x i c i t y studies by use of comparative pharmacokinetic data. Measurements of plasma concentrations alone can provide data on the degree of absorption of a drug following administration, i t s systemic b i o a v a i l a b i l i t y , gender, age, and species differences related metabolism and k i n e t i c s , p r o f i l e s a f t e r various routes of drug administration, the relationships between dose and systemic exposure with a given dose range, and plasma elimination k i n e t i c data (12-15). These points are recognized i n the d r a f t EC Guideline and where necessary, pharmacokinetic findings and those from toxicology studies should be brought together i n the Expert Report required by the Directives and by the MRL Regulation.


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As well as providing data useful for the assessment of e f f i c a c y , pharmacokinetic data i n the target animal, are invaluable i n i d e n t i f y i n g target tissues for residues, providing information on the presence or absence of metabolites shown to be toxic, mutagenic or carcinogenic i n laboratory species, and perhaps most importantly, providing k i n e t i c data which can be related to residues depletion. From the point of view of residues assessment, these are the most important uses of pharmacokinetic data. An example i s provided by the drug carbadox. Carbadox i s carcinogenic i n laboratory species but when i t was evaluated by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) i t was noted that the major metabolite present i n residues i n the p i g had been shown to be non-carcinogenic and hence of no r i s k to consumers (16). Residues data are time consuming and expensive to produce. Studies involve the treatment of a number of animals with the formulation for which marketing authorisation i s being sought, followed by t h e i r s e r i a l slaughter at various time points a f t e r dosing so that residues depletion can be studied. I t i s often h e l p f u l i f supporting data from pharmacokinetic studies can be used. One area i n which t h i s could prove useful although, i n p r a c t i c e i t i s rarely employed, i s i n the development of new products following the introduction of an i n i t i a l formulation. If studies on this initial formulation have correlated pharmacokinetic parameters, e s p e c i a l l y area under the curve (AUC) measurements, volume of d i s t r i b u t i o n , and plasma and renal clearance rates with residue levels i n the depletion study, then residues studies may not be required f o r new products (for example using higher doses) i f pharmacokinetic data for these are a v a i l a b l e . Moreover, the investigation of pharmacokinetics early on i n the development of a drug might not only provide useful data for e f f i c a c y considerations, i t may also lead to the better design of subsequent residues studies (17-19). Some caution i s , however, required when making comparisons of pharmacokinetic data. The benzimidazole anthelmintics triclabendazole and albendazole respectively show a similar spectrum of metabolites across a range of animal species including humans (21,21). However, i n rats and other species, absorption of albendazole a f t e r o r a l administration was i n excess of 30% whereas i n human i t was of the order of 1% (21). With triclabendazole, the C and AUC values were much higher i n ruminants than i n horses or humans for the sulphoxide metabolite whereas f o r the sulphone the horse was more s i m i l a r to ruminants which d i f f e r e d markedly from the values obtained i n man. Sulfamethazine and other sulfonamides show a s i m i l a r metabolite p r o f i l e i n c a t t l e , sheep and goats but here there are few data on quantitative aspects (22). Consequently i t i s important to have quantitative pharmacokinetic data i n addition to more q u a l i t a t i v e information before d i r e c t comparisons are made. Qualitative and quantitative differences across species also exist for ivermectin and s a l i c y l i c acid whereas the aminoglycosides and morantel are e s s e n t i a l l y s i m i l a r (23-28).



3. WOODWARD

Regulation & Importance of Pharmacokinetic Studies 31

Age plays an important part i n determining the pharmacokinetic behaviour of drugs (29). In sheep f o r example, the a c t i v i t i e s of a number of hepatic drug metabolizing enzymes including that of cytochrome P-450, a major component of the microsomal drug metabolizing system, are r e l a t i v e l y low i n animals aged up to the 6 months when compared with adult l e v e l s (30)» Such findings probably help to explain why f o r example the h a l f - l i v e s of sulfadoxine and trimethoprim i n neonatal calves and lambs are r e l a t i v e l y long, and why they shorten with increasing age ( 3 1 ) . It i s possible that the e f f e c t s of gender seen with some drugs are also due i n part to the a c t i v i t y of cytochrome P-450, and probably explain the differences i n hexobarbital-induced sleeping time i n rats where females sleep longer than males ( 3 2 , 3 3 ) . Antipyrine plasma elimination i n rats and c a t t l e shows sex differences and to some extent these differences may be mediated by sex hormones as clearance of antipyrine and sulfamethazine i n female dwarf goats was markedly decreased following implantation of trenbolone, a synthetic steroid with anabolic properties (33). These findings have implications f o r withdrawal periods as residues studies are often conducted i n one sex and they underline the need f o r pharmacokinetic data i n t h e i r design phase. Similar sentiments could also be made f o r the s i t u a t i o n involving sick animals. Residues studies are notable i n that they are invariably conducted i n healthy, mature young animals and yet the drugs being examined are intended f o r sick animals. Several drugs i n several species are known to have different pharmacokinetic behaviour when the animal i s sick, a factor which may a f f e c t both the e f f i c a c y and the withdrawal period. The volume of d i s t r i b u t i o n f o r o r a l l y administered trimethoprim i s s i g n i f i c a n t l y increased i n f e b r i l e rabbits compared with t h e i r healthy counterparts, and absorption i s reduced (34). The prolonged terminal elimination phase of gentamicin i s prolonged i n the d i a b e t i c dog r e s u l t i n g i n longer plasma half l i v e s (35). Several drugs including trimethoprim i n the c a l f , sulfamethazine and oxytetracycline i n the goat and oxytetracycline i n the p i g show prolonged plasma elimination h a l f - l i v e s i n f e b r i l e or infected animals (36-38). On the other hand, the same disease states had no e f f e c t s on the pharmacokinetics of a m o x i c i l l i n and chloramphenicol i n the c a l f , nor on a m p i c i l l i n and sulfamethazole i n goats (36,37). Although f e b r i l e pigs showed reduced elimination h a l f - l i v e s and increased AUC when oxytetracycline was given o r a l l y , there was no e f f e c t apparent a f t e r intravenous administration suggesting an e f f e c t on g a s t r o i n t e s t i n a l absorption ( 3 8 , 3 9 ) . Such findings lead one to wonder whether residues studies ought to be conducted i n sick animals rather than healthy ones or to question whether pharmacokinetic studies should be conducted i n both sick and healthy animals so that withdrawal periods might be adjusted where disease states are shown to a f f e c t drug clearance. F i n a l l y , i t i s important to r e a l i s e that pharmacokinetics not be the answer to every problem! This i s exemplified reference to residues of sulfamethazine i n pigs. P i g kidneys several countries including the UK and the USA have been found


may by in to


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contain residues of sulfamethazine at above the MRL of 0.1 mg/kg (40-42). The l e v e l of v i o l a t i o n s at one time i n the UK (1980-1983) reached around 20% of p i g kidneys examined jj40)_ but t h i s has f a l l e n steadily since that period u n t i l i n 1989 the figure stood at below 6% (43). I t might have been tempting at one stage to suggest that the withdrawal periods were of i n s u f f i c i e n t duration and that pharmacokinetic studies could be useful to throw some l i g h t on the problem. However, the r e a l reasons are complex and involve carry over of the drug i n the feces and urine of treated pigs, contamination of unmedicated feed with medicated feed, contamination of drinking water at slaughterhouses with feces from treated animals, and f a i l u r e to observe withdrawal periods ( 4 1 , 4 4 - 4 6 ) . Residues at the s i t e of i n j e c t i o n present s p e c i f i c problems. The persistence of residues at intramuscular i n j e c t i o n s i t e s may be due i n part to the i r r i t a n t response produced i n the muscle. Chloramphenicol, t y l o s i n , p e n i c i l l i n s , dihydrostreptomycin and oxytetracycline have been shown to produce l o c a l i r r i t a t i o n at the s i t e of i n j e c t i o n leading to residues persistence and t h i s may be exacerbated by the solvent used (47-49); with one oxytetracycline product which produced l i t t l e i r r i t a t i o n , residues d i d not p e r s i s t (49). Large variations i n pharmacokinetic behaviour were noted i n addition to the persistence at the i n j e c t i o n s i t e and in p a r t i c u l a r with oxytetracycline, b i o a v a i l a b i l i t y was reduced. These studies demonstrate the usefulness of pharmacokinetic data when studying s p e c i f i c routes of administration, and i n p a r t i c u l a r they demonstrate the need to take into account other b i o l o g i c a l phenomena when a t t r i b u t i n g withdrawal periods, i n t h i s case, i r r i t a t i o n at the i n j e c t i o n s i t e . The new d r a f t EC Guideline requires that i n j e c t i o n s i t e s are examined i n residues studies with injectable products and i n the case of persistence at the s i t e , then the withdrawal period w i l l be based on t h i s . Residues may occur i n food of animal o r i g i n e i t h e r as the free parent drug, as free metabolites, as bound parent compound or metabolites, or biologically incorporated into endogenous biochemicals (50). The investigation of the nature of residues can be conveniently considered as an area of pharmacokinetics as i t involves the study of metabolism, organ d i s t r i b u t i o n , molecular d i s t r i b u t i o n and clearance. It i s important as there i s an obvious need to correlate the findings i n toxicology studies with the nature of the residues present i n food of animal o r i g i n . It would of course be impractical to subject a l l known metabolites of a drug to t o x i c o l o g i c a l t e s t i n g . Some drugs give r i s e to numerous metabolites e.g. the anthelmintic agent levamisole affords over 50 i n the r a t (51). It i s normally assumed that the metabolites present represent the sum of the t o x i c i t y noted. However, bound residues present a p a r t i c u l a r problem and i f they are s i g n i f i c a n t t h e i r a f f e c t on the ADI must be assessed. JECFA has proposed an approach for the assessment of the b i o a v a i l a b i l i t y of bound residues which makes use of extraction procedures and i n vivo models ( 1 6 ) . The i n vivo systems make use of relay (residue transfer) methodologies whereby the r a d i o l a b e l e d drug i s given to the target animal and i t s tissues containing the bound residues



3. WOODWARD


are then incorporated into the food of experimental animals, u s u a l l y the r a t . B i o a v a i l a b i l i t y c a n t h e n be d e t e r m i n e d by m e a s u r i n g t h e r a d i o a c t i v i t y and d i s t r i b u t i o n i n t h e t i s s u e s o f ':he e x p e r i m e n t a l s p e c i e s (52-60). These t y p e s o f s t u d i e s have been used t o demonstrate that bound r e s i d u e s o f r o n i d a z o l e , carbadox, cambendazole, and f u r a z o l i d o n e a r e o f no t o x i c o l o g i c a l c o n c e r n (61-68). The "bound" r e s i d u e s a s s o c i a t e d w i t h t h e m i l k p r o d u c t i o n e n h a n c e r a c t a p l a n i n and t h e a n t h e l m i n t i c d r u g p - t o l u o y l chloride p h e n y l h y d r a z o n e were shown to be moieties metabolically i n c o r p o r a t e d i n t o normal c e l l u l a r c o n s t i t u e n t s and t h e r e f o r e o f no biological significance (69,70). On t h e o t h e r hand, reactive m e t a b o l i t e s c a n be r e g e n e r a t e d from bound r e s i d u e s o f t r e n b o l o n e by hepatic monooxygenases in vitro (71), although the t o x i c o l o g i c a l s i g n i f i c a n c e f o r the i n vivo s i t u a t i o n i s unclear. Such f i n d i n g s underline the importance of investigations into bound r e s i d u e s , p a r t i c u l a r l y i f long withdrawal periods imposed b e c a u s e o f l o n g d e p l e t i o n t i m e s f o r t o t a l r e s i d u e s a s measured by r a d i o l a b e l l i n g t e c h n i q u e s , a r e t o be a v o i d e d . Summary European Community D i r e c t i v e s governing veterinary medicinal p r o d u c t s have r e q u i r e m e n t s f o r p h a r m a c o k i n e t i c s t u d i e s w h i c h c a n be u s e f u l i n the i n t e r p r e t a t i o n of the r e s u l t s of toxicology s t u d i e s and i n t h e d e s i g n o f r e s i d u e s depletion experiments. There a r e no s t r i c t guidelines f o r the conduct of these p h a r m a c o k i n e t i c s t u d i e s s i n c e d e s i g n w i l l depend on t h e n a t u r e o f t h e d r u g under i n v e s t i g a t i o n and on t h e p r e l i m i n a r y f i n d i n g s from the t o x i c o l o g y . Used w i s e l y , t h e r e s u l t s from i n v e s t i g a t i o n s i n t o pharmacokinetic behaviour can r e v e a l an i n s i g h t i n t o s p e c i e s and gender d i f f e r e n c e s i n toxicity and r a t e s of metabolism, d i s p o s i t i o n and e x c r e t i o n and h e l p t o p r o v i d e a more c o m p l e t e p i c t u r e o f t h e b i o l o g i c a l p r o p e r t i e s o f drugs i n l a b o r a t o r y and f o o d - p r o d u c i n g a n i m a l s and p r o v i d e r e a s s u r a n c e on t h e e x t r e m e l y i m p o r t a n t i s s u e o f consumer s a f e t y .

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