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Pharmacokinetic and pharmacodynamic aspects of site-specific drug delivery
Advanced Drug Delivery Reviews, 3(1989)155-163
155
Elsevier A D R 00029
Pharmacokinetic and pharmacodynamic aspects of site-specific drug delivery Alan Boddy and Leon Aarons Pharmacy Department, University of Manchester, Manchester, U. K. (Received April 15, 1988) (Accepted May 1, 1988)
Key words: Drug targeting; Macromolecule; Selective distribution; Drug carrier; Concentration-effect relationship; Therapeutic response; Toxicity
Contents Summary .................................................................................................................
156
I. Introduction ...................................................................................................
156
II. Pharmacokinetic considerations .......................................................................... 1. Rate of elimination of drug-carrier conjugate .................................................. 2. Rate of delivery of drug-carrier conjugate to the target site ............................... 3. Rate of removal of drug carrier from the target site ......................................... 4. Rate of release of free drug at the target site .................................................. 5. Rate of removal of free drug from the target site ............................................. 6. Rate of elimination of free drug from the body ............................................... 7. Rate of release of free drug at non-target sites ................................................
156 157 158 158 158 159 159 160
II1. Pharmacodynamic considerations .......................................................................
160
IV. Conclusions ....................................................................................................
161
References ...............................................................................................................
162
Definitions: throughout this report the following definitions will apply: drug carrier, any part of a drug-targeting conjugate that is not the pharmacologically active moiety; (free) drug, drug free from conjugation to a drug carrier; (drug-carrier) conjugate, drug attached to a drug carrier; target site, a site which is distinct from sites where toxicity occurs and from the general circulation. While not identical to the pharmacological site of action, the target site must be in more rapid equilibrium with this site of action than with sites where toxicity occurs. Correspondence: A. Boddy, Pharmacy Department, University of Manchester, Oxford Road, Manchester M13 9PL, U.K. 0169-409X/89/$03.50 ¢~) 1989 Elsevier Science Publishers B.V. (Biomedical Division)
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Summary
The influence of the pharmacokinetics of drug-carrier conjugates and free drug and the pharmacodynamics of therapeutic and toxic response on the potential for success of a drug-targeting system have been considered. Using previous investigations and the present discussion it is possible to make some qualified statements about optimisation of drug targeting. These statements are dependent on the extent of understanding of the disease process, the anatomy and pathophysiology of the target site, the pharmacokinetics of drug carrier and free drug, the mechanism of drug release and the pharmacodynamics of therapeutic and toxic effects. I.
Introduction
The aim of drug targeting is to maximise the therapeutic response to a drug, by delivering it specifically to a target site, whilst minimising toxic effects. Conventional therapy depends on drugs that have an adequate ratio of therapeutic response to toxic effects due to innate pharmacokinetic or pharmacologic selectivity for the specific site or sites of action. Therapy with drugs which possess such selectivity probably does not merit the sophistication and expense of drug targeting. However, drugs which have a poor ratio of therapeutic to toxic effects, or are prevented from exercising a potentially beneficial effect due to adverse pharmacokinetic properties, may benefit from drug targeting [1]. Drug targeting, as defined above, is usually conceived of as systemic administration of a drug-carrier conjugate which delivers free drug selectively to a particular tissue [2]. This process may consist of a combination of steps including protection of drug in non-target tissues, selective distribution of drug-carrier conjugate to and binding of the conjugate within the target tissue and selective release of free drug within the tissue [1,3]. The contributions of macromolecules to each of these components are dealt with in detail elsewhere [4]. This report is concerned primarily with how the pharmacokinetics and pharmacodynamics of the free drug affect the degree of advantage due to drug targeting over conventional administration. The influence of the pharmacokinetics of the drug-carrier conjugate, its distribution and the rate of release of free drug will also be considered from a theoretical point of view. II.
Pharmacokinetic considerations
The purpose of administering a drug in any form is to optimise the concentration-time profile of drug at target and non-target sites. In conventional administration, the drug profile at some target site is determined by the rate of input of drug into and elimination from the body, the rate at which it is delivered to the target site and the rate at which it is removed from that site. Similar considerations apply to the non-target sites where toxicity may occur [5]. In the case of drug targeting the controlling processes are rate of input of drug-carrier conjugate into and elimination from the body, rate of distribution of drug-carrier conjugate to the tar-
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Scheme I. Simple three compartment model illustrating the processes in site-specific drug delivery. DC~, DCR and DC r are the concentrations of drug carrier in central, response and toxicity compartments, respectively. DX~, DXa and DXT are the resultant concentrations of free drug in these compartments. Qrt and QT are the blood flows to the response and toxicity compartments, respectively. get and rate of removal from the target, rate of release of free drug and rate of removal of free drug from the target site. Concentrations of free drug in the nontarget sites are determined by rate of removal of drug from the target site, rate of distribution to and from the non-target site and rate of elimination of free drug from the body (assuming absolute selectivity of release). These processes are illustrated in Scheme I, which shows a simple pharmacokinetic model incorporating central, response and toxicity compartments.
I1.1. Rate of elimination of drug-carrier conjugate Much of the work with macromolecular drug-carriers is concerned with developing a carrier which is not rapidly eliminated from the circulation [4]. This is necessary both to minimise the exposure of eliminating organs to the targeted drug and to maximise the fraction of the dose that reaches the target site. However, uptake of the drug-carrier conjugate by target tissue reduces blood concentrations and results in efficient targeting [6]. If the drug-carrier conjugate is eliminated more
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rapidly than it is delivered to the target, concentrations of conjugate at this site may be insufficient to maintain an adequate release rate of free drug. Also, if only a small fraction of the dose of drug-carrier conjugate reaches the target site, most of the dose of an expensive and sophisticated drug-targeting system is wasted.
H.2. Rate of delivery of drug-carrier conjugate to the target site Whereas selective distribution of drug-carrier conjugate may ensure relative selectivity of release of free drug [7], the kinetics of distribution of the conjugate become important if its rate of delivery to the target site limits the rate of release of free drug at that site. If drug-carrier conjugate distributes too slowly to the target site the rate of release of free drug may not be sufficient to generate the free drug concentrations necessary to achieve the desired therapeutic response. Rate of delivery of conjugate depends on blood flow to the target site and on the permeability of the target site to the drug-carrier. Drug-carrier conjugate which is presented to the target organ by the blood may have to cross several membrane barriers before reaching the site of free drug release (c.f. Ref. 18). The rate of transport across these barriers may limit the rate of drug-carrier conjugate access and so the rate of release of free drug. The upper limit to the rate of delivery is provided by the product of blood flow to the target site and blood concentration of conjugate.
H.3. Rate of removal of drug-carrier conjugate from the target site The concentration of drug-carrier conjugate at the target site is determined by the balance of delivery rate and rate of removal from the site, including physical removal in blood and lymph and the rate of release of free drug. The higher the rate of removal of conjugate, the lower is the concentration at the target site and, hence, the rate of release and the concentration of free drug are lower. Any species present at the target site is removed at a rate equal to the product of the sum of blood and lymph flow from the target site and the concentration of the species available for removal. Binding of macromolecular drug-carriers selectively at the target sites reduces the fraction available for removal and so reduces the rate of removal of the conjugate. However, if only unbound conjugate can release free drug, such binding may actually reduce the rate of release and so decrease free drug concentrations. The inability of macromolecules or charged species to cross membrane barriers may also act to retain drug-carrier conjugate at the target site, but only if access to the target site has first been achieved [3].
H.4. Rate of release of free drug at the target site Drug release at the target site is generally conceived of as occurring by one of two mechanisms. The first is dependent on a locally selective, but non-specific, chemical characteristic of the target site which is different from non-target sites, such as pH [8]. Release of free drug by this mechanism would be limited only by
PHARMACOKINETIC AND -DYNAMIC ASPECTS OF DRUG DELIVERY
159
the concentration of drug-carrier conjugate at the site available to release free drug, as determined by the factors considered above. The second type involves activation of the drug or cleavage of the drug-carrier conjugate by some specific enzymic mechanism peculiar to the target site [1,9]. The maximum rate of release by this type of mechanism is dependent on the concentration and activity of the enzyme involved. Thus, the limited capacity of the latter release mechanism would restrict the rate of release of free drug regardless of the concentration of conjugate at the target site, and selective and adequate delivery of the drug-carrier conjugate may not result in the desired therapeutic response. Also, since the concentrations of enzymes often vary between individuals [10], the rate of release of free drug will also vary if release is occurring at the maximal rate [11].
11.5. Rate of removal of free drug from the target site The counterpart to the rate of release of free drug at the target site is its removal from the site and transport to the rest of the body. As for drug-carrier conjugate, the rate of removal is equal to the product of blood flow and the concentration of free drug at the site which is available for removal [1]. Thus binding of the drug within the target site reduces the concentration available for removal, but may also reduce the effective concentration at the active site. Drugs which are ionised or polar and so do not easily cross membrane barriers between the target site and blood may increase the retention at the site [3], but do not reduce the overall exposure of the rest of the body to drug which must enter non-target tissues before it can be eliminated. Any mechanism of retention of free drug at the target site must retain drug in an active form, otherwise the mechanism of retention is analogous to removal of free drug from the site and reduces the therapeutic response. Apart from physical removal via the blood, free drug may also be removed directly from the target site if elimination of the free drug occurs at this site. If drug released within the target site can be eliminated without first entering non-target tissues, drug targeting offers a significantly increased advantage over conventional administration [5,12]. However, such elimination increases the rate of removal of free drug from the target site and so will lower the concentration at the active site such that a therapeutic response may not be achieved.
11.6. Rate of elimination of free drug from the body Concentrations of free drug at sites where toxicity occurs are dependent on the balance of rate of delivery to those sites and rate of removal. Assuming that the target site is not directly connected to a site associated with toxicity, the rate of delivery is equal to the product of blood flow to the site and blood concentration of free drug. Therefore, increasing the rate of elimination from the body reduces the blood concentration of free drug, the rate of delivery of free drug to non-target sites and so reduces the magnitude of toxic effects [1]. For efficient drug targeting the rate of elimination of free drug from the body should be rapid relative to the rate of transport from the target site to the blood [1,5,12,13].
1~
A. BODDY AND L. AARONS
H. 7. Rate of release of free drug at non-target sites Lack of absolute specificity of release may be due to failure of selective distribution (if the release mechanism is non-specific) or to failure of selective release (if distribution is non-specific). Either of these failures results in release of free drug directly into non-target sites. The consequences of such release are worse when release occurs at a site directly associated with toxicity, but reduces the benefit of drug targeting regardless of the site of release [7,12]. Release rates in toxicity-associated compartments are determined by the rate of delivery and removal of drugcarrier conjugate and the activity of the releasing mechanism at these sites. Free drug concentrations depend on the rate of release and the rate of removal of free drug from the site. If drug is released at a non-target site outside of the toxicityassociated site, the magnitude of the toxic effect depends on the rate of release, subsequent concentration in blood and rate of movement of free drug to and from the toxicity-associated site. The toxicity due to release of free drug in this way is least for those drugs which are rapidly eliminated from the body.
III. Pharmacodynamic considerations Although the primary aim of drug targeting is to generate concentrations at some target site which are high relative to non-target sites, some thought should be given to the pharmacodynamics of both therapeutic and toxic effects of the drug. In most investigations of the optimal conditions for drug targeting it is assumed that response is linearly related to concentration [1,12,14]. The selective advantage due to different sensitivities of therapeutic and toxic effects is allowed for by comparing drug targeting with conventional administration. However, the relationship between concentration and effect is often more complex and may vary with time, previous exposure to drug or the magnitude of the effect [2,15]. The relationship between concentration of free drug and effect may be different at target and non-target sites. For instance, the effects of many drugs increase linearly as concentration is increased at low levels, but at higher concentrations the effect tends towards a maximum. Other complex relationships between response and concentration, such as threshold concentrations, all-or-none effects, desensitization and feedback control [15] must also be considered where appropriate. Pharmacokinetic models incorporating the pharmacodynamics of therapeutic and toxic effects may be used to judge the efficiency of drug targeting (Boddy, A., unpublished results). Simulations using such models indicate that the advantage gained by drug targeting cannot always be judged by ratios of areas under concentration curves for different modes of administration. Where information is available, the relationship between concentration and effect must be considered when evaluating the efficiency of drug targeting both theoretically and practically.
PHARMACOKINETIC AND -DYNAMIC ASPECTS OF DRUG DELIVERY IV.
161
Conclusions
The influence of the pharmacokinetics of drug-carrier conjugates and free drug and the pharmacodynamics of therapeutic and toxic response on the potential for success of a drug-targeting system have been considered. The factors which limit this potential have been dealt with previously [1,12,13,14], but the mechanisms behind the influence of pharmacokinetic parameters on such factors as rate of drugcarrier conjugate delivery, rate of release and removal of free drug and rate of free drug input into non-target sites have not been dealt with comprehensively. Using previous investigations and the present discussion it is possible to make some qualified statements about optimisation of drug targeting. These statements are dependent on the extent of understanding of the disease process, the anatomy and pathophysiology of the target site, the pharmacokinetics of drug-carrier and free drug, the mechanism of drug release and the pharmacodynamics of therapeutic and toxic effects. With regard to the target site, the prime consideration is that it should be distinct from sites where toxicity occurs. If therapeutic and toxic effects occur at the same site then there is no potential for selective distribution of drug-carrier or selective release of free drug [1]. Therefore, drugs such as the oral anti-coagulant warfarin, whose therapeutic and toxic effects involve inhibition of the same enzyme to different extents, are not suitable for drug targeting. A second important consideration is blood flow to and from the target site. It has been stated in the past that to optimise drug targeting this blood flow should be as small as possible so as to minimise the rate of removal of free drug from the target and the rate of input of free drug into the rest of the system [12,13]. However, it should be noted that blood flow to the target organ also provides an upper limit to the rate of delivery of drug-carrier conjugate and so may limit the free drug concentration at the active site [16,17]. The pharmacokinetics of the drug-carrier conjugate are important with regard to the rate of distribution to and removal from the target site, distribution to nontarget sites and rate of elimination. Distribution to non-target sites will contribute to elimination from the general circulation if accumulation in those sites is rapid and of sufficient magnitude. The rate of distribution to the target site is limited by blood flow and permeability. However, the rate of removal may also be influenced by binding at the site. In some circumstances binding at the target site may be viewed as equivalent to removal, if only unbound conjugate is able to release free drug. The intrinsic pharmacokinetic properties of the free drug are the same irrespective of whether it is introduced into the body attached to a carrier or not. However, the site of release (or route of administration) can influence the concentration-time profiles observed in different tissues [5]. The pharmacokinetic parameter which has the most direct effect on the potential benefit of drug targeting is the clearance of drug from the body. For two drugs which are released at the same rate in the same target site, the one which is most rapidly eliminated will attain the lowest concentration outside the target site. Provided either the rate of release
162
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at the target site or the blood flow from the site is less than the rate of elimination from the body, concentrations at the target site are independent of the rates of elimination in other tissues. Thus, choosing a drug which is rapidly eliminated from the body minimises concentrations outside of the target site, without reducing therapeutic effects. Elimination of drug directly from the target site reduces the rate of input into and concentrations in non-target sites, but also reduces the concentration within the target site. This effect may be offset by increasing the rate of delivery of drugcarrier conjugate or the rate of release of free drug in the target site, but there may be maximum limits to these rates. Finally, the pharmacodynamics of therapeutic and toxic responses are important in designing the optimal drug-targeting system. If the optimum concentration-time profile for a drug at the target site is known, it may be possible to tailor the characteristics of the drug carrier, release mechanism and choice of drug to achieve this profile whilst minimising toxic effects. Unfortunately, details of the pharmacodynamics of a drug are frequently difficult to investigate. References 1 Stella, V.J. and Himmelstein, K.J. (1985) Prodrugs: a chemical approach to drug delivery. In: R.T. Borchardt, A.J. Repta and V.J. Stella (Eds.), Directed Drug Delivery, Humana Press, New York, pp. 247-267. 2 Tomlinson, E. (1987) Theory and practice of site-specific drug delivery, Adv. Drug Deliv. Rev. 1, 87-198. 3 Bodor, N. (1985) Targeting of drugs to the brain, Methods Enzymol. 112,381-396. 4 Sezaki, H. and Hashida, M. (1985) Macromolecule-drug conjugates in targeted cancer chemotherapy, CRC Crit. Rev. Ther. Drug Carriers 1, 1-38. 5 0 i e , S. and Huang, J.-D. (1981) Influence of administration route on drug delivery to a target organ, J. Pharm Sci. 70, 1344-1347. 6 Duncan, R., Lloyd, J.B., Rejmanova, P. and Kopecek, J. (1985) Methods of targeting N-(2-hydroxypropyl)methacrylamide copolymers to particular cell types, Makromol. Chem. Suppl. 9, 3-12. 70rlowski, M., Mizoguchi, H. and Wilk, W. (1980) N-Acyl--t-glutamyl derivatives of sulfamethoxazole as models of kidney-selective prodrugs, J. Pharmacol. Exp. Ther. 212, 167-172. 8 Shen, W.C. and Ryser, J.P. (1981) c/s-Aconityl spacer between daunomycin and macromolecular carriers: a model of pH-sensitive linkage releasing drug from a lysosomotropic conjugate, Biochem Biophys. Res. Commun. 102, 1048-1054. 9 Wilk, S., Mizoguchi, H. and Orlowski, M. (1978) 3,-Glutamyl dopa: a kidney-specific dopamine precursor, J. Pharmacol. Exp. Ther. 206, 227-232. 10 Houston, J.B. (1981) Drug metaholite kinetics, Pharmacol. Ther. 15,521-552. 11 Notari, R.E. (1985) Theory and practice of prodrug kinetics, Methods Enzymol. 112,309-323. 12 Hunt, C.A., MacGregor, R.D. and Siegel, R.A. (1986) Engineering targeted in vivo drug delivery. I. The physiological and physicochemical principles governing opportunities and limitations, Pharmaceut. Res. 3,333-344. 13 Levy, G. (1987) Targeted drug delivery - some pharmacokinetic considerations, Pharmaceut. Res. 4,3--4. 14 Stella, V.J. and Himmelstein, K.J. (1980) Prodrugs and site-specific drug delivery, J. Med. Chem. 23, 1275-1282. 15 Holford, N.H.G. and Sheiner, L.B. (1982) Kinetics of pharmacologic response, Pharmacol. Ther. 16, 143-166. 16 Levin, V.A., Patlak, C.S. and Landahl, H.D. (1980) Heuristic modeling of drug delivery to malignant brain tumors, J. Pharmacokin. Biopharm. 9, 257-296.
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17 Weinstein, J.N., Black, C.D.V., Barber, J., Eger, R.R., Parker, R.J., Holton, O.D., Mulshine, J.L., Keenan, A.M., Larson° S.M., Carrasquillo, J.A.. Sieber, S.M. and Covell, D.G. (1986) Selected issues in the pharmacology of monoclonal antibodies. In: E. Tomlinson and S.S. Davis (Eds.), Site-specific drug delivery. Cell biology, medical and pharmaceutical aspects, John Wiley, London, pp. 81-91. 18 Petrak, K. and Goddard, P. (1989) Transport of macromolecules across the capillary walls, Adv. Drug Deliv. Rev. 3, 185-000.
155
Elsevier A D R 00029
Pharmacokinetic and pharmacodynamic aspects of site-specific drug delivery Alan Boddy and Leon Aarons Pharmacy Department, University of Manchester, Manchester, U. K. (Received April 15, 1988) (Accepted May 1, 1988)
Key words: Drug targeting; Macromolecule; Selective distribution; Drug carrier; Concentration-effect relationship; Therapeutic response; Toxicity
Contents Summary .................................................................................................................
156
I. Introduction ...................................................................................................
156
II. Pharmacokinetic considerations .......................................................................... 1. Rate of elimination of drug-carrier conjugate .................................................. 2. Rate of delivery of drug-carrier conjugate to the target site ............................... 3. Rate of removal of drug carrier from the target site ......................................... 4. Rate of release of free drug at the target site .................................................. 5. Rate of removal of free drug from the target site ............................................. 6. Rate of elimination of free drug from the body ............................................... 7. Rate of release of free drug at non-target sites ................................................
156 157 158 158 158 159 159 160
II1. Pharmacodynamic considerations .......................................................................
160
IV. Conclusions ....................................................................................................
161
References ...............................................................................................................
162
Definitions: throughout this report the following definitions will apply: drug carrier, any part of a drug-targeting conjugate that is not the pharmacologically active moiety; (free) drug, drug free from conjugation to a drug carrier; (drug-carrier) conjugate, drug attached to a drug carrier; target site, a site which is distinct from sites where toxicity occurs and from the general circulation. While not identical to the pharmacological site of action, the target site must be in more rapid equilibrium with this site of action than with sites where toxicity occurs. Correspondence: A. Boddy, Pharmacy Department, University of Manchester, Oxford Road, Manchester M13 9PL, U.K. 0169-409X/89/$03.50 ¢~) 1989 Elsevier Science Publishers B.V. (Biomedical Division)
156
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Summary
The influence of the pharmacokinetics of drug-carrier conjugates and free drug and the pharmacodynamics of therapeutic and toxic response on the potential for success of a drug-targeting system have been considered. Using previous investigations and the present discussion it is possible to make some qualified statements about optimisation of drug targeting. These statements are dependent on the extent of understanding of the disease process, the anatomy and pathophysiology of the target site, the pharmacokinetics of drug carrier and free drug, the mechanism of drug release and the pharmacodynamics of therapeutic and toxic effects. I.
Introduction
The aim of drug targeting is to maximise the therapeutic response to a drug, by delivering it specifically to a target site, whilst minimising toxic effects. Conventional therapy depends on drugs that have an adequate ratio of therapeutic response to toxic effects due to innate pharmacokinetic or pharmacologic selectivity for the specific site or sites of action. Therapy with drugs which possess such selectivity probably does not merit the sophistication and expense of drug targeting. However, drugs which have a poor ratio of therapeutic to toxic effects, or are prevented from exercising a potentially beneficial effect due to adverse pharmacokinetic properties, may benefit from drug targeting [1]. Drug targeting, as defined above, is usually conceived of as systemic administration of a drug-carrier conjugate which delivers free drug selectively to a particular tissue [2]. This process may consist of a combination of steps including protection of drug in non-target tissues, selective distribution of drug-carrier conjugate to and binding of the conjugate within the target tissue and selective release of free drug within the tissue [1,3]. The contributions of macromolecules to each of these components are dealt with in detail elsewhere [4]. This report is concerned primarily with how the pharmacokinetics and pharmacodynamics of the free drug affect the degree of advantage due to drug targeting over conventional administration. The influence of the pharmacokinetics of the drug-carrier conjugate, its distribution and the rate of release of free drug will also be considered from a theoretical point of view. II.
Pharmacokinetic considerations
The purpose of administering a drug in any form is to optimise the concentration-time profile of drug at target and non-target sites. In conventional administration, the drug profile at some target site is determined by the rate of input of drug into and elimination from the body, the rate at which it is delivered to the target site and the rate at which it is removed from that site. Similar considerations apply to the non-target sites where toxicity may occur [5]. In the case of drug targeting the controlling processes are rate of input of drug-carrier conjugate into and elimination from the body, rate of distribution of drug-carrier conjugate to the tar-
PHARMACOKINETIC AND -DYNAMIC ASPECTS OF DRUG DELIVERY
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Scheme I. Simple three compartment model illustrating the processes in site-specific drug delivery. DC~, DCR and DC r are the concentrations of drug carrier in central, response and toxicity compartments, respectively. DX~, DXa and DXT are the resultant concentrations of free drug in these compartments. Qrt and QT are the blood flows to the response and toxicity compartments, respectively. get and rate of removal from the target, rate of release of free drug and rate of removal of free drug from the target site. Concentrations of free drug in the nontarget sites are determined by rate of removal of drug from the target site, rate of distribution to and from the non-target site and rate of elimination of free drug from the body (assuming absolute selectivity of release). These processes are illustrated in Scheme I, which shows a simple pharmacokinetic model incorporating central, response and toxicity compartments.
I1.1. Rate of elimination of drug-carrier conjugate Much of the work with macromolecular drug-carriers is concerned with developing a carrier which is not rapidly eliminated from the circulation [4]. This is necessary both to minimise the exposure of eliminating organs to the targeted drug and to maximise the fraction of the dose that reaches the target site. However, uptake of the drug-carrier conjugate by target tissue reduces blood concentrations and results in efficient targeting [6]. If the drug-carrier conjugate is eliminated more
158
A. B O D D Y A N D L. A A R O N S
rapidly than it is delivered to the target, concentrations of conjugate at this site may be insufficient to maintain an adequate release rate of free drug. Also, if only a small fraction of the dose of drug-carrier conjugate reaches the target site, most of the dose of an expensive and sophisticated drug-targeting system is wasted.
H.2. Rate of delivery of drug-carrier conjugate to the target site Whereas selective distribution of drug-carrier conjugate may ensure relative selectivity of release of free drug [7], the kinetics of distribution of the conjugate become important if its rate of delivery to the target site limits the rate of release of free drug at that site. If drug-carrier conjugate distributes too slowly to the target site the rate of release of free drug may not be sufficient to generate the free drug concentrations necessary to achieve the desired therapeutic response. Rate of delivery of conjugate depends on blood flow to the target site and on the permeability of the target site to the drug-carrier. Drug-carrier conjugate which is presented to the target organ by the blood may have to cross several membrane barriers before reaching the site of free drug release (c.f. Ref. 18). The rate of transport across these barriers may limit the rate of drug-carrier conjugate access and so the rate of release of free drug. The upper limit to the rate of delivery is provided by the product of blood flow to the target site and blood concentration of conjugate.
H.3. Rate of removal of drug-carrier conjugate from the target site The concentration of drug-carrier conjugate at the target site is determined by the balance of delivery rate and rate of removal from the site, including physical removal in blood and lymph and the rate of release of free drug. The higher the rate of removal of conjugate, the lower is the concentration at the target site and, hence, the rate of release and the concentration of free drug are lower. Any species present at the target site is removed at a rate equal to the product of the sum of blood and lymph flow from the target site and the concentration of the species available for removal. Binding of macromolecular drug-carriers selectively at the target sites reduces the fraction available for removal and so reduces the rate of removal of the conjugate. However, if only unbound conjugate can release free drug, such binding may actually reduce the rate of release and so decrease free drug concentrations. The inability of macromolecules or charged species to cross membrane barriers may also act to retain drug-carrier conjugate at the target site, but only if access to the target site has first been achieved [3].
H.4. Rate of release of free drug at the target site Drug release at the target site is generally conceived of as occurring by one of two mechanisms. The first is dependent on a locally selective, but non-specific, chemical characteristic of the target site which is different from non-target sites, such as pH [8]. Release of free drug by this mechanism would be limited only by
PHARMACOKINETIC AND -DYNAMIC ASPECTS OF DRUG DELIVERY
159
the concentration of drug-carrier conjugate at the site available to release free drug, as determined by the factors considered above. The second type involves activation of the drug or cleavage of the drug-carrier conjugate by some specific enzymic mechanism peculiar to the target site [1,9]. The maximum rate of release by this type of mechanism is dependent on the concentration and activity of the enzyme involved. Thus, the limited capacity of the latter release mechanism would restrict the rate of release of free drug regardless of the concentration of conjugate at the target site, and selective and adequate delivery of the drug-carrier conjugate may not result in the desired therapeutic response. Also, since the concentrations of enzymes often vary between individuals [10], the rate of release of free drug will also vary if release is occurring at the maximal rate [11].
11.5. Rate of removal of free drug from the target site The counterpart to the rate of release of free drug at the target site is its removal from the site and transport to the rest of the body. As for drug-carrier conjugate, the rate of removal is equal to the product of blood flow and the concentration of free drug at the site which is available for removal [1]. Thus binding of the drug within the target site reduces the concentration available for removal, but may also reduce the effective concentration at the active site. Drugs which are ionised or polar and so do not easily cross membrane barriers between the target site and blood may increase the retention at the site [3], but do not reduce the overall exposure of the rest of the body to drug which must enter non-target tissues before it can be eliminated. Any mechanism of retention of free drug at the target site must retain drug in an active form, otherwise the mechanism of retention is analogous to removal of free drug from the site and reduces the therapeutic response. Apart from physical removal via the blood, free drug may also be removed directly from the target site if elimination of the free drug occurs at this site. If drug released within the target site can be eliminated without first entering non-target tissues, drug targeting offers a significantly increased advantage over conventional administration [5,12]. However, such elimination increases the rate of removal of free drug from the target site and so will lower the concentration at the active site such that a therapeutic response may not be achieved.
11.6. Rate of elimination of free drug from the body Concentrations of free drug at sites where toxicity occurs are dependent on the balance of rate of delivery to those sites and rate of removal. Assuming that the target site is not directly connected to a site associated with toxicity, the rate of delivery is equal to the product of blood flow to the site and blood concentration of free drug. Therefore, increasing the rate of elimination from the body reduces the blood concentration of free drug, the rate of delivery of free drug to non-target sites and so reduces the magnitude of toxic effects [1]. For efficient drug targeting the rate of elimination of free drug from the body should be rapid relative to the rate of transport from the target site to the blood [1,5,12,13].
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H. 7. Rate of release of free drug at non-target sites Lack of absolute specificity of release may be due to failure of selective distribution (if the release mechanism is non-specific) or to failure of selective release (if distribution is non-specific). Either of these failures results in release of free drug directly into non-target sites. The consequences of such release are worse when release occurs at a site directly associated with toxicity, but reduces the benefit of drug targeting regardless of the site of release [7,12]. Release rates in toxicity-associated compartments are determined by the rate of delivery and removal of drugcarrier conjugate and the activity of the releasing mechanism at these sites. Free drug concentrations depend on the rate of release and the rate of removal of free drug from the site. If drug is released at a non-target site outside of the toxicityassociated site, the magnitude of the toxic effect depends on the rate of release, subsequent concentration in blood and rate of movement of free drug to and from the toxicity-associated site. The toxicity due to release of free drug in this way is least for those drugs which are rapidly eliminated from the body.
III. Pharmacodynamic considerations Although the primary aim of drug targeting is to generate concentrations at some target site which are high relative to non-target sites, some thought should be given to the pharmacodynamics of both therapeutic and toxic effects of the drug. In most investigations of the optimal conditions for drug targeting it is assumed that response is linearly related to concentration [1,12,14]. The selective advantage due to different sensitivities of therapeutic and toxic effects is allowed for by comparing drug targeting with conventional administration. However, the relationship between concentration and effect is often more complex and may vary with time, previous exposure to drug or the magnitude of the effect [2,15]. The relationship between concentration of free drug and effect may be different at target and non-target sites. For instance, the effects of many drugs increase linearly as concentration is increased at low levels, but at higher concentrations the effect tends towards a maximum. Other complex relationships between response and concentration, such as threshold concentrations, all-or-none effects, desensitization and feedback control [15] must also be considered where appropriate. Pharmacokinetic models incorporating the pharmacodynamics of therapeutic and toxic effects may be used to judge the efficiency of drug targeting (Boddy, A., unpublished results). Simulations using such models indicate that the advantage gained by drug targeting cannot always be judged by ratios of areas under concentration curves for different modes of administration. Where information is available, the relationship between concentration and effect must be considered when evaluating the efficiency of drug targeting both theoretically and practically.
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The influence of the pharmacokinetics of drug-carrier conjugates and free drug and the pharmacodynamics of therapeutic and toxic response on the potential for success of a drug-targeting system have been considered. The factors which limit this potential have been dealt with previously [1,12,13,14], but the mechanisms behind the influence of pharmacokinetic parameters on such factors as rate of drugcarrier conjugate delivery, rate of release and removal of free drug and rate of free drug input into non-target sites have not been dealt with comprehensively. Using previous investigations and the present discussion it is possible to make some qualified statements about optimisation of drug targeting. These statements are dependent on the extent of understanding of the disease process, the anatomy and pathophysiology of the target site, the pharmacokinetics of drug-carrier and free drug, the mechanism of drug release and the pharmacodynamics of therapeutic and toxic effects. With regard to the target site, the prime consideration is that it should be distinct from sites where toxicity occurs. If therapeutic and toxic effects occur at the same site then there is no potential for selective distribution of drug-carrier or selective release of free drug [1]. Therefore, drugs such as the oral anti-coagulant warfarin, whose therapeutic and toxic effects involve inhibition of the same enzyme to different extents, are not suitable for drug targeting. A second important consideration is blood flow to and from the target site. It has been stated in the past that to optimise drug targeting this blood flow should be as small as possible so as to minimise the rate of removal of free drug from the target and the rate of input of free drug into the rest of the system [12,13]. However, it should be noted that blood flow to the target organ also provides an upper limit to the rate of delivery of drug-carrier conjugate and so may limit the free drug concentration at the active site [16,17]. The pharmacokinetics of the drug-carrier conjugate are important with regard to the rate of distribution to and removal from the target site, distribution to nontarget sites and rate of elimination. Distribution to non-target sites will contribute to elimination from the general circulation if accumulation in those sites is rapid and of sufficient magnitude. The rate of distribution to the target site is limited by blood flow and permeability. However, the rate of removal may also be influenced by binding at the site. In some circumstances binding at the target site may be viewed as equivalent to removal, if only unbound conjugate is able to release free drug. The intrinsic pharmacokinetic properties of the free drug are the same irrespective of whether it is introduced into the body attached to a carrier or not. However, the site of release (or route of administration) can influence the concentration-time profiles observed in different tissues [5]. The pharmacokinetic parameter which has the most direct effect on the potential benefit of drug targeting is the clearance of drug from the body. For two drugs which are released at the same rate in the same target site, the one which is most rapidly eliminated will attain the lowest concentration outside the target site. Provided either the rate of release
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at the target site or the blood flow from the site is less than the rate of elimination from the body, concentrations at the target site are independent of the rates of elimination in other tissues. Thus, choosing a drug which is rapidly eliminated from the body minimises concentrations outside of the target site, without reducing therapeutic effects. Elimination of drug directly from the target site reduces the rate of input into and concentrations in non-target sites, but also reduces the concentration within the target site. This effect may be offset by increasing the rate of delivery of drugcarrier conjugate or the rate of release of free drug in the target site, but there may be maximum limits to these rates. Finally, the pharmacodynamics of therapeutic and toxic responses are important in designing the optimal drug-targeting system. If the optimum concentration-time profile for a drug at the target site is known, it may be possible to tailor the characteristics of the drug carrier, release mechanism and choice of drug to achieve this profile whilst minimising toxic effects. Unfortunately, details of the pharmacodynamics of a drug are frequently difficult to investigate. References 1 Stella, V.J. and Himmelstein, K.J. (1985) Prodrugs: a chemical approach to drug delivery. In: R.T. Borchardt, A.J. Repta and V.J. Stella (Eds.), Directed Drug Delivery, Humana Press, New York, pp. 247-267. 2 Tomlinson, E. (1987) Theory and practice of site-specific drug delivery, Adv. Drug Deliv. Rev. 1, 87-198. 3 Bodor, N. (1985) Targeting of drugs to the brain, Methods Enzymol. 112,381-396. 4 Sezaki, H. and Hashida, M. (1985) Macromolecule-drug conjugates in targeted cancer chemotherapy, CRC Crit. Rev. Ther. Drug Carriers 1, 1-38. 5 0 i e , S. and Huang, J.-D. (1981) Influence of administration route on drug delivery to a target organ, J. Pharm Sci. 70, 1344-1347. 6 Duncan, R., Lloyd, J.B., Rejmanova, P. and Kopecek, J. (1985) Methods of targeting N-(2-hydroxypropyl)methacrylamide copolymers to particular cell types, Makromol. Chem. Suppl. 9, 3-12. 70rlowski, M., Mizoguchi, H. and Wilk, W. (1980) N-Acyl--t-glutamyl derivatives of sulfamethoxazole as models of kidney-selective prodrugs, J. Pharmacol. Exp. Ther. 212, 167-172. 8 Shen, W.C. and Ryser, J.P. (1981) c/s-Aconityl spacer between daunomycin and macromolecular carriers: a model of pH-sensitive linkage releasing drug from a lysosomotropic conjugate, Biochem Biophys. Res. Commun. 102, 1048-1054. 9 Wilk, S., Mizoguchi, H. and Orlowski, M. (1978) 3,-Glutamyl dopa: a kidney-specific dopamine precursor, J. Pharmacol. Exp. Ther. 206, 227-232. 10 Houston, J.B. (1981) Drug metaholite kinetics, Pharmacol. Ther. 15,521-552. 11 Notari, R.E. (1985) Theory and practice of prodrug kinetics, Methods Enzymol. 112,309-323. 12 Hunt, C.A., MacGregor, R.D. and Siegel, R.A. (1986) Engineering targeted in vivo drug delivery. I. The physiological and physicochemical principles governing opportunities and limitations, Pharmaceut. Res. 3,333-344. 13 Levy, G. (1987) Targeted drug delivery - some pharmacokinetic considerations, Pharmaceut. Res. 4,3--4. 14 Stella, V.J. and Himmelstein, K.J. (1980) Prodrugs and site-specific drug delivery, J. Med. Chem. 23, 1275-1282. 15 Holford, N.H.G. and Sheiner, L.B. (1982) Kinetics of pharmacologic response, Pharmacol. Ther. 16, 143-166. 16 Levin, V.A., Patlak, C.S. and Landahl, H.D. (1980) Heuristic modeling of drug delivery to malignant brain tumors, J. Pharmacokin. Biopharm. 9, 257-296.
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17 Weinstein, J.N., Black, C.D.V., Barber, J., Eger, R.R., Parker, R.J., Holton, O.D., Mulshine, J.L., Keenan, A.M., Larson° S.M., Carrasquillo, J.A.. Sieber, S.M. and Covell, D.G. (1986) Selected issues in the pharmacology of monoclonal antibodies. In: E. Tomlinson and S.S. Davis (Eds.), Site-specific drug delivery. Cell biology, medical and pharmaceutical aspects, John Wiley, London, pp. 81-91. 18 Petrak, K. and Goddard, P. (1989) Transport of macromolecules across the capillary walls, Adv. Drug Deliv. Rev. 3, 185-000.