Pharmacokinetic and pharmacodynamic basis for peptide drug delivery system design

Journal of Controlled Release, 2 1 ( 1992) S- 10 0 1992 Elsevier Science Publishers B.V. All rights reserved

0168-3659/92/$05.00

COREL 00732

Pharmacokinetic

and pharmacodynamic basis for peptide drug delivery system design Douwe D. Breimer

Center for ~~o-phar~~ce~ti~alSciences, L&den University,Leiden, Netherlands (Received 22 October 199 1; accepted in revised form 9 January 1992 )

Key words: New drug delivery; Pharmacokinetics; Pharmacodynamics; Peptide and protein drugs

Introduction The principles underlying the design of appropriate delivery systems and delivery regimens for peptide and protein drugs are not essentially different from those relevant for conventional drug molecules. The safe and effective use of any drug requires in depth knowledge of its pharmacokinetics and pharmacodynamic properties. The inter-relationship between these processes and with drug delivery at the beginning and the ultimate objective of rational treatment of disease at the end is schematically depicted in Fig. 1. In the design of approp~ate drug delivery systems at least two fundamental questions should be asked and answered prior to their development [ 1 ] : (a) a clinical pharmacological one in terms of the optimal rate and timing at which the drug should be delivered; this requires knowledge on the concentration-effect profile of the drug in man and its dependence on the rate and time profile of drug input (e.g. continuous versus pulsatile or intermittent); (b) a pharmaceutical-technological one in terms of the most suitable system that can proCorrespondence to: D.D. Breimer, Center for Bio-Pharmaceutical Sciences, Leiden University, P.O. Box 9503, 2300 RA Leiden, Netherlands.

vide the required rate and time specification via the desired route of administration; this requires knowledge on the capacity, flexibility, rate and time programming possibilities. For “conventional” drugs it is already quite complicated to obtain the relevant answers to these two key questions. For peptide and protein drugs this is even more so, because several additional difficulties have to be overcome, both at the pharmacokinetic and the dynamic level. Peptides and proteins are relatively unstable in most biological fluids, do not readily pass biological membranes, and are often rapidly broken down by peptidases and therefore in general have high clearance properties and very short elimination half-lives [ 2,3 1. In addition the pharmacology of most compounds in man has not intensively been studied, let alone the relationship between pharmacokinetics and dynamics. However, there are some drugs that clearly illustrate the importance of time programming in delivery to achieve optimal therapeutic results, for example the continuous versus pulsatile delivery of LH-RH for different indications [ 41. Since endogenous peptides and proteins play an impo~ant regulatory role in health and disease, and exhibit oscillatory plasma and tissue level profiles, it is likely that exogenously administered compounds that

6

regulation, which may be desirable under certain pathological conditions. pharmacokineti~/pharmacodynRealistic amic models must be developed to describe and predict the time-course of drug action under physiological and pathophysiological conditions and thereby provide the essential “feedback” information for optimal time profiles of drug dosing and delivery (Fig. 1). Obviously it is quite appropriate and good practice in science to study the different drug disposition and dynamic processes separately as well, because that will allow the procurement of more in depth and mechanistic knowledge. Subsequent integration is, however, essential in formulating the criteria for optimal drug delivery. In this introductory paper some issues will be briefly reviewed or referred to which seem to be relevant to this topic.

Pharmacokinetics An extensive review on the pharmacokinetics of peptide and protein drugs has recently been published by Kompella and Lee [ 5 1. Pharmacokinetics comprises the drug disposition processes in the body: absorption, distribution, metabolism and elimination. Lack of absorption through biological membranes (epithelia) is a major drawback of peptide and protein drugs and they are therefore generally administered by injection. considerable research efforts are currently undertaken to develop methods that will make it possible to enhance peptide drug transFEEDBACK

Fig. 1. Schematic representation of the relationship between drug delivery, pharmacokinetics, pharmacodynamics and the treatment ofdisease.

port across membranes at different routes of drug entry (oral, buccal, nasal, rectal, dermal). For this purpose in vivo as well as in vitro techniques, like appropriate cell culture systems, are being used. Different concepts like the use of absite selective delivery, sorption enhancers, bioadhesion biopolymers and others are explored. Success has been achieved at the nasal [6 ] and at the rectal [ 7 ] level by applying absorption enhancement, however, the safety aspects of this approach remain an important issue to consider. At present the nasal cavity represents the best alternative to parenteral drug administration, but several aspects related to pharmacokineti~s and pharmacodynamics of each drug in relationship with their efficacy and safety are still to be adequately assessed. This includes the design of such delivery platforms that allow a greater degree of control of the rate of drug input. Once drugs have entered the systemic blood circulation they are carried to all capillary endothelia. Their passage across membranes is determined by molecular and physicochemical properties and if appropriate they may enter the extracellular fluid. For peptides acting at the level of the brain, passage across the blood-barrier is of considerable importance; it has been shown that several neuro-peptides are indeed capable of being transported into the central nervous system, albeit to a very minor extent as related to the dose administered [ 8,9]. Subsequent uptake into cells (both peripheral and central) is often a specific process for peptide and protein drugs, which require carrier systems that are available to transport endogenous compounds. An alternative is receptor-mediated endocytosis, which also - at least at the level of the liver - contributes to a great extent to the very rapid elimination of protein from the general circulation [ lo]. In addition the abundantly available peptidases play an important role in peptide and protein metabolism, which in most cases gives rise to extremely short elimination halflives. Obviously this limits very much the exposure time of this type of drugs to the target tissues and requires therefore exogenous control of

the rate of delivery and/or specific targeting. Attempts are being undertaken to achieve this by conjugation to macro-molecules to circumvent for example hepatic and renal clearance, leading to extended elimination half-lives [ 111. However, this is still far away from achieving precise control of drug release at the site of action only. One aspect that has received relatively little attention in studies on the disposition of peptide and protein drugs is the role of hepatic blood flow. This is surprising, because most of such compounds are very rapidly cleared by the liver and therefore the rate at which they are presented to the liver is often a limiting factor in their elimination. Liver blood flow may vary considerably as caused by factors like food, posture, exercise, disease, drugs and this may therefore also give rise to substantial variation in the kinetics of peptide and protein drugs. This hypothesis was tested for recombinant human tissue-type plasminogen activator (i-t-PA), the thrombolytic agent used in the treatment of acute myocardial infarction. The influence of changes in liver blood flow on the clearance of this compound was studied in healthy subjects [ 121. Physical exercise reduced liver blood flow on average by 56%, whereas rt-PA levels increased by 125% during constant-rate infusion of the drug (Fig. 2 ). Since considerable inter- and intra-individual differences in hepatic blood flow occur under conditions of acute myocardial infarction, this observation may have important implications for optimal dosage and delivery rates in patients, assuming that there is a straightforward relationship between rt-PA plasma concentrations and thrombolytic effects. Overall, substantial amounts of information on the various disposition processes of peptide and protein drugs are becoming available, including on rate and site limiting factors. However, still very little rationale is emerging with respect to the possibilities to control such drug disposition with respect to rate, time and site. Also few data are available on clear relationships between pharmacokinetics and drug effects, because only in few instances have they been studied simultaneously.

0

50

100

Time

150

200

250

(rnrd

Fig. 2. Mean time courses of indocyanin green (ICG) ( 0 ) and rec. tissue-type plasminogen activator (rt-PA) ( A ) during ICG infusion (90 mg over 120 min), r&PA infusion ( 18 mg over 120 min) and exercise for 20 min at 50 min after the start of the infusions. Changes in ICG concentrations reflect changes in liver blood flow, which also have major effects on rt-PA concentrations (from ref. 12).

Pharmacodynamics In drug delivery systems design only too often most emphasis is laid on the pharmacokinetic performance of the system, i.e. the plasma level versus time profile of the drug to be accommodated. However, drug effects (pharmacodynamics) also exhibit their own rate and time profiles, although they are dependent on drug concentrations in plasma. It is very important that pharmacokinetics and pharmacodynamics are studied simultaneously, so that their relationship is clearly established. This will make it possible to predict the drug effect profile from pharmacokinetic data, including the rate of input from the delivery system. Such approaches will make it possible to better define the optimal rate and time profiles of drug delivery. The importance of a clear understanding of the relationship between pharmacokinetics and pharmacodynamics for the optimal delivery of peptide drugs has recently clearly been shown for a somatostatin derivative and for gonadotropin releasing hormone by Mazer [ 41, For the somatostatin derivative a continuous (zero-order) input rate was shown to be optimal for suppressing growth hormone secretion in the treatment of

8

acromegaly, which can in practice be achieved by subcutaneous infusion [ 13 1. On the other hand pulsatile delivery is optimal for gonadotropin releasing hormone in stimulating pituitary gonadotropin secretion, which is indicated for the induction of ovulation [ 141. If this hormone is given continuously (zero-order rate of input) gonadotropin secretion is suppressed through the mechanism of receptor down regulation, which is useful in the treatment of for example prostate and breast cancer [ 15 1. The examples as worked out by Mazer [4] clearly illustrate that novel experimental approaches using programmable infusion pumps in man are needed to define the optimal delivery rates and times of peptide drugs. Several other examples are available that clearly indicate apparent discrepancies between pharmacokinetics and the time course of drug effects. For calcitonin peak plasma levels are attained soon after S.C. or i.m. injection, whereas the maximum hypocalcaemic effect occurs later and lasts longer, sometimes persisting even after the plasma level has decreased below the level of detection [ 161. It may well be that there is a delay factor, either pharmacokinetic or pharmacodynamic, responsible for this observation which could be elucidated in appropriate pharmacokinetic/pharmacodynamic modelling experiments. This would subsequently lead to relevant information concerning the optimal rate of input and dosage regimen A complication often encountered in such studies with peptide and protein drugs is the nonspecificity of the assay methodology applied to measure unchanged active compound. Another example concerns recombinant-human granulocyte-colony stimulating factor (rhGCSF), for which differences were observed between the time courses of the concentrations of unchanged compound in serum after i.v. and S.C. administration and drug effects, i.e. increase of peripheral neutrophil counts [ 17 1. Clear time lags were seen which are likely to be explained by the time needed for hematopoietic progenitor cells to proliferate and differentiate. This compound is currently under clinical study for granulocytopenia and opportunistic infections and,

again, the ~netic/dynamic studies as referred are essential to provide the rationale for the drug delivery and dose regimen. A last elegant example of experimental approaches required to assess optimal rates and routes of peptide drug delivery refers to the neutrophic peptide Org 2766 ( ACTH 4-9)) that protects against cisplatin induced neurotoxicity and potentially other forms of neuropathy [ 181. In rats with a crush lesion of the sciatic nerve, continuous release of the drug from an implanted osmotic minipump or from biodegradable microspheres was compared to subcutaneous injections. The results obtained indicated that, to improve nerve regeneration, steady-state plasma levels of Org 2766 are not necessary, but peak amounts of the peptide must be available repeatedly in a short, critical period following the injury [ 191. This comparison of the injection-infusion regimen of drug delivery indeed provides relevant information, which may also be extrapolated to the clinical situation. In general, the best data that define the optimal rate and time pattern of drug delivery are those based on pharmacokinetic-pharmacodynamic modelling studies. However, pharmacodynamic measures to allow such modelling and prediction can only rarely be obtained with peptide and protein drugs. The reason is that most of their pharmacological effects do not fulfill most of the following criteria [ 201: they should be gradual (preferably not all-or-nothing effects), sensitive, reproducible in the same individual, objective and meaningful from a therapeutic point of view. More indirect methods are often needed, because of the “triggering” nature of several macromolecular drugs, like growth factors, modulators of cell function and several hormones. In such cases the timing of administration may also play a very important role in determining their therapeutic success. This may be related to chronobiological issues, which need to be considered in the context of the entire drug development process [ 2 I].

Biofeedback Ideally, at least in the research phase, the body’s need for therapeutic intervention should be

9

monitored continuously and the information obtained should be fed back into the drug delivery system. In other words, this system should be connected with a “sensor” in the body that continuously produces a feedback signal to the delivery module (see Fig. 1). Through sophisticated computer programming (that is based on information obtained on the relationship between dose requirements and therapeutic response) the correct drug delivery profile is provided continuously. The feedback signal should of course represent or reflect the degree of severity of the pathophysiological process to be interfered with by drug treatment. Feedback signals could be glucose in the blood to trigger insulin delivery in diabetic patients. The insulin delivery profile should be of a pulsatile nature, since that seems to be more efficient than continuous infusion [ 221. Such “closed loop” insulin delivery systems are in the process of clinical research and development [ 23 1. Several relevant body functions can currently be monitored continuously, like blood pressure, EEG and EGG signals, muscle tension and circulating endogenous substances. These could be used as feedback signals in the research and development phase of drugs in general, which would provide very important information to define the optimal rate and time of drug delivery. For peptide and protein drugs the need for this more sophisticated approach seems to be evident, considering their complex pha~acokinetic and pharmacodynamic properties,

4

5

6

7

8

9

10

11

12

13

References 14 D.D. Breimer, Drug deIivety system design inter-related with clinical pharmacology and drug metabolism. Yakuzaigaku48 (1988)75%X V.H.L. Lee, Peptide and protein delivery: problems and some solutions, in: S.R. Bloom and G. Burnstock (Ed. ), Peptides, a Target for new Drug Development, IBC Technical Services, London, 199 1, pp. 120-I 34. J.C. Verhoef. H.E. Bodde, A.G. de Boer, J.A. Bouwstra, H.E. Junginger, F.W.H.M. Merkus and D.D. Breimer, Transport of peptide and protein drugs across biological membranes. Eur. J. Drug Met. Pharmacokinet. 15 ( 1990) 83-93.

15

16 17

N.A. Mazer, Pharmacokinetic and pharmacodynamic aspects of polypeptide delivery. J. Controlled Release 11 ( 1990) 343-356. U.B. Kompella and V.H.L. Lee, Pha~a~okineti~s of peptide and protein drugs, in: V.H.L. Lee (ed. ), Peptide and Protein Drug Delivery, Marcel Dekker, New York, 1991, pp. 391-486. J. Verhoef, W.A.J.J. Hermens, N.G.M. Schipper, S.G. Romeijn and F.W.H.M. Merkus, Absorption enhancement in nasal drug delivery. In: D.J.A. Crommelin and K.K. Midha (Eds), Topics in Pha~aceuti~al Sciences 1992, Medpharm GmbH, Stuttgart, pp. 17 I-l 88. E.J. van Hoogdalem, A.G. de Boer and D.D. Breimer, Intestinal drug absorption enhancement. An overview, Pharmac. Ther. 44 ( 1989) 407-443. J.B.M.M. van Bree, A.G. de Boer, J. Verhoef, M. Danhof and D.D. Breimer, Peptide transport across the blood-brain barrier, J. Controlled Release 13 ( 1990) 175-l 84. A. Ermisch and H.-J. Rilhle, Peptide blood brain barrier interactions: kinetics and dynamics. J. Controlled Release, this volume. Y. Sugiyama, H. Sato, S. Yanai, DC. Kim, S. Miyauchi, Y. Sawada, T. Iga and M. Hanano, Receptor mediated hepatic clearance of peptide hormones, in: D.D. Breimer, D.J.A. Crommelin and K.K. Midha (Eds.), Topics in Pharmaceutical Sciences, F. I. P., The Hague, 1989, pp. 429-443. F.F. Davis, G.M. Kazo, M.L. Nucci and A. Abuchowski, Reduction of immunogeni~ity and extension of circulating half-life of peptides and proteins, in: V.H.L. Lee (Ed. ). Peptide and Protein Drug Delivery, Marcel Dekker, New York, 199 1, pp. 83 l-864. A. de Boer. C. Kluft, F.J. Kasper, J.M. Kroon, H.C. Schoemaker, D.D. Breimer, P.A. Soons, J.J. Emeis, J. Prins and A.F. Cohen, Liver blood flow as a major determinant of the clearance of rectissue-type Plasminogen Activator, Thromb. Haemostas, in press. S.E. Christensen, J. Weeke, H. Orskov, N. MolIer, A. Flyvbjerg, A.G. Harris, E. Lund and J. Jorgensen, Continuous subcutaneous pump infusion of somatostatin analogue SMS 20 l-995 versus subcutaneous injection schedule in acromegalic patients. Clin. Endocrinol. 27 f 1987) 297-306. E. Knob& The neuroendocrine control of the menstrual cycle, Recent Progr. Harm. Res. 36 ( 1980) 53-88. B.H. Vickey, Comparison of the potential for therapeutic utilities with gonadotropin-releasing hormone agonists and antagonists, Endocrinol. Rev. 7 ( 1986) 115124. M. Azria, The Calcitonins: Physiology and Pharmacology, Karger, Basel, 1989, pp. 108- 114. H. Tanaka, Y. Okada, M. Kawagishi and T. Tokiwa, Pharmacokinetics and pharmacodynamics of rec-human granulocyte-colony stimulating factor after i.v. and S.C.administration in the rat, J. Pharmacol. Exp. Ther. 251 (1989) 1199-1203.

10

18

19

20

21

R. Gerritsen van de Hoop, C.J. Vecht, M.E.L. van der Burg, A. Elderson, W. Boogerd, J.J. Heimans, E.P. Vries, J.C. van Houwelingen, F.G.I. Jennekens, W.H. Gispen and J.P. Neijt, Prevention of cisplatin neurotoxicity with an ACTH(4-9) analogue in patients with ovarian cancer, N. Engf. J. Med. 322 ( 1990) 89-94. W.H. Gispen and V.M. Wiegant, Melanocortins in peripheral nerve regeneration: influence of dosage forms and routes of administration. J. Controlled Rel. 13 (1990) 203-211. J. Dingemanse, M. Danhof and D.D. Breimer, Pharmacokinetic-pharmacodynamic modelling of CNS drug effects, Pharmac. Ther. 38 (1988) l-52. J.G. Hatter and C.C. Peck, Chronobiology - Su~estions

22

23

for integrating it into drug development, in: W.J.M. Hrushesky, R. Langer and F. Theeuwes (Eds.), Annals of the New York Academy of Sciences 618, 1990, pp. 563-571. G. Paolisso, S. Sgambato, R. Torella, M. Varricchio, A. Scheen, F. D’ Onofrio and P.J. Lefebvre. Pulsatile insulin delivery is more efficient than continuous infusion in modulating islet cell function in normal subjects and patients with Type 1 diabetes, J. Clin. Endocrinol. Metab. 66 ( 1988) 1220-I 226. J.C. Pickup, Self-regulating insulin delivery systems, in: L.F. Prescott and W.S. Nimmo (Eds.), Novel drug delivery and its therapeutic application. John Wiley & Sons, Chichester, 1989, pp. 3 13-322.