Microdialysis in clinical drug delivery studies

LAdvanced Drug Delivery Reviews 45 (2000) 255–269www.elsevier.com/ locate /drugdeliv

Microdialysis in clinical drug delivery studies*¨Markus Muller (M.D.)

Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics, Vienna University School of Medicine,¨ ¨Vienna General Hospital — AKH Wien, Wahringer Gurtel 18 –20, A-1090 Vienna, Austria

Received 7 July 2000; accepted 28 July 2000

Abstract

The introduction of in vivo microdialysis (MD) to clinical pharmacological studies has opened the opportunity to obtainpreviously inaccessible information about the drug distribution process to the clinically relevant target site. The aim of thisreview is to provide a comprehensive overview of the current literature about MD in drug delivery studies from a clinicalperspective. In particular the application of MD in clinical — antimicrobial, oncological and transdermal — and neurologicalresearch will be described and the scope of MD in pharmacokinetic–pharmacodynamic (PK-PD) studies will be discussed. Itis concluded that MD has a great potential for both academic and industrial research, and may become the method of choicefor drug distribution studies in humans. 2000 Elsevier Science B.V. All rights reserved.

Keywords: Microdialysis; Human; Pharmacokinetics; Pharmacodynamics

Contents

1. Introduction ............................................................................................................................................................................ 2551.1. The issue of tissue distribution in clinical studies................................................................................................................ 2551.2. Early reports on MD and validation studies ........................................................................................................................ 257

2. Application of microdialysis in human drug studies ................................................................................................................... 2582.1. Antimicrobial agents ........................................................................................................................................................ 2582.2. Antineoplastic agents ....................................................................................................................................................... 2592.3. Drugs for topical use, dermatological research ................................................................................................................... 2592.4. Drugs acting on the central nervous system........................................................................................................................ 2612.5. Metabolically active compounds: reverse microdialysis....................................................................................................... 261

3. Conclusions and outlook .......................................................................................................................................................... 263Acknowledgements ...................................................................................................................................................................... 264References .................................................................................................................................................................................. 264

Abbreviations: CNS, central nervous system; IC, interstitial 1. Introductionconcentration; ISF, interstitial space fluid; MD, microdialysis;NSAID, non-steroidal antiinflammatory drug; PD, pharmacody- 1.1. The issue of tissue distribution in clinicalnamics; PK, pharmacokinetics; US-FDA, United States Food and

studiesDrug Administration*Tel.: 1 43-1-40400-2981; fax: 1 43-1-40400-2998.

¨E-mail address: [email protected] (M. Muller). Physicians frequently face the challenge to select

0169-409X/00/$ – see front matter 2000 Elsevier Science B.V. All rights reserved.PI I : S0169-409X( 00 )00113-7

¨256 M. Muller / Advanced Drug Delivery Reviews 45 (2000) 255 –269

appropriate drugs on the basis of the presumed drug within the human body [9,10]. By applyingability of a drug to reach the target site. Due to the these techniques to clinical studies it became clearlimited availability of reliable techniques to measure that the previously often neglected drug distributionthe distribution process to the target site, however, process to the target site may represent an importantthe success of this approach was often hampered by determinant of clinical outcome [9,10]. Whereas thethe physician’s uncertainty about actual target tissue new cost- and labour-intensive imaging techniquesconcentrations. This unfortunate situation was al- are not readily applicable in clinical routine settingsready acknowledged as early as in 1900 when Mark and are only available for a small number ofTwain complained in a letter to a friend about the compounds, in vivo MD offers the opportunity to‘‘grotesque system of physicians, . . . to empty study the distribution of a large variety of chemicalmiscellaneous and harmful drugs into a persons entities in many different clinical settings. Understomach, which could not reach the disease at all’’ appropriate ethical conditions, in vivo MD is feasible[1]. in virtually every human tissue (Table 1). One

Fortunately, recent years have seen the develop- particular advantage of MD relates to the fact thatment of novel methods, notably innovative imaging MD selectively measures the unbound, i.e., thetechniques [2–4], and in vivo tissue microdialysis pharmacologically active drug fraction, in the inter-(MD; [5–8]), which enable us to follow the path of a stitial space fluid (ISF), i.e., the space which directly

Table 1Potential applications of microdialysis in clinical drug studies

Accessible tissue Key applications Selectedreferences

Soft tissues Penetration studies of antibiotics and analgesics [12,13,18,19,44–55,58,74,75,79,100–135](e.g., adipose tissue In vivo PK/ in vitro PD studies for antibioticsor skeletal muscle) Topical penetration studies

Metabolic PK-PD studies

Skin Penetration of antibiotics, analgesics [14,30,35,38,47,52,70–84,100,114–116,128–130]and antihistaminesIn vivo PK/ in vitro PD studies for antibioticsTopical penetration studiesTopical bioequivalence studiesMetabolic PK-PD studies

Brain Penetration studies of antibiotics [22,56,87–91]In vivo PK/ in vitro PD studies for antibioticsPenetration studies of antiepilepticsMetabolic PK-PD studies

Neoplastic tissue Penetration studies of cytotoxic drugs [25,33,59–62,67,68]In vivo PK/ in vitro PD studies forcytotoxic drugsApplication as a therapeutic tool for targetsite-specific drug delivery

Heart Metabolic PK-PD studies [23]

Blood Drug monitoring without blood loss [94–97](e.g., in neonates)

Lung Penetration studies of antibiotics As yet unpublishedIn vivo PK/ in vitro PD studies for antibiotics data (see Fig. 1)

Bone Penetration studies of antibiotics [24]Metabolic PK-PD studies

¨M. Muller / Advanced Drug Delivery Reviews 45 (2000) 255 –269 257

surrounds the target structures and may thus be absolute interstitial concentrations (ICs) for a varietyconsidered the anatomically defined target site in of analytes and conditions [13,16–20]. Providedmany cases [11]. proper in vivo calibration procedures, intraindividual

In recent years, the application of clinical MD has variation coefficients for IC measurements by MDmoved from a stage of evaluation and validation to a were shown to range between 10 and 20% forstage of broad clinical application which is also different analytes [13,18,20,21].reflected by a considerable growth of the literature Whereas MD was initially confined to the subcuta-on clinical MD. The aim of this review is to provide neous layer, numerous reports were published ina comprehensive overview of the current literature recent years on the clinical application of MD inabout MD in drug delivery studies from a clinical different human tissues (Table 1) including brainperspective. [22], heart muscle [23], bone [24], lung (Fig. 1) and

1.2. Early reports on MD and validation studies

The first publication on the application of MD inhumans dates back to 1987 and is a study on thecharacterization of the interstitial glucose concen-tration in healthy volunteers [5]. Although an ex-ponential growth of the literature on human MD,mostly in the metabolic field, and on the applicationof MD in preclinical studies (for recent reviews seeRefs. [6–8]) could be observed in the followingyears, it was not until 1991 that the first reports onMD in clinical drug studies were published [12–14].

Apart from providing the first experimental evi-dence for the suitability of MD for clinical drugdelivery studies, these publications already high-lighted the need for proper calibration procedures.As most drugs exert their pharmacological effect in awell-defined concentration range at the target orreceptor site, most drug distribution studies aim atmeasuring absolute interstitial concentrations. Thiswas not a requirement in most neurochemical andmetabolic studies where a recording of relative timeversus concentration profiles is considered sufficient.Thus, in vivo calibration of MD probes became animportant issue and finding the ‘true’ concentrationis mandatory for clinical pharmacological MDstudies today. Traditionally, the equilibrium methodis considered to be the gold standard for in vivocalibration of MD probes [5,15]. However, this Fig. 1. Clinical setting for microdialysis studies in human lungmethod has considerable disadvantages since it is tissue. Under appropriate conditions microdialysis may be per-

formed in intraoperative settings in lung tissue to measure drugtime-consuming and requires steady-state conditionspenetration into the parenchyma of the lung. Following awhich are not readily attainable in many clinicalthoracotomy (small arrows) microdialysis probes are inserted via a

˚conditions. Therefore, Stahle proposed a simplified, guide cannula into the parenchyma of the lung. The large arrow‘reverse dialysis’ approach [13,16], which was indicates the insertion site of the probe at the pleural surface of theshown to be reliable and reproducible for measuring lung.


solid tumors [25] and on derivative techniques like are mostly based on skin blister or biopsy studies,transcutaneous MD [26] and ultrafiltration [27]. It two techniques with considerable disadvantagesalso became clear that MD offers many advantages [11,18,28,29]. In particular, the measurement of thein comparison to established tissue pharmacokinetic total drug tissue concentrations from blister fluid andtechniques [28–30]. In particular, it was shown that from tissue homogenates may be misleading sinceMD is superior to skin-blister and saliva sampling only the unbound, drug fraction in the ISF exerts[28–30]. antibacterial activity [41,42]. As clinical tissue dis-

The increasing use of MD in human phar- tribution studies, however, are encouraged by regula-macokinetic studies was further promoted by the tory authorities, a quest for alternative methods wasavailability of commercially available MD probes started and following a first publication in 1995 [18]and by the refinement in chemical analytical pro- several manuscripts were published on the use ofcedures [31–34], which today, at least theoretically, MD in this application. For the field of antimicrobialallow for online concentration measurements in the drug research MD constitutes a particularly suitableISF [32]. These developments also led to an in- technique, because it actually allows for the mea-creased diversification of clinical MD, and caused a surement of unbound drug concentrations in the ISF.shift from a stage of pure technique-oriented research Recently, a US-FDA advisory committee acknowl-to a stage of increasingly problem-oriented research, edged that MD might be a potentially attractivemostly dealing with pharmacokinetics (PK) of low- approach for clinical studies on tissue distribution ofmolecular weight drugs. antimicrobial drugs [43].

As we approach an era where unconventional To date, MD was employed to measure themolecular entities such as liposomes, gene vectors, pharmacokinetics of gentamicin [18,44], ciprofloxa-oligonucleotides, antibodies or genetically en- cin [45], moxifloxacin [46], fleroxacin [47], phenox-gineered cells are becoming increasingly available in ymethylpenicillin [47], cefodizime [47,48], cef-drug development studies [10], MD will face the pirome [47–49], piperacillin [50], dirithromycinchallenge to adopt also to the measurement of [47], cefaclor [51] and antiviral agents like penci-lipophilic and high-molecular weight compounds clovir [52] in soft tissues of healthy volunteers. Inwith molecular weights of . 3kDa [35–40]. Fortu- patients, the effect of obesity [53], surgery [50],nately, there are a number of promising results intensive care procedures [50,54] and septicemiashowing the scope and future applicability of clinical [54] on peripheral distribution of piperacillin and theMD with ultrafiltration-membranes for high-molecu- effect of inflammation on antibiotic penetration intolar weight analytes [36–40]. To date, however, MD foot lesions in diabetics [55] and dermatologicalhas been most successful in providing previously patients [47] was described. Recently, the first paperinaccessible information on the tissue distribution on antibiotic drug penetration into the interstitialprocess of compounds with molecular weights of space fluid of the human brain was published [56]., 3 kDa. Below, the current knowledge of the These studies led to a reappraisal of formerlyapplication of MD in different areas of conventional believed concepts about ‘tissue-penetration’ of anti-clinical drug research will be described by focusing microbial drugs. In particular, it was shown that ICson different groups of these very compounds. of betalactames and aminoglycosides were in the

range of free serum concentrations, whereas forchinolones and macrolides, target site concentrationswere considerably lower than predicted from tissue

2. Application of microdialysis in human drug biopsies. The results of these studies further demon-studies strated that antimicrobial concentrations at the effect

site may be subinhibitory although effective con-2.1. Antimicrobial agents centrations are attained in serum [45,50,54]. Interest-

ingly it was also shown that local inflammationStudies on target tissue penetration of antibiotics exerted very little influence on ICs of select drugs

are a critical part in clinical drug development and [47,55], whereas capillary damage associated with


septicemia or postoperative trauma significantly af- for the measurement of cytotoxic drugs in the ISF offected ICs [50,54]. tumors [59]. So far MD was employed to study drug

Although MD is an almost ideal technique for penetration of carboplatin [59], 5-FU [25,33], mel-providing information on target site PK of anti- phalan [60] and methotrexate [61,62] in patientsbiotics, MD may not only provide information on PK suffering from malignant melanoma [59,60], breastbut also lends itself for pharmacodynamic (PD) cancer [25,33,61] and malignant fibrous histiocytomastudies of antibiotics. The application of MD in [62]. A pertinent observation in these studies wasPK/PD-research is based on the fact that MD that there was virtually no association between serumselectively monitors the time profile in the ISF, i.e., concentrations and the corresponding absolute con-the fluid which directly surrounds the infective centrations attained at the tumor site — a findingagents, a profile which may easily be simulated in an which corroborates the concept of an unusually highin vitro setting on bacterial cultures [57]. Two recent variability of the transendothelial transfer of cytotox-publications describe a MD-based in vivo PK/ in ic drugs in solid tumors [63,64]. The potential of MDvitro PD model which may be employed to predict in clinical oncological studies was further underlineddrug effects at the target site [45,58]. By employing by preliminary evidence that measurement of inter-such combined in vivo PK/ in vitro PD approaches stitial PK of select cytotoxic agents by in vivo MD(Fig. 2) it was shown that therapeutic success and may predict response to chemotherapy [25].failure in antimicrobial therapy may be explained by Besides its use in PK studies, a different applica-PK variability in ICs [45]. This could provide strong tion of MD was proposed by Ronquist et al. whosupport for PK-PD modeling procedures and may successfully employed MD probes as therapeuticalso support dose optimization and replace current tools for site-specific drug delivery in the treatmentconcepts for establishing dosing guidelines of select of gliomas [67].tissue infections [57,58]. As for antimicrobial agents, MD may also have its

merits for PK-PD characterization of antineoplastic2.2. Antineoplastic agents agents. Applying MD-based PK-PD models it was

shown that success and failure in cytotoxic therapySeveral studies have described the suitability of with 5-FU may be explained by PK variability in ICs

MD for in vivo measurements of antineoplastic [68].agents in human tissues and solid human tumors It thus emerges that the measurement of ICs in[25,33,59–62]. In principle, tumor MD studies are of solid human tumors by MD may explain drugconsiderable clinical importance as it is becoming resistance in select groups of patients and may helpincreasingly recognized that insufficient drug pene- optimize dosing and administration schedules. There-tration into the ISF of solid tumors represents a rate by the selection of novel cytotoxic compounds withlimiting step in clinical response to antineoplastic favorable tumor penetration characteristics might bechemotherapy [25,63,64]. Insufficient penetration facilitated in the future.across tumor vessels may thus explain why manydrugs which initially raised enthusiasm concerning 2.3. Drugs for topical use, dermatologicaltheir therapeutic potential against solid tumors failed researchto prove efficacious in clinical trials. Given anincidence of metastases in the puncture channel after Topical application of drugs, mostly of NSAIDsfine needle biopsy of tumours of 0.003 to 0.005%, aims at achieving high local drug concentrations inhowever, MD investigations need be limited to connective tissues underneath the application site.ethically appropriate clinical settings, although there Although this concept theoretically provides theis evidence that the puncture of tumor lesions does advantage of achieving a therapeutic effect withoutnot influence the course or prognosis of the underly- the risks of potentially severe systemic side effectsing disease [65,66]. associated with systemic administration, the validity

A first pilot study in melanoma patients was of this approach has hardly been documented in apublished in 1996 and demonstrated that MD allows convincing fashion [69]. To date, information on


Fig. 2. Schematic illustration of the general concept of the combined in vivo-PK/ in vitro-PD approach applied in microdialysis studies forantimicrobial agents. In a first step tissue pharmacokinetics are measured in vivo by microdialysis at the target site following single doseadministration (upper left panel). Thereafter the time profile obtained in vivo is simulated in vitro on select bacterial cultures (upper rightpanel). Thereafter the information generated by the two initial steps is integrated in a combined PK-PD model which simulates an optimalscenario for the eradication of the causative pathogen (bottom panel).


transdermal drug transport was mostly obtained from literature on MD in the preclinical neurochemicalin vitro studies or ex vivo measurements in skin field (for review see Ref. [86]). As an extension ofbiopsies, since, until recently no method has been this tradition, Hillered et al. and Meyerson et al.available for the direct characterization of time published the first reports on human brain MD inversus concentration profiles of in vivo drug release 1990 [87,88], an event which triggered a worldwideat the site of administration, the human skin, and for interest in human brain MD in neuro-intensive careproviding information on processes in tissue layers settings. In 1997, a commercially available MDdeeper than the stratum corneum (for a review see probe qualified for the CE-mark which enabled theRef. [70]). routine application of MD for bedside analysis of

Addressing this issue has become possible by tissue chemistry in the neuro-intensive care setting inemploying MD and 2D ultrasound [14,71] (see also Europe (Fig. 4). Therefore, in recent years a largeFig. 3a), and some recent studies provided, for the number of clinical MD studies on the human brainfirst time, in vivo PK data on the penetration were published with particular focus on metaboliccharacteristics of various compounds into subepider- monitoring for the definition of predictive markers ofmal layers. Thus, a new dimension — depth — was impaired brain function [89] as well as on theintroduced by microdialysis to transdermal research penetration of antiepileptic [22,90,91], and anti-(see Fig. 3b). In particular, formulations and dose microbial [56] agents across the blood–brain barrierregimens could be identified where topical adminis- to the intracerebral target site. MD was also used totration of non-steroidal antiinflammatory drugs monitor L-valproic acid [92,93], L-DOPA [94–97],(NSAIDs) leads to effective [72–74] or ineffective L-3,4-dihydroxyphenylalanine [98] and topiramate[75] target site concentrations. To date, MD has [99] in peripheral tissues, blood and cerebrospinalprovided important information on the degree of fluid in volunteers and epileptic patients with thedirect penetration of ethanol [14], nicotine [71,76], ultimate goal to optimize antiepileptic and anti-Par-estradiol [71], salicylic acid [77], acetylsalicylic acid kinson therapy [95,96]. Direct in vivo measurements[30], salicylate esters [72,73], local anaesthetics [78], in human brain parenchyma were performed foribuprofen [79], lipophilic analytes [35], organic carbamazepine [22,91], carbamazepine epoxidesolvents [80], methylnicotinate [81] and diclofenac [22,91], phenytoin [90] and rifampicin [56]. Byfollowing single [75] and multiple-dose administra- extrapolating the great success of MD in the preclini-tion [74]. In addition attempts were made to study cal field to clinical settings there is still amplethe enhancement of topical penetration by ion- opportunity for future clinical neuropharmacologicaltophoresis [82,83], tape stripping [77] and by local studies. In contrast to preclinical studies, however,administration of chemicals like sodium lauryl sul- there are serious ethical limitations for human drugfate [77]. Some studies have also addressed the studies, mostly due to the limited availability ofpenetration of dermatologically active compounds ethically appropriate clinical settings.like antihistamines [84] or NSAIDS [30,79] follow-ing systemic administration. 2.5. Metabolically active compounds: reverse

MD may also address the issue of transdermal microdialysisbioequivalence of various new formulations like gelsor foams, a fact which was also acknowledged at a Peripheral drug delivery may not only be studiedrecent workshop of the US-FDA [85]. The applica- directly by measuring drug concentrations with MDtion of MD in topical drug research may thus lead to but also indirectly by measuring drug effects. Con-a critical reappraisal of cost /benefit ratios of topical- ventionally, the concentration–response relation toly administered drugs in clinical drug development. pharmacologically active compounds is established

using cell cultures or isolated perfused organs. Up to2.4. Drugs acting on the central nervous system date, extension of these studies to human tissues was

hardly feasible in vivo. Some recent studies, mostlyFor many years MD was considered a neuro- in the metabolic field, showed the suitability of

chemical technique and there is an abundant body of microdialysis for in vivo drug response measure-


Fig. 3. Assessment of microdialysis probe position in transdermal penetration studies. (a) To obtain a positional information on thepenetration depth of the study drug the appropriate position of the microdialysis probe is established by 2D ultrasound and the distancebetween the skin surface (1) and the tip of the microdialysis probe (2) is measured. The tip of the microdialysis probe and the site where theprobe penetrates the epidermis (3) are also indicated by arrows. (b) Microdialysis introduces a new dimension, ‘depth from the skin surface’,in transdermal research. This is shown for transdermal penetration of nicotine following administration of a transdermal therapeutic system(TTS) to healthy volunteers (data from Ref. [71]).


Fig. 4. Clinical setting for microdialysis studies in human brain tissue. Under appropriate conditions microdialysis may be performed inintensive care settings in brain tissue to measure drug penetration into the parenchyma of the brain. For this purpose microdialysis probes areinserted simultaneously with an intracerebral pressure probe and an O -sensor via a guide cannula into the parenchyma of the brain. The2

arrow indicates the position of the guide cannula.

ments in human tissues following systemic adminis- ondansetron [132], salmeterol and salbutamol [133],tration. In addition, it was shown that drug effects on lidocaine [134], atropine and L-NAME [135].the local release and degradation of mediators andchanges in the concentration pattern of metabolitesand drugs in situ may be studied by reverse-mi-crodialysis, i.e., by employing microdialysis probes 3. Conclusions and outlookas delivery tools and, at the same time, for samplingof analytes [100] (see also Fig. 5). So far, these The application of MD in clinical pharmacologicalconcepts were successfully applied for both, (i) studies has provided previously inaccessible infor-endogenous mediators like insulin [100,101], brady- mation about the drug distribution process and haskinin [100,103,104], adrenergics [105–110], pros- shed new light on the target site distribution oftanoids [111], oxytocin [111] or estradiol [111] and pharmaceutical compounds. Employment of MD in(ii) exogenous drugs like glucocorticoids [112,113], clinical drug development will enhance our knowl-H1-antagonists [114,115], ranitidine [116], NSAIDs edge on proper drug dosing and may help improve[117–119], enalaprilate [120,121], losartan [121], the design of pivotal studies in clinical drug develop-compound 48/80 [100], phosphodiesterase inhibitors ment. Given the recent developments in clinical MD-[100,122,123], nicotine [124], metformin [125,126], research it may, thus, be concluded that MD has aopioids [127,128], metacholine [129], allergens great potential for both, academic and industrial[130], acetyl-salicylic acid [131], granisetron [132], research and may become the method of choice for


Fig. 5. Principle of reverse microdialysis studies. Microdialysis can be employed for controlled administration of drugs in vivo into theinterstitial space fluid (reverse microdialysis). For this purpose, compounds present in the perfusion solution are filtered by diffusion via thesemipermeable membrane out of the probe into the interstitial space. Simultaneously, biochemical markers of tissue drug response arefiltered out of the extracellular fluid into the probe.

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