Pharmacokinetic/pharmacodynamic studies in drug product development

MINIREVIEW

Pharmacokinetic/Pharmacodynamic Studies in DrugProduct Development

BERND MEIBOHM,1 HARTMUT DERENDORF2

1Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee, 874 Union Avenue,Room 5p, Memphis, Tennessee 38163

2Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida 32610

Received 12 September 2000; revised 16 May 2001; accepted 18 May 2001

ABSTRACT: In the quest of ways for rationalizing and accelerating drug productdevelopment, integrated pharmacokinetic/pharmacodynamic (PK/PD) concepts providea highly promising tool. PK/PD modeling concepts can be applied in all stages ofpreclinical and clinical drug development, and their bene®ts are multifold. At thepreclinical stage, potential applications might comprise the evaluation of in vivo potencyand intrinsic activity, the identi®cation of bio-/surrogate markers, as well as dosageform and regimen selection and optimization. At the clinical stage, analytical PK/PDapplications include characterization of the dose±concentration±effect/toxicity rela-tionship, evaluation of food, age and gender effects, drug/drug and drug/diseaseinteractions, tolerance development, and inter- and intraindividual variability inresponse. Predictive PK/PD applications can also involve extrapolation from preclinicaldata, simulation of drug responses, as well as clinical trial forecasting. Rigorousimplementation of the PK/PD concepts in drug product development provides arationale, scienti®cally based framework for ef®cient decision making regarding theselection of potential drug candidates, for maximum information gain from theperformed experiments and studies, and for conducting fewer, more focused clinicaltrials with improved ef®ciency and cost effectiveness. Thus, PK/PD concepts arebelieved to play a pivotal role in streamlining the drug development process of thefuture. ß 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci

91:18±31, 2002

Keywords: drug development; pharmacokinetics; pharmacodynamics; PK/PD model-ing; preclinical and clinical pharmacology

INTRODUCTION

Entering the 21st century, the pharmaceuticalindustry is challenged by further transforming itsresearch and development operations to meet anever-growing demand for more and more afford-able drugs brought to a highly competitive marketin a shorter time period. Demand for innovativeand highly ef®cacious medications will increasedue to higher lifestyle expectations and changing

demographic pro®les.1 The link between genomicsand disease and the fallout of the Human GenomeProject are expected to provide numerous newmolecular targets.2 High throughput screeningand combinatorial chemistry will identify anexploding number of potential therapeutic agentsfor these targets that need to be evaluated.3,4

Pharmaceutical drug development has tradi-tionally been performed in sequential phases,preclinical as well as clinical phases I±III, toanswer two basic questions; they are, which com-pound should be selected for development andhow it should be dosed. This information-gather-ing process has recently been characterized astwo successive learning±con®rming cycles.5,6 The

18 JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 1, JANUARY 2002

Correspondence to: B. Meibohm (Telephone: 901-448-1206;Fax: 901-448-6940; E-mail: [email protected])

Journal of Pharmaceutical Sciences, Vol. 91, 18±31 (2002)ß 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association

®rst cycle (traditional phases I and IIa) compriseslearning what dose is tolerated in healthy subjectsand con®rming that this dose has some measur-able bene®ts in the targeted patients. An af®rma-tive answer at this ®rst cycle provides thejusti®cation for a larger and more costly secondlearn±con®rm cycle (phases IIb and III), wherethe learning step is focused on how to use the drugin representative patients for maximizing itsbene®t/risk ratio, whereas the con®rm step isaimed at demonstrating acceptable bene®t/risk ina large patient population.

To manage the increasing number of com-pounds to be tested, a more rigorous selectionprocess at early stages in the development will beneeded to focus on potential winners and weedout losers. This process will ensure that limitedresources available are allocated to the mostpromising drug candidates. Thus, it has beensuggested to leave the sequential approach ofpreclinical/clinical phases and streamline drugdevelopment by combining preclinical and earlyclinical development as parallel, exploratory end-

eavors and expanding the learning process to allphases of drug development.7 Such a strategymight provide a deeper understanding of theaction of the drug prior to taking it further indevelopment (Fig. 1).

The increased application and integrationof pharmacokinetic/pharmacodynamic (PK/PD)concepts in all stages of preclinical and clinicaldrug development is one potential tool to enhancethe information gain and the ef®ciency of the deci-sion making process during drug development.8,9

PK/PD analysis links PK and PD as subdisci-plines of clinical pharmacology by mathematicalmodeling. This modeling allows characterizingthe time course of the effect intensity resultingfrom a certain dosing regimen.10,11 PK/PD analy-sis will thus support identi®cation and evaluationof drug response determinants; especially ifmechanism-based modeling is applied.6 PK/PDanalysis will also facilitate predictive simulationsof effect intensity±time courses for optimizingfuture development steps. This article will focuson examples for the application of PK/PD concepts

Figure 1. Potential applications of PK/PD conceptsduring preclinical and clinical drug product develop-ment. Depicted are the traditional phased approach(preclinical and clinical phases I±III) as well as the

previously described two successive learning±con®rm-ing cycles.5,6 The listings are not intended to beconclusive, rather a summary of the examples providedin this mini-review.

DRUG PRODUCT DEVELOPMENT±STUDIES OF PHARMACOKINETICS/PHARMACODYNAMICS 19

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 1, JANUARY 2002

at different stages of the drug developmentprocess.

PK/PD DURING PRECLINICAL DRUGEVALUATION

A thorough and rigorous PK/PD program in theearly learning phase of preclinical drug develop-ment can provide a linkage between drug dis-covery and preclinical development. As it sets thestage for any further development activities, theobtained information at this point is key tosubsequent steps. Important speci®c aims mightinclude:

� Identi®cation of potential surrogates and ani-mal models for ef®cacy/toxicity

� Development of mechanism-based models foref®cacy/toxicity

� valuation and prediction of in vivo potency andintrinsic activity

� Evaluation of drug interactions� Dosage form and dosage regimen optimization� Supporting the decision making process

Identi®cation of Potential Surrogates andAnimal Models for Ef®cacy/Toxicity

The identi®cation of appropriate PD endpoints iscrucial to the application of PK/PD modelingconcepts during drug development.12±15 Thus,biomarkers or receptor occupancy should betested early in exploratory preclinical develop-ment for their potential use as surrogate markersor endpoints.

Rolan et al.16,17 described the development of anew surrogate, the proportion of hemoglobinmolecules modi®ed to a high-af®nity form, forthe PD effect of the antisickling agent tucaresol.Narjes et al.18 evaluated the use of inhibition of exvivo platelet aggregation as surrogate for PDactivity of glycoprotein IIb/IIIa receptor antago-nists. Barrett et al. 19 identi®ed the guinea pig asthe most appropriate rodent species to investigatethe PK/PD of glycoprotein IIb/IIIa inhibitors dueto PD similarities with humans in drug/receptorbinding.

Development of Mechanism-Based Models forEf®cacy/Toxicity

Mechanism-based modeling in contrast to empi-rical modeling is the preferred methodology for

PK/PD correlations as it appreciates the under-lying physiological processes for the observedpharmacologic response.20 Development and ap-plication of mechanism-based PK/PD models invarious animal species has several potentialbene®ts: (a) it provides an accurate and thoroughcharacterization of the dose±concentration±effect relationship, (b) it gives measures ofpotency and intrinsic activity based on concentra-tions rather than dose, and (c) it allows one toinvestigate the role of modulating physiologicaland pathophysiological parameters as well astolerance phenomena.21,22

Benincosa et al.23 developed physiologicalPK/PD correlations to identify the major determi-nants controlling the effects of a humanized anti-factor IX monoclonal antibody (SB249417) inmonkeys; namely, endogenous and antibody-ligand binding. The resulting modeling appro-ach was suggested to have wide applicability inpredicting the effect of drugs with similarmechanism of action; that is, therapeutically usedmonoclonal antibodies. The immune suppressiveeffect of another monoclonal antibody, mAB 5c8,was characterized in monkeys by establishing aphysiologically based immunodynamic model thatis assumed to guide future research includinghuman studies in terms of optimized experi-mental design, sampling strategies, and dosingregimens.24 Finally, van der Graaf et al.25 applieda mechanism-based operational model of agonismfor evaluating the adenosine A1 receptor-medi-ated effect of N6-cyclopentyl-adenosine analogson heart rate in rats.

Evaluation and Prediction of In Vivo Potencyand Intrinsic Activity

A crucial question in drug development is theextent of predictability of the potency and intrin-sic activity of a drug in humans based on PK/PDdata obtained in animal studies. Although inter-individual variability in PD is generally large,26 ithas been demonstrated that unbound effectiveconcentrations for numerous drugs are similar inanimals and humans.27

Cox et al.28 reported similar concentrationranges for the concentration at half-maximumeffect (EC50) of various opioids for rats andhumans. Thus, a thorough characterization ofthe PD of investigational opioids may be used toidentify compounds with superior properties atthe preclinical stage. A PK/PD-based EEG modelalso allowed evaluation of the active, major

20 MEIBOHM AND DERENDORF


metabolite of remifentanil in rats as testing inhumans was not possible for regulatory andethical reasons.29 The obtained results led tothe conclusion that the maximum concentrationsof the metabolite accumulated during therapywere too low to expect an effect or PD interactionwith the parent compound. Similarly, Meibohmet al.30 applied PK/PD analysis to evaluate PD of anovel, sildena®l-like phosphodiesterase-5 inhibi-tor (EMD 221829) in dogs. The data from thisstudy provided valuable insight into the in vivopotency of the novel compound, which, due to alack of feasibility of the experimental design,would not be accessible in human studies. Inaddition to these traditional PK/PD methods,population analyses have also been used to assessthe in vivo pharmacology of drugs at the pre-clinical stage.31

Evaluation of Drug Interactions

A PK/PD relationship once established can also beused to elucidate complex drug interactionsbetween different compounds or a parent com-pound and its active metabolite.32,33 Mandemaet al.34 investigated the interaction betweenbenzodiazepines and the competitive antagonist¯umazenil in rats with a competitive interactionmodel that allowed characterization and predic-tion of the time course of the EEG effect onadministration of any given combination. Simi-larly, Dalla Costa et al.35,36 used in vitro measure-ments and PK/PD analysis to characterize theeffect of the b-lactamase inhibitor tazobactam onthe antimicrobial activity of piperacillin.

Dosage Form and Dosage Regimen Optimization

Previously developed PK/PD relationships mightalso be applied to evaluate and optimize variousdosage forms and drug delivery systems. Forrecombinant human growth hormone, a PK/PDmodeling technique was applied to compare theeffect of a drug in monkeys after subcutaneous(sc) administration of a sustained-release formu-lation with biodegradable microspheres comparedwith conventional sc application.37 The measuredeffect was induction of insulin-like growth factor 1(IGF-1). The sustained-release formulation waseffective in maintaining growth hormone concen-trations above the EC50 for IGF-1 induction,thereby providing a rationale and dosing gui-dance for subsequent clinical studies in growthhormone-de®cient children.

Bauer et al.38 developed a PK/PD model for thehemodynamic tolerance towards prolonged con-tinuous administration of nitroglycerin. Applica-tion of this modeling approach allowed designingsuitable dosage regimens to overcome experimen-tal nitroglycerin tolerance in rats.

Supporting the Decision Making Process

The ultimate goal of real-time implementation ofPK/PD modeling in preclinical drug developmentis to build a wide knowledge base for a moreef®cient selection of drug candidates and toprovide decision makers as early as possible withsuf®cient evidence-based information for their go/no-go decision at key transition steps in drugdevelopment. Bies et al.39 provided a case studyfor such an integrated use of an extensivepreclinical database in building PD, PK, toxico-dynamic and allometric relationships to guide anew, anonymous drug development program intoa ®rst human study. Based on the integratedevaluation of the available data, development ofthe lead compound was discontinued and shiftedto alternates in the program.

PK/PD AT THE TRANSITION FROMPRECLINICAL TO CLINICAL STUDIES

One of the most challenging steps in drugdevelopment is the choice of an appropriate doserange for early phase I studies. PK/PD conceptsmight be helpful in extrapolating preclinical datafrom animal species to humans, thereby facilitat-ing dose escalation selection as well as the choiceof bio- and surrogate markers. Lieberman andMcMichael40 reported, with the development oftacrolimus, compelling evidence for the use ofpreclinical PK/PD data extrapolated from in vitroimmune assays and in vivo animal models as areliable guide to identify a safe and effective doseand therapeutic concentration range for phase Iclinical studies.

Although pharmacodynamically effective un-bound concentrations are often comparable be-tween different species, PK processes generallyfollow a much wider interspecies variability.Extrapolation of animal data by allometric scalingis an often-used tool in drug development withmultiple approaches available at variable successrates.41 Cosson et al.42 used a combination ofallometric scaling and mixed effect modeling toretrospectively perform dose selection for earlyphase I studies of sumatriptan. These authors



concluded that design and ef®ciency of subse-quent clinical studies would bene®t from earlyapplication of the technique. Khor et al.43 appliedallometric and PK/PD modeling in the doseselection for phase I trials of a recombinant P-selectin antagonist (rPSGL-Ig).

PK/PD DURING THE LEARNING PHASESOF CLINICAL DRUG DEVELOPMENT

Similar to the preclinical phase, drug develop-ment at the clinical stage provides severalopportunities for a bene®cial integration of PK/PD concepts. Clinical phase I dose escalationstudies provide, from a PK/PD standpoint, theunique chance to evaluate the dose±concentra-tion±effect relationship for therapeutic and toxiceffects over a wide range of doses up to or evenbeyond the maximum tolerated dose under con-trolled conditions.44 It should be kept in mind,however, that often only biomarkers are followed,which might not necessarily correlate with theultimate therapeutic outcome. Nevertheless, PK/PD evaluations at this stage of drug developmentcan provide crucial information as to the potencyand tolerability of the drug in vivo and theveri®cation and suitability of the PK/PD conceptestablished during preclinical studies. For thegrowth hormone releasing peptide ipamorelin,data obtained from a dose escalation trial wereused in a PK/PD model to characterize itsconcentration-dependent effect on endogenousgrowth hormone levels across a wide range ofdoses. Moreover, interindividual variability in PDparameters of ipamorelin was found to be higherthan in PK parameters.45

Additional questions that might be addressedby PK/PD analysis procedures during the learn-ing phases of clinical drug development areoutlined in the following:

� Evaluation of Dosage Forms and Administra-tion Pathways

� Evaluation of Food and Gender Effects� Evaluation of Special Populations� Characterization of Therapeutic Index� Characterization of Active Metabolites� Characterization of Drug±Drug Interactions� Characterization of Drug±Disease Interactions� Characterization of Tolerance Development� Characterization of and Discrimination

between Drug Analogues� Bridging Studies in Global Drug Development

Evaluation of Dosage Forms and AdministrationPathways

In analogy to the preclinical phase, PK/PDevaluations might be extremely helpful in theclinical dosage form design because they mayallow assessing the impact of administrationpathways and release rates on the effects of thedrug in vivo.46 Kleinbloesem et al.47 provided aclassical example with the dissociation of theeffect of nifedipine on heart rate and meanarterial blood pressure dependent on the infusionrate. Pechstein et al.48 used a PK/PD analysis tocompare the suppressive effect of the luteinizinghormone-releasing hormone antagonist cetrorelixon endogenous testosterone and luteinizing hor-mone after intravenous (iv) and sc administra-tion, respectively. Similarly, Radwanski et al.49

identi®ed the subcutaneous route as favorable forthe administration of interleukin 10 (IL-10)compared with iv dosing.

Evaluation of Food and Gender Effects

Schaefer et al.50 used PK/PD modeling to evaluatethe clinical relevance of a food interaction for acontrolled release dosage form of nisoldipine.Based on the additional blood pressure decreaseafter concomitant food intake, the authors con-cluded that mild adverse events might occur whenthe dosage form is taken with food. Salazar et al.51

applied a PK/PD method to evaluate effect ofgender on the clinical pharmacology of d-sotalolusing QTc-prolongation as a PD endpoint.Although no differences were identi®ed, womenwere found to have a higher baseline QTc thanmen. Similarly, Marino et al.52 found that the PK,but not the PD of pyridostigmine bromide, weregender dependent when assessing its effect onacetylcholinesterase activity. PK/PD modeling alsorevealed that women seem to have a higher eli-mination rate from a hypothetical effect compart-ment (ke0) for neuromuscular blocking agents likecisatracurium and atracurium. However, no signi-®cant differences in the onset and recovery pro®leof neuromuscular blockade could be detected.53±55

Evaluation of Special Populations

PK/PD analysis might also be helpful in identify-ing pharmacological differences and their poten-tial causes in patient subpopulations. Andersonet al.56 used a PK/PD modeling technique tocharacterize the analgesic effect of acetamino-phen after tonsillectomy in children. The goal was



to determine the acetaminophen concentrationnecessary for post-tonsillectomy pain control.Marshall et al.57 established the concentration±effect relationship for the loop diuretic bumeta-mide in critically ill pediatric patients withedema. Pihoker et al.58 used PK/PD modeling toevaluate the increase in endogenous growthhormone concentrations after administration ofgrowth hormone-releasing peptide-2 to children.

Similarly, Sorooshian et al.59 used PK/PDmodeling to identify differences in the clinicalpharmacology of cisatracurium between youngand elderly adults. Although PK differences wereonly marginal, effect onset was delayed in theelderly because of a slower biophase equilibration.

Characterization of Therapeutic Index

Continuous PK/PD integration of ef®cacy as wellas adverse effect information throughout theclinical development process provides a broadbasis to establish the `Therapeutic Index' of acompound. Simultaneous characterization ofdose±concentration±effect relationships for ther-apeutic as well as adverse effects by utilizingadverse effect data from more ef®cacy focusedphase II and phase III trials also allows a moreconclusive evaluation of the toxicity potential of adrug in applied pharmacotherapy and thus sup-ports dosage selection.

Characterization of Active Metabolites

If active metabolites are contributing to thetherapeutic effect or toxicity of a drug, PK/PDmodeling concepts may be applied to quantify thein vivo potency of the metabolites and theircontributions to the overall effect. In addition,this modeling might even reveal the presence ofpreviously unknown active metabolites. Rague-neau et al.60 determined by PK/PD modeling, thatthe N-dealkylated metabolite of the direct sinusnode inhibitor ivabradine contributes substan-tially to the bradycardiac effect of the parentdrug. Similarly, Tuk et al.61,62 characterized thePD interaction between midazolam and its activemetabolite a-hydroxymidazolam with a receptor-theory-related, mechanism-based interactionmodel.

Characterization of Drug±Drug Interactions

PK/PD approaches also allow evaluating potentialdrug±drug interactions and identifying the PK

and/or PD parameters affected. Van den Berget al.63 identi®ed by PK/PD modeling that theinteraction between formoterol and theophyllinewith regard to their eosinopenic and hypokalemiceffects was limited to a noncompetitive PDinteraction, whereas PK remained unaffected.Belani et al.64 identi®ed by PK/PD correlationthat in the absence of any PK interaction,paclitaxel has a platelet-sparing effect on thedose-limiting thrombocytopenia of carboplatinduring the combination therapy of both drugs inpatients with non-small-cell lung cancer.

Characterization of Drug±Disease Interactions

The perturbations of disease states on the clinicalpharmacology of a drug can also be assessed byPK/PD techniques. Koch et al.65 concluded thatrenal elimination of ranitidine in patients withrenal impairment declined in parallel with renalfunction. The sensitivity to ranitidine-inducedgastric pH elevation, however, remained inde-pendent of renal function. Similarly, Lehne et al.66

found the systemic clearance of the glycoproteinIIb/IIIa inhibitor lami®ban was linearly relatedto renal function. But, patients with impairedrenal function were sensitized to its antiplateleteffect assessed via ex vivo inhibition of plateletaggregation.

Characterization of Tolerance Development

If drugs undergo functional tolerance develop-ment, PK/PD modeling may be a helpful tool incharacterizing its time course and extent asshown for ranitidine.67 Tolerance developmentto the acid inhibitory effect of ranitidine increasedEC50 by 100% within 6±10 h after prolonged ivtherapy. The increase in tolerance was slower forintermittent compared with continuous dosing.

Characterization of and DiscriminationBetween Drug Analogues

Established PK/PD models for a class of com-pounds with the same mechanism of action maybe applied to discriminate between different druganalogues and to de®ne the therapeutic place ofnewly developed compounds based only on pre-clinical and/or in vitro PD information. Derendorfet al.68±70 showed the applicability of an inte-grated PK/PD model to predict the systemic PD ofcorticosteroids based on human PK and in vitroreceptor binding data. Likewise, Lemmens et al.71



used PK/PD modeling to evaluate the bene®t ofthe opioid trefentanil in comparison with fentanyland alfentanil, and identi®ed a more rapid re-covery from the effects of trefentanil quanti®ed asEEG changes compared to the other compounds.

Bridging Studies in Global Drug Development

In the process of global drug development, brid-ging studies might be performed to providesupplemental pharmacologic data that allow theextrapolation of clinical results from one toanother region with major cultural and/or racialdifferences in the target population.72 PK/PDmodeling concepts might be applied to compara-tively search for differences in a drug's dose±concentration±effect relationship related tointrinsic, that is, genetic and physiologic, char-acteristics, as de®ned in the ICH E5 guideline.73

Jonsson et al.74 comparatively evaluated PK andPD of iv glibenclamide in Chinese and Caucasianpatients with type-2 diabetes, concluding that thesame dosage principles should be employed forboth groups.

PK/PD DURING THE CONFIRMING PHASESOF CLINICAL DRUG DEVELOPMENT

With the transition from more learning-orientedinvestigations during the early phases of clinicaldrug development to more con®rmatory studies inthe later phases, the methodology of applied PK/PD techniques is also shifted from the exploratoryanalysis of data rich concentration±effect datasets in individuals to more sophisticated analy-tical tools. These include population PK/PDapproaches as well as PK/PD-based effect simula-tion and computer-aided trial design.

Population PK/PD Analysis

The application of population PK/PD methods indrug development has widely been advocated75±78

and is documented by the respective guidancedocument of the US Food and Drug Administra-tion.79 Population analysis can and shouldalready be applied in preclinical and early clinicalphases of the drug development process;75,76 forexample, if circumstances limit sampling or if asuf®cient number of individuals is available toassess interindividual variability.56,80 The majordomain of population PK/PD analyses, however,lies in clinical trials of the phases IIb and III as

well as postmarketing studies, in which they mayeither be integrated prospectively or performedretrospectively summarizing one or multiplestudies.76 Sparse sampling design with unba-lanced and fragmented data from larger groupsof individuals may be studied for well-known andless well-known sources of interindividual varia-bility in response (e.g., genetic polymorphisms indrug metabolizing enzymes or receptor systems),but also effect-modulating physiological or patho-physiological conditions, as well as environmen-tal, demographic, or cultural factors.78 Lalondeet al.81 provided an example for using populationanalysis in a phase I study in postmenopausalwomen characterizing the PD for the investiga-tional calcimimetic drug R-568. Because this doseranging study used a crossover design, populationanalysis not only allowed establishment of patientspeci®c dose±response curves, but also assess-ment of their distribution and thus interindivi-dual variability.82

In a phase II, parallel group, multicenter study,Samara et al.83 applied population PK/PD meth-odology to evaluate the PD of the thromboxanereceptor antagonist seratrodast in asthmatics.Although the improvement in lung function waslinearly correlated to seratrodast plasma concen-trations, patients with more severe airwayobstruction were found to have a steeper slopefor this relationship; that is, higher improvementper drug concentration. Thus, interpatient varia-bility in response could mainly be attributed tothe initial severity of the disease.

Based on population PK/PD modeling, doseintensity and the average peak plasma concen-tration during multiple dosing were furthermoreidenti®ed as primary determinants for predictinglesion response to PEGylated liposomal doxorubi-cin in patients with AIDS-related Kaposi's sar-coma.84 Subsequent simulations with theobtained population PD model revealed that dosessubstantially lower than the maximum tolerateddose might be suf®cient for achieving the max-imum probability of partial response, therebyreducing the potential for toxicity.

Hempel et al.85 retrospectively analyzed thePD of the I1-receptor agonist moxonidine for bloodpressure reduction using 24-h ambulatory bloodpressure measurements from a phase II study. Bydeveloping a sophisticated population model forvariability and periodicity in baseline bloodpressure, the extensive number of effect samplesper individual obtained by ambulatory bloodpressure measurement could be utilized to



characterize the dose±concentration±effect rela-tionship of moxonidine.

Schmith et al.86 prospectively incorporated apopulation PK/PD program in eight phase I±IIItrials of the neuromuscular blocking agent cisa-tracurium. Relaxing inclusion/exclusion criteriaand studying the drug under various dosingregimens in ef®cacy/safety studies obtained suf®-cient data heterogeneity to predict the time courseof drug effects in different patient subpopulationsfollowing various dosing regimens. Consequently,four formal PK/PD studies on dose proportional-ity, drug interaction with inhalation agents, andthe effects of obesity and mild-to-moderate renaldysfunction were rendered unnecessary.

Clinical Trial Simulations

In clinical drug development, PK/PD modelingapproaches can be applied as analytical tools foridentifying and characterizing the dose±responserelationship of drugs and the mechanisms andmodulating factors involved. Additionally, theymay be used as predictive tools for exploringvarious dosage regimens and perturbations aswell as for optimizing further clinical trialdesigns, which might allow one to perform fewer,more focused studies with improved ef®ciency andcost effectiveness. These simulation techniquesare commonly referred to as in silico or in numerostudies. The PK/PD database established duringthe preclinical and clinical learning phases in thedevelopment process and supplemented by popu-lation data analysis provides the backbone forthese assessments. Simulation studies performedare generally based on Monte Carlo simulationtechniques and might comprise one or severalspeci®c aspects of drug response, but also com-plete (`full') trial forecasting.87

Levy et al. used PK/PD-based computer simula-tions to differentiate the utility of effect-controlledversus concentration-controlled clinical trials withsparse data sampling88,89 and the utility of apreceding, data-intensive pilot study to applyoptimal sampling theory.90 Using a populationanalysis, Minto et al.91 identi®ed age and lean bodymass as signi®cant covariates for the EEG effect ofthe short-acting opioid remifentanil. Based onsimulations with this PK/PD model, the authorsconcluded that bolus doses should be halved andinfusion rates decreased to one third in elderlycompared with young patients.92 Brickl et al.93

performed simulations of ®brinogen receptor occu-pancy including interindividual PK and PD vari-

ability to determine appropriate dosing regimensfor achieving prede®ned receptor occupancy withthe ®brinogen receptor antagonist frada®ban in anearly phase II study. Jackson94 presented acomplex PK/PD model including cytokinetic pro-cesses and disease progression that describes thedevelopment of drug resistance towards reversetranscriptase inhibitors and aspartyl proteaseinhibitors during the chemotherapy of HIV infec-tion. Simulations performed with this model wereused to explore ways of delaying the resistancedevelopment to these antiretroviral agents.

Simulation of complete clinical trials (`trialforecasting') recently emerged as an extension ofPK/PD-based simulations.95,96 Although PK/PDmodeling concepts and inter- and intraindividualvariability of their related parameters form thecore of these clinical trial simulations, they mightalso include model components for the involvedphysiological and pathophysiological processes,including disease development and progression,and factors modifying trial outcome like compli-ance and adverse events. Potential bene®ts oftrial simulation include the upfront comparison ofalternative study designs, identi®cation of appro-priate dosing regimens to meet the study objec-tives, determination of the number of subjectsneeded for adequate power, and evaluation ofdrug interaction and disease effects.97

Hale et al.98 applied PK/PD-based simulationtechniques with data from a preliminary pilotstudy to determine the optimum study design for arandomized, concentration-controlled trial evalu-ating the immunosuppressive agent mycopheno-late mofetil. Gieschke et al.99 presented anexample for PK/PD-based simulation of a clinicaltrial for an oral anticancer drug, which was ap-plied to select an appropriate dosing regimen andevaluate consequences of dose adaptation rules onef®cacy and adverse events. Although clinical trialsimulation is still in its infancy and reportedexamples for its application are still rare, thediscipline is rapidly evolving due to its potentialusefulness in substantially rationalizing and ac-celerating drug development.87,97 A consensusdocument describing good practices for simula-tions of clinical trials became recently available.100

PK/PD DURING NDA REVIEW ANDPOSTMARKETING

Even beyond the preclinical and clinical drug de-velopment phases, application of PK/PD concepts



might be bene®cial during the life cycle of a drug;namely, during the preparation and review ofregulatory documents for NDA submissions, andduring postmarketing surveillance.

Preparation and Review of Regulatory Documents

The value of PK/PD during the NDA submissionand review phase is that it integrates informationfrom preclinical as well as clinical phases I, II, andIII, including the various subpopulations. It thusallows comparisons of the dose±concentration±effect relationship across species and subpopula-tions. Existence of a well-de®ned PK/PD modelfurthermore enables the reviewer to perform PK/PD simulations for various scenarios. This abilityhelps the reviewer gain a deeper understandingfor the compound and provides an argumentativebasis for dose selection. Thus, PK/PD can facil-itate the NDA review process and help resolveregulatory issues.

Postmarketing Surveillances

Although currently only rarely performed, inte-gration of PK/PD analysis into postmarketingsurveillance should be encouraged. Especiallypopulation PK/PD within a structured surveil-lance approach might have tremendous bene®t indetecting drug±drug interactions, drug±diseaseinteractions or other covariates (e.g., demo-graphics or genetics) that interfere with the effector toxicity of the drug.101

Guentert et al.102 related the occurrence ofadverse events during moclobemide therapy toaverage plasma contractions estimated via apopulation PK approach. Adverse event frequ-ency was concentration dependent, but was 1.4times more frequent in females than in males.

The signi®cance of PK/PD evaluations duringpostmarketing surveillance studies was illu-strated by Grasela et al.103 These authors showedthat population PK parameters for tianeptineobtained during premarketing studies did notaccurately predict drug concentrations in patientsreceiving the drug in the postmarketing setting.

FUTURE ROLE OF PK/PD CONCEPTS INDRUG DEVELOPMENT

For several years, the widespread application ofPK/PD concepts in all phases of drug develop-ment has repeatedly been promoted by industry,

academia, and regulatory authorities.104±109 Itsrigorous application in practice, however, is stillhampered by rigid structures, negligence, or lackof interaction and collaboration between involvedscientists, clinicians, and management, and anunmet growing demand for speci®cally trained,highly quali®ed pharmaceutical scientists in thisarea.

PK/PD strategy has recently been character-ized as `a way of thinking as it is a type of studydesign, data analysis, or explicit mathematicalmodel'.110 Implementation of a PK/PD strategy indrug discovery and development requires sub-stantial changes in current practice, including itsrigorous implementation in the discovery anddevelopment plan as well as the initiation ofmultidisciplinary collaborations between all indi-viduals involved in the development process. Asillustrated by the examples presented in thisarticle, PK/PD modeling concepts can be appliedin all stages of preclinical and clinical drugdevelopment (Fig. 1). Their potential bene®tsare multifold and often provide a rationale,scienti®cally based framework for ef®cient deci-sion making. So far, however, only two reportshave publicly demonstrated the bene®ts andpositive impact of the integration of PK/PDmodeling concepts in the drug developmentprocess at Hoffmann La Roche111 and Parke-Davis.112 Further documentation in this area isurgently needed.

Streamlining the drug development process isbecoming an inevitable economic and competitivenecessity. At the same time regulatory authoritiesincrease their requests for PK/PD-data during thedrug approval process. In this scenario, theopportunities offered by a PK/PD guided appro-ach to drug development will clearly outweightraditional drug development strategies. Thus,PK/PD concepts are believed to play a pivotal rolein the drug development process of the future andtheir widespread adoption will ®nally result in ascienti®cally driven, evidence-based, more focus-ed, and accelerated drug product development.

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