dexibuprofen , s(+)-ibuprofen , is a pharmacologically active form and is more potent than ibuprofen , which has equal quantities of r()- and s(+)-enantiomers . ibuprofen is an nsaid and is widely used to reduce pain , fever , and inflammation . this drug inhibits cyclooxygenases and activates peroxisome proliferators - activated receptors ; both of these actions result in reduced inflammation [ 24 ] . pharmacokinetic - pharmacodynamic ( pk - pd ) modeling is a scientific tool to help developers selecte a rational dosage regimen for confirmatory clinical testing . pk / pd modeling can be executed using various approaches , such as direct versus indirect response models and parametric versus nonparametric models . the limits of pk / pd approaches include the development of appropriate models , the validity of surrogate endpoints , and the acceptance of these models in a regulatory environment . pk - pd modeling allows the estimation of pk - pd parameters and the prediction of these derived , clinically relevant parameters as well . pk - pd simulations allow the assessment of the descriptive parameters as the functions of dose and dose rate . these simulations can provide the dose - response curve for onset , magnitude , and the duration of effect . currently , there is a growing recognition of the importance of pk - pd studies in all phases of drug development [ 69 ] . in preclinical studies , pk - pd is used to interpret toxicokinetics data and via physiological modeling and allometric scaling , it is also used to extrapolate results from animals to humans [ 10 , 11 ] . during early clinical testing , pk - pd is used to aid in the interpretation of dose - response and escalation studies . in addition , there are several instances in which pk - pd modeling has been used by regulatory agencies to recommend a dose and/or regimen not originally studied as part of the clinical program . as in the case of pharmacokinetics , methods to measure pharmacologic effects and bio - mathematical models had to be developed to characterize and evaluate pharmacodynamic processes . mathematical models can be considered as the simplifications of a phenomenon described in terms of an algebraic or differential equation . in the case of pk - pd modeling , it is expected to not only describe , but also predict distinct situations , such as scaling between preclinical to clinical trials , multiple dosing schemes , or different routes of administration [ 12 , 13 ] . to choose the most appropriate pk - pd model , it is essential to identify the significance of the biological processes involved in eliciting a drug - induced response . eventually , pk processes , biophase distribution , drug - receptor interaction , signal transduction , and secondary postreceptor events are factors altering the pd behavior of a drug . it is possible to link pk and pd with actual physiologic support instead of only abstract numbers . then , the model - building process involves fitting the available data and the consideration of possible biological differences that usually are translated into inter- and intravariability . in the case of pd variability , it becomes important to identify the useful predictor ( covariates ) of pd individuality to facilitate the individually optimized pharmacotherapy . it is necessary , therefore , to establish very comprehensive patient profiles during the development of studies . moreover , the study populations must be representative of the target patient population with respect to age , gender , race , and environmental and pathophysiological characteristics . if these requirements are absent , the relevance and usefulness of covariates may be questionable [ 14 , 15 ] . because of the multiple factors intervening in a pk - pd study , it then appears adequate to divide the modeling project into the following two basic blocks such as concerning the clinical or experimental design by itself and the data analysis . diverse models have been suggested to describe the pk - pd relationship depending upon the nature of drug administration scheme ( single doses , multiple doses , long - term infusions , etc . ) and the time dependency of pd parameters . thus , when the system is kinetically at steady state , the concentrations of the active moiety at the active site are constant ( after long - term infusions or multiple doses ) ; relatively simple models are needed to characterize the pk - pd relationship . otherwise , after single doses ( nonsteady - state condition ) and when time variant pd parameters are present , more complex models are needed to account for phenomena involved in the pk - pd relationship . approaches such as disequilibrium between biophase and plasma compartment , the appearance of active metabolites [ 16 , 17 ] , indirect mechanisms of action [ 18 , 19 ] , sensitization , and tolerance [ 2022 ] have been proposed to explain the apparent dissociation between time courses of concentration and effect . recently , the combination of powerful nonlinear , mixed effect regression models , statistically robust software tools , and the integration of pharmacokinetic - pharmacodynamic knowledge has permitted optimization of the decision process in therapeutic management . by the incorporation of previous information into these systems , bayesian forecasting certainly promises the more adequate individualized therapy for a particular patient . the development and validation of a pk / pd is based on the ability of the fraction of the drug absorbed versus the fraction of the drug - dissolved relationship of various formulations . for the estimation of the drugs present in the biological fluids , hplc method [ 2328 ] is considered to be more suitable since it is a powerful and rugged method and also extremely specific , linear , precise , accurate , sensitive , and rapid . the present study is developed and validated pk / pd of selected modified release formulations containing dexibuprofen . at present acetonitrile , methanol , orthophosphoric acid , sodium acetate , perchloric acid , and triethylamine were supplied by qualigens fine chemicals and s.d . fine chemicals . water ( hplc grade ) was obtained from milli - q system . working standards of dexibuprofen was purchased from noven life sciences ( hyderabad , india ) hpmc ( methocel - k100-cr , apparent viscosity , 2% in water at 20c is 80,00012000  cp ) ; xanthen and starch 1500 were gift samples from colorcon asia pvt ltd ( goa , india ) . polyvinyl pyrrolidine ( pvp - k-30 ) was a gift sample from anshul agencies ( mumbai , india ) . this chapter describes the experimental details of the preformulation study , tablet manufacture , bio availability study design and data handling , optimization and validation of the bio analytical methods for the estimation of dexibuprofen in human plasma samples , preparation of standard and sample solutions , development of in vitro dissolution methods , in vitro data analysis , in vivo data analysis , statistical analysis of pharmacokinetic data , and development of pharmacokinetic - pharmacodynamic model . preformulation in the broadest sense encompasses all the activities and studies that are required to convert an active pharmacological substance into a suitable dosage form . it can be defined as an investigation of the physical and chemical properties of a drug substance alone and also when combined with the excipients . in the present study , therefore , the evaluation of granulations , development of in vitro dissolution method , and the compatibility between the drug and the selected polymer were determined . all the composition , with the exception of magnesium stearate and aerosol , were thoroughly mixed in a tumbling mixer for 5  min and wetted in a mortar with isopropyl alcohol . the wet mass was sieved ( 16 mesh ) and granules were dried at 40c for 16  h. the dried granules were sieved ( 22 mesh ) and these granules were lubricated with a mixture of magnesium stearate and aerosil ( 2  :  1 ) . compression was performed after granulation process with a single punch press applying a compression force of a 9  kn ( preliminary work ) or 12  kn ( experimental design ) , equipped with a 12  mm flat - faced punch . for the preliminary work , each batch of experimental design consisted of 100 tablets ( drug content in the tablet was 300  mg ) . three batches were prepared for each formulation and the compositions of different batches of dexibuprofen sr tablets are given in table 1 . the compressed tablets were evaluated for average weight and weight variation , thickness , diameter , drug content and content uniformity , hardness , friability , disintegration , and in vitro drug release . bioavailability studies of the optimized formulations were carried out in crossover design in healthy human volunteers between the developed formulations and the conventional dosage form . the protocol of the study was submitted to the institutional human ethical committee and the approval for conducting the same was obtained and a prior consent of the volunteers participated in the study was taken . randomized , two - treatment , two - period , two - sequence , single - dose , crossover bioavailability studies were carried out in healthy human volunteers between the developed sustained release ( sr ) formulation and the marketed conventional immediate release ( ir ) formulation to prove the safety and efficacy of the developed sr formulation . a reproducible analytical technique was developed for the estimation of the drugs in the plasma samples . various pharmacokinetic parameters such as cmax , tmax , t1/2 , kel , auc0t , and auc0 were estimated . a visual analogue scale ( vas ) is a measurement instrument that tries to measure a characteristic or attitude that is believed to range across a continuum of values and can not easily be directly measured . for example , the amount of pain that a patient feels ranges across a continuum from none to an extreme amount of pain . from the patient 's perspective , this spectrum appears continuous  ; their pain does not take discrete jumps , as a categorization of none , mild , moderate , and severe would suggest . it was to capture this idea of an underlying continuum that the vas was devised . operationally a vas is usually a horizontal line , 100  mm in length , anchored by word descriptors at each end ( see figure 6 ) . the patients mark on the line the point that they feel it represents their perception of their current state . the vas score is determined by measuring in millimetres from the left hand end of the line to the point that the patient marks . there are many other ways in which vas has been presented , including vertical lines and lines with extra descriptors . wewers and lowe   provide an informative discussion of the benefits and shortcomings of different styles of vas . as such an assessment is clearly highly subjective , these scales are of most value when looking at change within individuals and are of less value for comparing across a group of individuals at one time point . it could be argued that a vas is trying to produce interval / ratio data out of subjective values that are at best ordinal . many researchers prefer to use a method of analysis that is based on the rank ordering of scores rather than their exact values , to avoid reading too much into the precise vas score . this section describes the experimental results obtained in the present investigation in the form of tables and figures along with a detailed analysis on the results of preformulation study , tablet manufacture , bioavailability study design , data handling , optimization and validation of the bio analytical methods for theestimationofdexibuprofen in human plasma samples , amount of the selected drugs present in plasma samples , in vitro dissolution method , determination of pharmacokinetic parameters , statistical evaluation , in vivo and in vitro data analysis , and pharmacodynamic model . the physical properties of different batches of developed tablets are given in table 1 and figure 1 of dexibuprofen , respectively . the average percentage deviation of 20 tablets of each formula was less than 5% and hence all formulations passed the test for uniformity of weight as per official requirements ( pharmacopoeia of india 1996 ) . the percentage friability for all the formulations was below 1% , indicating that the friability is within the prescribed limits . all the tablets formulations showed acceptable pharmaco technical properties and complied with the specifications for weight variation , drug content , hardness , and friability . a single - dose , randomized , complete , two - treatment crossover study was conducted in healthy human subjects for the selected drug formulations . seven days prior to the commencement of the study , volunteers were subjected to preliminary screening and standard clinical and biochemical investigations . after overnight fasting , the volunteers were given code numbers and allocated to the treatment in accordance with the randomized code . the order of treatment administration was randomized in two sequences ( ab and ba ) in blocks of two . in each dosing session , volunteers received reference product a ( immediate release formulations ) and test b ( sustained release formulations ) . blood samples ( 4  ml ) were collected at 0 ( before drug administration ) , 0.5 , 1.0 , 1.5 , 2.0 , 2.5 , 3.0 , 4.0 , 6.0 , 8.0 , 12.0 , 18.0 , and 24.0  h after dosing . there were no serious adverse effects observed during the entire study ( table 2 and figure 2 ) . pharmacokinetic parameters such as peak plasma concentration ( cmax ) , time to peak concentration ( tmax ) , area under the plasma concentration - time curve ( auc0t and auc0 ) , elimination rate constant ( kel ) , and elimination half - life ( t1/2 ) were calculated separately and the blood level data of selected formulations were compared . the pharmacokinetic parameters of two different drug formulations of dexibuprofen was compared statistically by one - way anova ( analysis of variance ) using spss version 16.0 . the results were expressed as the mean  sd . the pharmacokinetic parameters cmax , auc0t , and auc0 of the immediate release and sustained release formulations of dexibuprofen were found to be significantly different by one - way anova . the results indicated by the pain scale   of the developed dexibuprofen sr tablets have shown notable pain relief when compared to the marketed ir tablets . the quantification of the chromatogram was performed using peak area ratios ( response factor ) of the drug to an internal standard . the individual and mean concentration of the drugs present in the plasma samples were calculated and are presented in tables 3 and 4 and illustrated in figures 3 , 4 , and 5 . based on these observations , it is concluded that the formulated matrix tablets containing dexibuprofen are capable of exhibiting sustained release properties , stable and feasible for industrial scale production . thus they are capable of reducing the dose intake , minimize the blood level oscillations , dose - related adverse effects and cost , and ultimately improve the patient compliance in the therapeutic management of pain and hypertension . it is also concluded that the present pk / pd studies have demonstrated that pain and blood pressure management were found to be effective in developed sr formulations of dexibuprofen as compared with marketed immediate release formulations . further studies involving their suitability for long - time application , shelf life determination , bioavailability , and clinical investigations in large populations may , however , be necessary to further establish its potential and therapeutic efficacy .
pharmacokinetic - pharmacodynamic ( pk - pd ) modeling has emerged as a major tool in clinical pharmacology to optimize drug use by designing rational dosage forms and dosage regimes . 
 quantitative representation of the dose - concentration - response relationship should provide information for the prediction of the level of response to a certain level of drug dose . 
 this paper describes the experimental details of the preformulation study , tablet manufacture , optimization , and bioanalytical methods for the estimation of dexibuprofen in human plasma . 
 the hydrophilic matrix was prepared with xanthen gum with additives avicel ph 102 . 
 the effect of the concentration of the polymer and different filler , on the in vitro drug release , was studied . 
 various pharmacokinetic parameters including auc0t , auc0 , cmax , tmax , t1/2 , and elimination rate constant ( kel ) were determined from the plasma concentration of both formulations of test ( dexibuprofen 300  mg ) and reference ( dexibuprofen 300  mg tablets ) . 
 the merits of pk - pd in the development of dosage forms and how pk - pd model development necessitates the development of new drugs and bio analytical method development and validation are discussed . 
 the objectives of the present study , namely , to develop and validate the methods to estimate the selected drugs in the biological fluids by hplc , the development of in vitro dissolution methods , and pk - pd model development have been described .