Analogous to the elimination T1/2 in pharmacokinetics, the effect bisection time (TED50) can be stated as a measure of the effect duration in pharmacodynamics (10). The median ratios of the individual predicted Cmax and Cmax,ss to EC50 represented, respectively, near two-fold increases from 0.11 to 6.8 EC50 units for the single-dose studies and from 0.25 to 16 EC50 units for the multiple-dose studies with the increase in doses. 2011 Mar-Apr;39(2):117-25. doi: 10.1002/bmb.20479. For the single-dose scenarios (Table 2, Fig. This was not true, however, for 50 mg dose (Cmin=0.63 and Cmax=0.99 EC50 units) with of 5 and 200 mg dose (Cmin=2.5 and Cmax=3.9 EC50 units) with of either 5 or 10. For the multiple dose studies, the parameter estimation performance was not good. Methods The Emax model follows the "law of diminishing returns" at higher doses. No dose reduction would be needed if the infusion time could be extended in parallel with the four-fold prolongation in the elimination T1/2. 1997 Apr;86(4):825-35. doi: 10.1097/00000542-199704000-00013. The site is secure. An essential component of drug development is to understand the dose-response relationship of a pharmaceutical . The relationship between crizanlizumab concentration and ex vivo P-selectin inhibition was fitted to a non-linear sigmoidal Emax model. To increase efficiency, drugs with a concentration-dependent action require the application of a higher dose (e.g., apixaban). Applications of pharmacometrics in the clinical development and pharmacotherapy of anti-infectives. To meet this target a bolus loading dose of 1500 mg (20 mg/kg) with a subsequently administered continuous infusion might be needed. [9] However, drug exposure often does not cover the higher range of values required to estimate maximum effect (Emax) since higher concentrations can either result in toxicity or the testing doses in dose escalation study have little information on dose-response surface. Emax can also explain how polypharmacy might work: in the case of synergistically acting drugs such as losartan and a thiazide, the receptor-mediated effects and thus the Emax values are additive on BP (E=Emax1+Emax2). 7 Greenhouse Road, Values for pharmacodynamic parameters can be extracted from the published literature using respective key words. (9.1) Keywords. Because the CE50 corresponds to the Kd, a high CE50 is associated with only a weak effect (Supplemental Material). Among the remaining sixty two scenarios which were successful, one scenario in single-dose studies had 1 failure and eight scenarios in multiple-dose studies had 1 to 3 failure(s) during 100 simulations and estimations for each scenario. Accessibility AAPS J. However, in nature and thus in medicine, basic laws can be identified that apply not only to every drug but also to every patient. The normal dose of the CD20+ B cell antibody rituximab is 375 mg/sqm weekly for 4 weeks. Aymanns C, Keller F, Maus S, Hartmann B, Czock D: Review on pharmacokinetics and pharmacodynamics and the aging kidney. Rasche FM, Klotz CH, Czock D, Karges W, Muche R, Jehle PM, Mertz A, Keller F: Cyclophosphamide pulse therapy in advanced progressive IgA nephropathy. The linear or Emax model described pharmacodynamics most successfully, with relatively large interindividual variability for both slope and EC50 (more than 25%). Fast and Reliable Electronic Assay of a Xylella fastidiosa Single Bacterium in Infected Plants Sap. It is identical to the Creative Commons Attribution Non-Commercial License (. Optimal designs based on the maximum quasi-likelihood estimator. . Kreutz R, Persson PB, Kubitza D, Thelen K, Heitmeier S, Schwers S, Becka M, Hemmrich M: Dissociation between the pharmacokinetics and pharmacodynamics of once-daily rivaroxaban and twice-daily apixaban: A randomized crossover study. Concentration P relationship of 20 simulated individuals (thin lines) using the sigmoid E, Difference ( P ) between the profiles of P obtained with sigmoid E, Relationship between * and C50 obtained by Monte Carlo simulation (open symbols),, Relationship between * and obtained by Monte Carlo simulation (open symbols),, MeSH The role of pharmacokinetic (PK) and pharmacodynamic (PD) modeling and simulation is expanding in almost all drug development processes, from non-clinical to different phases of clinical trials. The purpose of this simulation study is to explore the limitation of the population PK/PD analysis using data from a clinical study and to help to construct an appropriate PK/PD design that enable precise and unbiased estimation of both fixed and random PD parameters in PK/PD analysis under different doses and Hill coefficients. For the multiple-dose studies (Table 3, Supplementary Fig. Pharmacokinetics and pharmacodynamics follow the logic of cause and consequence. In addition, it is investigated whether IIV in the model parameters can be estimated accurately by population modeling. A Summary of Various Pharmacodynamic Models, Predicts the baseline effect when the concentration is zero Unable to define the maximum effect at high concentrations Error-prone at high or low drug concentrations, Suitable for predicting drug effects over 20-80%of the maximum effect Unable to define the baseline and the maximum effects, Able to describe the pharmacodynamic relationship over a wide range of drug concentrations Predicts the baseline and the maximum effects, Able to describe an S-shape pattern of effect curve by adjusting n values. As a library, NLM provides access to scientific literature. Ce is the drug concentration at the effect site, E is the intensity ofthe effect, E0 is the baseline effect in the absence of the drug, and S is the slope. However, the exposure-response relationship can be easily understood and applied, if concentrations are normalized by EC50. The .gov means its official. Response surface model for anesthetic drug interactions. Parameter estimates of were mostly accurate and precise except for those at 12.5 mg dose (Cmax=0.11 EC50 units) with of 2 and 800 mg dose (Cmax=6.8 EC50 units) with of 10, whereas the parameter estimates of 2 were reliably estimated only when the doses were 50 mg (Cmax=0.21 EC50 units) with of 0.5 and 1 or 100 (Cmax=0.85 EC50 units) and 200 mg (Cmax= 1.7 EC50 units) with all except for 100 mg dose (Cmax=0.85 EC50 units) with of 0.5 and 200 mg (Cmax= 1.7 EC50 units) dose with of 10. This is an important property of the Emax model that is the basis of pharmacodynamics. Oguri T, Shimokata T, Inada M, Ito I, Ando Y, Sasaki Y, Hasegawa Y: Pharmacokinetic analysis of carboplatin in patients with cancer who are undergoing hemodialysis. The purpose of this simulation study is to explore the limitation of the population PK/PD analysis using data from a clinical study and to help to construct an appropriate PK/PD design that enable precise and unbiased estimation of both fixed and random PD parameters in PK/PD analysis under different doses and Hill coefficients. Conflict of interest: The authors have nothing to declare. Pharmacodynamic modeling is based on a quantitative integration of pharmacokinetics, pharmacological systems, and (patho-) physiological processes for understanding the intensity and time-course of drug effects on the body. : go/nomodeling7. [1] The number of regulatory decisions, including new drug approval and labeling, that were effected by pharmacometric analysis increased from 45 submissions between 2000 and 2004 to 87 submissions between 2007 and 2008. Antimicrobial drugs with concentration-dependent action are distinguished from drugs with time-dependent action. Accessibility The linear pharmacodynamic model is useful when the efficacy of a drug is proportional to its concentrations at the effect site. Carboplatin and kidney failure: Near-normal elimination kinetics can be established by hemodialysis (HD) initiated 2 hours after carboplatin infusion. doi: 10.1002/cpt1979253358. FOIA Impact of pharmacometric analyses on new drug approval and labelling decisions: a review of 198 submissions between 2000 and 2008. -. Leveraging prior quantitative knowledge to guide drug development decisions and regulatory science recommendations: impact of FDA pharmacometrics during 2004-2006. Goutelle S, Maurin M, Rougier F, Barbaut X, Bourguignon L, Ducher M, Maire P. Fundam Clin Pharmacol. In this simulation study, seven doses of virtual drugs with equal potency and efficacy but different Hill coefficients were used for generality of interpretation and comparison among virtual drugs and for easy application to PK/PD modeling and simulation of various drugs in clinical use or development. [8] Emax models play important roles in describing excitatory or inhibitory exposure-response relationship. When the concentration producing the half-maximum effect increases (CE50: 40) a higher dose will be needed. Pharmacodynamics (PD) follow pharmacokinetics (PK). Clin Pharmacol Ther. 1990;50:53185327. found that all and 2 were biased and imprecise when the Hill coefficient was high (=6.22), 4 to 5 blood samples were gathered[10] and Pai et al. Receptor-mediated and reversible effects can be distinguished from direct and irreversible effects. When the maximum effect is diminished (Emax: 50) more of the drug or another drug should be given. Great progress has been made by distinguishing antimicrobial drugs with a concentration-dependent effect from drugs with a time-dependent effect. and transmitted securely. Statistical analyses of the data revealed that the inherent potencies of fluticasone propionate, mometasone furoate, and hydrocortisone . Using a naive pooling procedure, the population estimates * are significantly lower than the value of used for simulation. This process is experimental and the keywords may be updated as the learning . Residual variability was 15.3% and 17.1% in BUNmax and Clcrmin, respectively. If it is assumed that the effect is directly proportional to the binding then the C 50 will be the same as the Kd. Emax is the maximal effect at high drug concentrations when all the receptors are occupied by the drug, and EC50 is the drug concentration to give the half . In some cases, it is the logarithm of the dose that is plotted on the . Eight scenarios out of total seventy scenarios failed stochastic simulation and estimation (SSE), in spite of numerous attempts. However, the recommended administration interval differs with 12 hours for apixaban and 24 hours for rivaroxaban. Accessibility a Simulation Study The relationship between the concentration of a drug and its pharmacological effect is often described by empirical mathematical models. But such a four-times-longer infusion time (T=8 hours) would be unfeasible with carboplatin in clinical practice and this regimen does not solve the problem of an increased risk for toxicity due to a rise in the AUC. Huang CM, Atkinson AJ Jr, Levin M, Levin NW, Quintanilla A: Pharmacokinetics of furosemide in advanced renal failure. doses of TAK-875 achieve efficacy as comparable with or better than that of commonly used antidiabetic agents. Federal government websites often end in .gov or .mil. Published online ahead of print. Antagonistic combinations such as a typical antipsychotic with a dopaminergic anti-Parkinson drug are unfavorable because the Emax is mutually minimized (E=Emax1Emax2). Model-based simulations over 24 weeks indicated that the 25- and 50-mg q.d. Alterations of pharmacodynamic parameters are conceivable but only rarely reported in kidney failure. As illustrated by apixaban with a reversible effect, the effect duration will last longer and can be predicted exactly from pharmacodynamic parameters when elimination is impaired in kidney failure. where C is drug concentration, k e is elimination rate constant, obtained by CL over V, F is bioavailability and D is dose, respectively. The .gov means its official. Using virtual drugs with different Hill coefficients and ratios of concentration to EC50 would facilitate general interpretation and easy application to the real drugs. Taprogge J, Gape PMD, Carnegie-Peake L, Murray I, Gear JI, Leek F, Hyer SL, Flux GD. sharing sensitive information, make sure youre on a federal High serum peak levels and ototoxicity will be avoided by a continuous infusion. We investigated the relationship between the steepness of the concentration-effect relationship and inter-individual variability (IIV) of the parameters of the sigmoid Emax model, using the similarity between the sigmoid Emax model and the cumulative log . The number of blood samples was ten in each scenario. Moreso F, Sern D, Morales JM, Cruzado JM, Gil-Vernet S, Prez JL, Fulladosa X, Andrs A, Griny JM: Incidence of leukopenia and cytomegalovirus disease in kidney transplants treated with mycophenolate mofetil combined with low cyclosporine and steroid doses. To evaluate the estimation performance for PD parameters at each dose, the following statistics were obtained using individual predicted values. For instance, the analgesic effect of clonidine is mediated by two agonistic effects, both of which can be described by different Emax models, producing a stepwise increase in effect with concentration [Eq. As a library, NLM provides access to scientific literature. PMC Therefore, a grade 3 neutropenia should not give reason to reduce the dose: Some toxicity is needed for anticancer chemotherapy to meet the therapeutic target. E max values were used as the metric to assess potency. 1979;25:358371. For a high H, the CE95 will be low but, simultaneously, the CE05 is high (Supplemental Figure 1). Pharmacokinetics and pharmacodynamics of apixaban and rivaroxaban (12). [10] found that the accuracy and precision of the PD parameter estimates got worse as the number of subjects decreased from 100 to 25 with sparse sampling design. The two key parameters of pharmacodynamics are the maximum response (Emax) and the concentration producing 50% of Emax (C50). Mendes M, Ferreira AC, Navarro D, Pinto B, Gomes F, Matias P, Jorge C, Aires I, Ferreira A: Optimizing the use of darbepoetin- with a split strategy: A concept change. This article contains supplemental material online at http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN.10960917/-/DCSupplemental. plasma. government site. Application of a new approach for the quantitation of drug synergism to the combination of cis-diamminedichloroplatinum and 1-beta-D-arabinofuranosylcytosine. This is a relatively smaller value than the result form a study which reported that the 2 to 3 EC50 region is needed to get an unbiased and precise estimate of Emax2, when was 6.22 and blood sampling was sparse. where Pest is the fixed or random effect parameter estimate and Psim is the true fixed and or random effect parameters (, 2, 2) value used for each simulation. The Hill coefficient (H), sometimes referred to as the coefficient, represents a purely empiric parameter that determines the sigmoidicity of the effect-concentration correlation. Kinetic interpretation of log-logistic dose-time response curves. But the dose adjustment on the basis of the pharmacodynamics of an irreversible effect suggests that a dose of 770 mg not 210 mg will be needed to stop the cancer cells: Thus the normal standard dose will be reduced by 23% when giving the 770 mg (1.0770/1000=0.23) but not by 79% as when reducing to 210 mg (1.0210/1000=0.79). For an increasing number of drugs, however, it is becoming evident that there may be either multiple receptors, Table 11.1. and transmitted securely. The relative bias and RMSE of 2 for the PD observations were less than 0.9% and 5.1% for multiple-dose study, respectively. Anesthesiology. inter-individual variability; pharmacokinetic-pharmacodynamic modeling; sigmoid Emax model; simulation. Instead, the target is the average steady state serum concentration Css of up to 25 mg/L (Css24 hours=area under the curve [AUC]) which is equivalent to an AUC of 400600 hoursmg/L (7). A total of 70 scenarios with 100 subjects were simulated and estimated 100 times applying 1-compartment PK model and sigmoid Emax model. Epub 2014 Aug 23. 1Department of Clinical Pharmacology, Pusan National University Hospital, Busan 49241, Republic of Korea. Nonetheless, drug development remains a slow and costly process. The Hill equation: a review of its capabilities in pharmacological modelling. In adolescents limited data are available on the pharmacokinetics (PK) and pharmacodynamics (PD) of propofol. Time-dependent effects are associated with a high threshold concentration and the target is the high trough. Principles of Drug Response and Alterations in Kidney Disease, Center for Internal Medicine, University Hospital, Ulm, Germany, GUID:77BA0EA9-37BA-4B13-B028-60E1CBDC82E9, Tacrolimus, pharmacokinetics, kidney failure, chemotherapy, Kinetics of pharmacologic response. Before 19.4 Integrated PK-PD Models: Integrated Bolus Injection in a 1 Compartment Model and the Sigmoidal Emax Model The dosing regimen can be adjusted to the individual condition by changing either the dose or the length of the administration interval (). 3), because the bottom area of the effects were measured with lower doses and the ceiling area were measured with higher doses. Simultaneous modeling of PK/PD is one of the causes of poor IIV estimation, and certain types of sequential approaches may result in better performance.[17]. National Library of Medicine The hemodialysis can be seen as an artificial substitute of normal kidney function (Figure 3). The time course of effect is illustrated under the assumption that drug effects are immediately related to concentration in the central compartment e.g. Otherwise, the trend for apixaban underdosing becomes apparent when the dose for patients receiving dialysis is recommended as 5 mg twice daily, whereas rivaroxaban could still be dosed at 15 mg once a day (13). Topics relevant to this model are covered in the following sections: 19.3 Direct Effect Pharmacodynamic Models However, the concentrations were derived from sigmoid Emax curve and pharmacokinetics was not considered. Rolling KE, Jorgenson MR, Descourouez JL, Mandelbrot DA, Redfield RR, Smith JA: Ganciclovir-resistant cytomegalovirus infection in abdominal solid organ transplant recipients: Case series and review of the literature, Assessment of extended-release opioid analgesics for the treatment of chronic pain, Clinical Journal of the American Society of Nephrology : CJASN, http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN.10960917/-/DCSupplemental, Counter-regulatory (competing) influences at the receptor, Decreased receptor number (Emax) and sensitivity (CE, Drug toxicity (S-shaped effect-concentration correlation and Hill coefficient), Grade 34 neutropenia and thrombocytopenia, Neutropenia or leukopenia or anemia or thrombocytopenia grade 34. Population pharmacodynamic parameter estimation from sparse sampling: effect of sigmoidicity on parameter estimates. 2016 Dec;43(6):583-596. doi: 10.1007/s10928-016-9487-8. -, Greco WR, Park HS, Rustum YM. Stevens DR, Sawinski D, Blumberg E, Galanakis N, Bloom RD, Trofe-Clark J: Increased risk of breakthrough infection among cytomegalovirus donor-positive/recipient-negative kidney transplant recipients receiving lower-dose valganciclovir prophylaxis. Bethesda, MD 20894, Web Policies Pharmacokinetic and pharmacodynamic data were simultaneously simulated and estimated using the same model. Unauthorized use of these marks is strictly prohibited. An increased sensitivity and a higher drug potency also can be due to a decrease in CE50 values in the elderly. In addition, the concentration producing the CE50 can visually be determined with CE50=50 g/L for apixaban and with CE50=20 g/L for rivaroxaban just at the time where 50% of the maximum effect is produced (Figure 2). The two key parameters of pharmacodynamics are the maximum response (Emax) and the concentration producing 50% of Emax (C50). Birkett; Aust Prescr 1995;18:102-4; 1 October 1995 ; DOI: 10.18773/austprescr.1995.088; . Qu K, Lin T, Wei J, Meng F, Wang Z, Huang Z, Wan Y, Song S, Liu S, Chang H, Dong Y, Liu C: Cisplatin induces cell cycle arrest and senescence via upregulating P53 and P21 expression in HepG2 cells. The https:// ensures that you are connecting to the For the single-dose studies, the SSE processes failed when the doses were 12.5 (Cmax=0.11 EC50 units) and 50 mg (Cmax=0.42 EC50 units) and was either 5 or 10, because the simulated concentrations were located at lower flat area of the sigmoid Emax curve (Fig. A dose-response curve is a coordinate graph relating the magnitude of a dose (stimulus) to the response of a biological system. The accuracy and precision of Emax and Emax2 were getting better with the increase in dose, regardless of , while those of EC50 and EC502 gradually improved with increase in both dose and (Fig. Accessibility The scenarios with of 0.5 and 1 resulted in poor estimates of EC50 in most doses, while estimates of EC50 were reliable at more than or equal to 200 mg doses or Cmax of 0.85 EC50 units with of 1. Lesko LJ, Schmidt S. Individualization of drug therapy: history, present state, and opportunities for the future. Motivated by the principle that efficacy is driven by pharmacology, we conducted simulations using a generalized pathogen dynamic model, to assess the properties of an alternative efficacy predictor: the area under the effect curve (AUEC), computed using in vitro PD and in vivo PK. The target is the peak level close to the CE95 for a life-saving induction therapy. With the target AUC of 7 minutesmg/ml the normal dose of 1000 mg would have to be reduced to 210 mg for kidney failure with a GFR of 5 ml/min (24) when using the Calvert equation (210=7[5+25]). Thus, the suggested apixaban administration interval is just equal to the 24-hour interval of rivaroxaban in kidney failure not requiring dialysis. Dayneka NL, Garg V, Jusko WJ. Copyright University of Rhode Island | University of Rhode Island, Kingston, RI 02881, USA | 1.401.874.1000, URI is an equal opportunity employer committed to the principles of affirmative action. also reported similar results from spare sampling design, when were 1 or 2.51. PK/PD modeling is related to the field of pharmacometrics . Ette et al. The effect (E) depends on concentrations (C) according to the sigmoid Emax model. [14] The parameter estimation of sigmoid Emax model is an important part in dose-finding study. Pharmacodynamic parameter estimation: population size versus number of samples. The effect cannot grow higher than the Emax, meaning that no more than a 100% response can be elicited due to the biologically limited number of molecular binding sites. The estimates of Emax and Emax2 met the acceptance criteria of bias and precision when the doses were within the range of 50 (Cmin=0.63 and Cmax=0.99 EC50 units) and 200 mg (Cmin=2.5 and Cmax=3.9 EC50 units) and was either 5 or 10. Because apixaban has a concentration-dependent effect, the aim should be the normal peak of 139 g/L. On the other side, the CE50 parameter reflects the intrinsic power of the drug. I. Le Bras F, Sebert M, Kelaidi C, Lamy T, Dreyfus F, Delaunay J, Banos A, Blanc M, Vey N, Schmidt A, Visanica S, Eclache V, Turlure P, Beyne-Rauzy O, Guerci A, Delmer A, de Botton S, Rea D, Fenaux P, Ads L: Treatment by lenalidomide in lower risk myelodysplastic syndrome with 5q deletion--the GFM experience. The time after dosing when 50% of maximum effect (Emax) is produced is 15 hours with apixaban but 29 hours with rivaroxaban. These can cause cascade- or U-shape concentration-effect curves. Drug concentration at the effect site (Ce). doi: 10.1097/00000542-200004000-00015. Since all CV% of IIV and RV were set at moderate values of 30% and 20%, respectively, prediction of exposure-response relationship of a drug with larger variability might show deviations from our findings. Would you like email updates of new search results? Single and multiple-dose studies were simulated with each of the doses and Hill coefficients. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). In this case a higher dose results in a stronger effect (Supplemental Figure 1). One can also see the effect of the concentration producing the half-maximum effect (CE50). In contrast to tacit presumptions, a change in the CE50 can be predicted for furosemide and canagliflozin in CKD. This leads to potentially biased or imprecise PD parameter estimates or overly-simplified models such as linear or log-linear models that are not useful for extrapolation. Receptor-mediated and reversible effects can be distinguished from direct and irreversible effects. This target is in agreement with the time-dependent meropenem action because for H>2.0 the CE50 value roughly corresponds to four times the CE05 (4CE05=CE50) and the CE05 relates to the MIC (CE05MIC). Bethesda, MD 20894, Web Policies The PK/PD modeling results using only steady-state data may be carefully interpreted. Accurate measurement of both Emax and EC50 are critical in the Emax model. Pharmacokinetic and pharmacodynamic models are used to predict and explore drug infusion schemes and their resulting concentration profiles for clinical application. It is a drug-related parameter. Sarcina L, Macchia E, Loconsole G, D'Attoma G, Bollella P, Catacchio M, Leonetti F, Di Franco C, Elicio V, Scamarcio G, Palazzo G, Boscia D, Saldarelli P, Torsi L. Adv Sci (Weinh). On the other hand, errors in PD parameter estimates might have negatively affected PK parameter estimation, and this is hinted from different levels of bias and precision with different combinations Hill coefficients and doses, although the Hill coefficient had no relation to pharmacokinetics. [11] These results suggest that dense sampling design may be essential to get accurate and precise estimates of and 2. Contrary to the results of single-dose studies, the performance of estimating E0 represented considerably poor accuracy and precision. The tested study design is not suited to estimate the IIV in C50 and with reasonable precision. A high H will result in an augmented CE50/C ratio value if the ratio is >1.0 (>>1.0). The adverse drug reaction can even be used for a pharmacodynamic monitoring of the therapeutic effect. 2005 Oct 5;7(2):46. doi: 10.1208/aapsj070246. An increased sensitivity has been reported for midazolam (CE50: 522223 ng/ml), nifedipine, morphine, phenytoin, and warfarin, but more resistance with a higher CE50 has been observed for albuterol and metoprolol (2). sharing sensitive information, make sure youre on a federal 2022 Oct;9(30):e2203900. In the case of kidney failure, however, a less rigorous dose reduction is required than proportionate to the rise of the T1/2 because only the higher dose can here produce the same irreversible effect as with normal conditions (E irrev=const. The PK/PD model library is combining our library of standard pharmacokinetic models with a library of standard pharmacodynamic models. Purchase from Amazon, Avedisian Hall This chapter covers the following pharmacodynamic models - linear, Emax, sigmoidal Emax, and splines. found that Emax, EC50, and of sigmoid Emax model were poorly estimated if the maximum concentration was not attained up to 95% of Emax applying clinical data simulation. The antithrombotic efficacy and the bleeding risk were not different for apixaban and rivaroxaban even in CKD (13). This site needs JavaScript to work properly. This study has some limitations. On the recording of sample times and parameter estimation from repeated measures pharmacokinetic data. Individual predicted values were calculated from the parameter estimates from 100 simulated subjects and simulated time points in each scenario. Thus, it is primarily a patient-related, not a drug-related, parameter. where C is drug concentration, ke is elimination rate constant, obtained by CL over V, F is bioavailability and D is dose, respectively. In single-dose studies, since the baseline of effects before dosing was measurable, all the E0 and E02 were estimated with accuracy and precision.