Indirect Response Pharmacodynamic Model Research Articles

Development of a Semimechanistic Pharmacokinetic-Pharmacodynamic Model Describing Dextroamphetamine Exposure and Striatal Dopamine Response in Rats and Nonhuman Primates following a Single Dose of Dextroamphetamine.

Acute central nervous system exposure to dextroamphetamine (d-amphetamine) elicits a multitude of effects, including dual action on the dopamine transporter (DAT) to increase extracellular dopamine, and induction of a negative feedback response to limit the dopamine increase. A semimechanistic pharmacokinetic and pharmacodynamic (PK/PD) model with consideration of these multiple effects as a basis was developed. Integrated pharmacokinetics of d-amphetamine in plasma, brain extracellular fluid (ECF) via microdialysis, and cerebrospinal fluid were characterized using a population approach. This PK model was then linked to an indirect-response pharmacodynamic model using as a basis the measurement of extracellular striatal dopamine, also via microdialysis. In both rats and nonhuman primates (NHPs), d-amphetamine stimulation of dopamine outflow (reverse transport) through DAT was primarily responsible for the dose-linear increase in dopamine. As well, in both species a moderator function was needed to account for loss of the dopamine response in the presence of a relatively sustained d-amphetamine ECF exposure, presumptive of an acute tolerance response. PK/PD model structure was consistent between species; however, there was a 10-fold faster return to baseline dopamine in NHPs in response to an acute d-amphetamine challenge. These results suggest preservation from rodents to NHPs regarding the mechanism by which amphetamine increases extracellular dopamine, but a faster system response in NHPs to tolerate this increase. This microdialysis-based PK/PD model suggests greater value in directing preclinical discovery of novel approaches that modify reverse transport stimulation to treat amphetamine abuse. General value regarding insertion of an NHP model in paradigm rodent-to-human translational research is also suggested.

A pre-clinical quantitative model predicts the pharmacokinetics/pharmacodynamics of an anti-BDCA2 monoclonal antibody in humans.

BIIB059 is a novel humanized monoclonal antibody (mAb) that is currently under development for the treatment of Systemic Lupus Erythematosus and Cutaneous Lupus Erythematosus. BIIB059 is targeted against the blood dendritic cell antigen 2 (BDCA2), a receptor exclusively expressed on the surface of plasmacytoid dendritic cells (pDCs). Herein, we utilized pre-clinical pharmacokinetic (PK) and pharmacodynamic (PD) data to develop a non-human primate (NHP) model and to address whether the NHP model can be successfully scaled to predict the human PK/PD. In particular, PK data from 17 cynomolgus monkeys were utilized for PK model development, wherein BIIB059 was administered intravenously (1 and 10mg/kg single-dosing and 5mg/kg multiple-dosing) or subcutaneously (0.2 and 7.5mg/kg single-dosing). Additionally, PD data (BDCA2 receptor density on pDCs) from 6 cynomolgus monkeys were used for the development of the PD model. The developed NHP two-compartment PK model, linked with an indirect response PD model, was subsequently scaled to humans by combining traditional allometric PK scaling with sensitivity-analysis-driven scaling of the PD. The scaled PK/PD model was then used to simulate the human PK/PD for different dose levels. When clinical data from the BIIB059 Phase I study became available, they were used to evaluate the predictability of the scaled PK/PD model and the model simulations were in agreement with the clinical data. Therefore, the presented approach is suggested to be employed in scaling pre-clinical mAb models to support the selection of safe first-in-human doses and, more broadly, the prediction of PK/PD in the clinic.

From an indirect response pharmacodynamic model towards a secondary signal model of dose-response relationship between exercise training and physical performance

The aim of this study was to test the suitability of using indirect responses for modeling the effects of physical training on performance. We formulated four different models assuming that increase in performance results of the transformation of a signal secondary to the primary stimulus which is the training dose. The models were designed to be used with experimental data with daily training amounts ascribed to input and performance measured at several dates ascribed to output. The models were tested using data obtained from six subjects who trained on a cycle ergometer over a 15-week period. The data fit for each subject was good for all of the models. Goodness-of-fit and consistency of parameter estimates favored the model that took into account the inhibition of production of training effect. This model produced an inverted-U shape graphic when plotting daily training dose against performance because of the effect of one training session on the cumulated effects of previous sessions. In conclusion, using secondary signal-dependent response provided a framework helpful for modeling training effect which could enhance the quantitative methods used to analyze how best to dose physical activity for athletic performance or healthy living.

Dose selection of siltuximab for multicentric Castleman's disease.

Siltuximab is a monoclonal antibody that binds to interleukin (IL)-6 with high affinity and specificity; C-reactive protein (CRP) is an acute-phase protein induced by IL-6. CRP suppression is an indirect measurement of IL-6 activity. Here, modeling and simulation of the pharmacokinetic (PK)/pharmacodynamic (PD) relationship between siltuximab and CRP were used to support dose selection for multicentric Castleman's disease (CD). PK/PD modeling was applied to explore the relationship between siltuximab PK and CRP suppression following intravenous siltuximab infusion in 47 patients with B cell non-Hodgkin's lymphoma (n=17), multiple myeloma (n=13), or CD (n=17). Siltuximab was administered as 2.8, 5.5, or 11mg/kg q2wks, 11mg/kg q3wks, or 5.5mg/kg weekly. Simulations of studied or hypothetical siltuximab dosage regimens (15mg/kg q4wks) were also performed to evaluate maintenance of CRP suppression below the cutoff value of 1mg/L. A two-compartment PK model and an inhibitory indirect response PD model adequately described the serum siltuximab and CRP concentration-time profiles simultaneously. PD parameter estimates were physiologically plausible. For all disease types, simulations showed that 11mg/kg q3wks or 15mg/kg q4wks would reduce serum CRP to below 1mg/L after the second dose and throughout the treatment period. PK/PD modeling was used to select doses for further development of siltuximab in multicentric CD. The dosing recommendation was also supported by the observed efficacy dose-response relationship. CRP suppression in the subsequent randomized multicentric CD study was in agreement with the modeling predictions.

English

The main purpose of this study was to predict the efficacy, potency and sensitivity of meloxicam (a preferential cyclooxygenase-2 (COX-2) inhibitor) antipyretic effect by using a simple indirect response model in rat, evaluated by Brewer’s yeast induced model. The rats received 1, 3, 7 and 10 mg/kg of meloxicam, after subcutaneous (sc) injection of Brewer’s yeast. The plasma concentrations of meloxicam were determined by high performance liquid chromatography-ultraviolet (HPLC-UV) method. Rectal temperature (Ta) was measured for the assessment of the pharmacodynamic (PD) of the meloxicam. Before injection of yeast, basal fever mediator’s synthesis (prostaglandin E2; PGE2) is maintained by physiological mechanism to regulate body temperature which is described by a constant rate synthesis (Ksyn) and a first order degradation of Kout. Ksyn is calculated by the equation, Ksyn = E0 Kout, where E0 is the baseline body temperature. After injection of yeast, the additional fever mediators’ synthesis is regulated by input rate (IR (t)). This process is governed by a first order rate constant (KIN), which can be inhibited by meloxicam. The pharmacokinetic (PK) parameters showed dose proportionality, with a Vd (4124.52, 4236.73, 4657.15, and 5912.1 ml/kg), CL (78.55, 149.25, 1313.57, and 1519.41 ml/h/kg), and Cmax (84.72, 258.29, 547.74, and 617.85 ng/ml). Indirect response PD model (inhibitory Emax model), estimated KIN (1.43, 0.63, 0.51, and 0.42 1/h), Kout (0.005, 0.008, 0.015, and 0.028 1/h), and Ksyn (0.29, 0.42, 0.076, and 0.03 h); estimates for IC50 (concentration of meloxicam in plasma eliciting half of maximum inhibition of IR(t) or KIN) were 146.19, 379.51, 645.05, and 676.44 ng/ml of 1, 3, 7 and 10 mg/kg dose received by groups, respectively. This model appropriately describes the time course of pharmacological response to meloxicam to various doses, in terms of its mechanism of action and pharmacokinetics.   Key words: Brewer’s yeast, cyclo-oxygenase-2, fever mediators (PGE2), meloxicam, pharmacokinetic/ pharmacodynamic modeling.

Population Pharmacokinetic and Pharmacodynamic Modeling of an Anti–Interleukin-6 Chimeric Monoclonal Antibody, Siltuximab (CNTO 328), in Patients with B-Cell Non-Hodgkin’s Lymphoma, Multiple Myeloma, or Castleman’s Disease

AbstractAbstract 1365 IntroductionSiltuximab (CNTO 328) is a chimeric, murine-human, monoclonal antibody that specifically binds human interleukin (IL)-6 with high affinity. C-reactive protein (CRP) can be a pharmacodynamic (PD) marker of IL-6 bioactivity, i.e., reductions in CRP suggest inhibition of systemic IL-6. A population mechanistic pharmacokinetic (PK)/PD model was developed to describe the relationship between siltuximab serum concentrations and CRP suppression in patients with B-cell non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), or Castleman's disease (CD). Simulation was used to support the dose selection in the CD registration study and future clinical studies. MethodsPK/PD data were obtained from a phase 1 clinical study examining multiple dosing regimens of siltuximab administered intravenously in patients with NHL, MM, or CD. Dosing regimens included siltuximab 2.8, 5.5, or 11 mg/kg every 2 weeks; 11 mg/kg every 3 weeks; or 5.5 mg/kg every week. Serial samples to determine serum concentration of siltuximab and serial CRP samples were collected following the first dose. NONMEM 7 was used to simultaneously fit a two-compartment PK model and an inhibitory indirect-response PD model to the observed data. Simulation of 1000 replications was then used to identify siltuximab dosage regimens that would maintain CRP suppression below the lower limit of quantification (LLOQ) of 1 mg/L. ResultsThe mechanistic PK/PD model was able to describe the serum siltuximab and CRP concentration-time profiles. Volume of distribution and systemic clearance rate constant of siltuximab were estimated at 68.42 mL/kg and 0.0584/day, respectively. The PD parameter estimates (Kin and Kout of CRP) were 5.03 mg/L/day and 0.457/day, respectively, and were similar between the three disease types in this study. IC50was estimated at 9.73 μg/mL and was also similar between disease types. For all disease types, simulations showed that siltuximab 11 mg/kg every 3 weeks or 15 mg/kg every 4 weeks after the second dose would reduce serum CRP to below the LLOQ throughout the entire treatment period. However, lower dose intensive schedules, including a dose of 5.5 mg/kg every 2 weeks, would not reduce CRP to below the LLOQ at any time point during the treatment period. ConclusionThe population PK/PD modeling and simulation support using a siltuximab dose of 11 mg/kg every 3 weeks or 15 mg/kg every 4 weeks in future clinical development studies. This dosing recommendation is supported by the observed efficacy dose-response relationship in patients with CD (J Clin Oncol 2010;28:3701–8). Disclosures:Xie:Johnson & Johnson: Employment, Equity Ownership. Li:Johnson & Johnson: Employment, Equity Ownership. Kurzrock:Johnson & Johnson: Honoraria, Research Funding. van Rhee:Johnson & Johnson: Research Funding. Qin:Johnson & Johnson: Employment, Equity Ownership. Reddy:Johnson & Johnson: Employment, Equity Ownership. Qi:Johnson & Johnson: Employment, Equity Ownership. Davis:Johnson & Johnson: Employment, Equity Ownership. Zhou:Johnson & Johnson: Employment, Equity Ownership. Puchalski:Johnson & Johnson: Employment, Equity Ownership.

Pharmacokinetic and Pharmacodynamic Modeling of an Anti–Interleukin-6 Chimeric Monoclonal Antibody (Siltuximab) in Patients with Metastatic Renal Cell Carcinoma

Interleukin-6 (IL-6) induces tumor growth, invasion, metastasis, and angiogenesis. Siltuximab (CNTO 328) is a chimeric, murine-human monoclonal antibody that specifically binds human IL-6 with high affinity. C-reactive protein (CRP) can be a pharmacodynamic (PD) marker of IL-6 bioactivity. Reductions in CRP may correlate with clinical activity and IL-6 bioactivity. Starting-dose selection for this study was based on a previous siltuximab study in multiple myeloma patients. Pharmacokinetic (PK)/PD modeling explored the relationship between siltuximab PK and CRP suppression following i.v. siltuximab infusion in a three-part phase I/II study in 68 metastatic renal cell carcinoma patients. Modeling results were then used to simulate and determine which siltuximab dosage regimens would maintain CRP suppression below the lower limit of quantification (4 mg/L). Siltuximab was given at 1, 3, 6, or 12 mg/kg at weeks 1 and 4 and then every 2 weeks for 2 cycles in part 1; at 3 or 6 mg/kg every 3 weeks for 4 cycles in part 2; and at 6 mg/kg every 2 weeks for 6 cycles in part 3. A two-compartment PK model adequately described the serum siltuximab concentration-time data. An inhibitory indirect response PD model examined the relationship between siltuximab concentrations and CRP suppression. PD parameter estimates seemed reliable and physiologically relevant. Simulations showed that 6 mg/kg siltuximab every 2 weeks or 9 mg/kg every 3 weeks would reduce serum CRP to below 4 mg/L. Using a stepwise design, PK/PD modeling was used to select the dose levels in this study. Furthermore, PK/PD modeling results were used to help select doses to be used in future siltuximab clinical development.

D-optimal designs for parameter estimation for indirect pharmacodynamic response models

This report generates efficient experimental designs (dose, sampling times) for parameter estimation for four basic physiologic indirect pharmacodynamic response (IDR) models. The principles underlying IDR models and their response patterns have been well described. Each IDR model explicitly contains four parameters, k (in) (production), k (out) (loss), I (max)/S (max) (capacity) and IC (50)/SC (50) (sensitivity). The pharmacokinetics of an IV dose of drug described by a monoexponential function of time with two parameters, V and k (el), is assumed. The random errors in the response variable are assumed to be additive, independent, and normal with zero mean and variance proportional to some power of the mean response. Optimal design theory was used extensively to assess the role of both dose and sampling times. Our designs were generated in Mathematica (ADAPT 5 typically produces identical results). G-optimality was used to verify that the generated designs were indeed D-optimal. Such designs are efficient and robust when good prior knowledge of the estimated parameters is available. The efficiency of unconstrained D-optimal designs (4 dose, sampling time pairs) does not improve much when the drug doses are allowed to differ, compared with constrained single dose designs (4 sampling times) with one maximal feasible dose. Also, explored were efficiencies of alternative study designs and results from parameter misspecification. This analysis substantiates the importance of larger doses yielding greater certainty in parameter estimation in pharmacodynamics.

Pharmacokinetic-Pharmacodynamic Modeling of a Direct Thrombin Inhibitor, Argatroban, in Rats

This study was conducted to develop a pharmacokinetic-pharmacodynamic (PK/PD) model of a direct thrombin inhibitor, argatroban to predict the concentration-effect profiles in rats. Argatroban was i.v. injected to rats at 0. 2, 0.8 and 3.2 mg/kg doses (n = 4-5 per dose), and plasma drug levels were determined by a validated LC/MS/MS assay. The pharmacokinetics of argatroban was linear over the i.v. dose range studied. The thrombin time (TT) and the activated partial thromboplastin time (aPTT) were measured in rat plasma and they were found to linearly increase with increasing the dose. A 2-compartment pharmacokinetic model linked with an indirect response pharmacodynamic model was successfully utilized to evaluate the drug concentration-response relationship.

Pharmacokinetic-Pharmacodynamic Modelling of the Antihistaminic (H1) Effect of Bilastine

To model the pharmacokinetic and pharmacodynamic relationship of bilastine, a new histamine H(1) receptor antagonist, from single- and multiple-dose studies in healthy adult subjects. The pharmacokinetic model was developed from different single-dose and multiple-dose studies. In the single-dose studies, a total of 183 subjects received oral doses of bilastine 2.5, 5, 10, 20, 50, 100, 120, 160, 200 and 220 mg. In the multiple-dose studies, 127 healthy subjects received bilastine 10, 20, 40, 50, 80, 100, 140 or 200 mg/day as multiple doses during a 4-, 7- or 14-day period. The pharmacokinetic profile of bilastine was investigated using a simultaneous analysis of all concentration-time data by means of nonlinear mixed-effects modelling population pharmacokinetic software NONMEM version 6.1. Plasma concentrations were modelled according to a two-compartment open model with first-order absorption and elimination. For the pharmacodynamic analysis, the inhibitory effect of bilastine (inhibition of histamine-induced wheal and flare) was assessed on a preselected time schedule, and the predicted typical pharmacokinetic profile (based on the pharmacokinetic model previously developed) was used. An indirect response model was developed to describe the pharmacodynamic relationships between flare or wheal areas and bilastine plasma concentrations. Finally, once values of the concentration that produced 50% inhibition (IC(50)) had been estimated for wheal and flare effects, simulations were carried out to predict plasma concentrations for the doses of bilastine 5, 10 and 20 mg at steady state (72-96 hours). A non-compartmental analysis resulted in linear kinetics of bilastine in the dose range studied. Bilastine was characterized by two-compartmental kinetics with a rapid-absorption phase (first-order absorption rate constant = 1.50 h(-1)), plasma peak concentrations were observed at 1 hour following administration and the maximal response was observed at approximately 4 hours or later. Concerning the selected pharmacodynamic model to fit the data (type I indirect response model), this selection is attributable to the presence of inhibitory bilastine plasma concentrations that decrease the input response function, i.e. the production of the skin reaction. This model resulted in the best fit of wheal and flare data. The estimates (with relative standard errors expressed in percentages in parentheses) of the apparent zero-order rate constant for flare or wheal spontaneous appearance (k(in)), the first-order rate constant for flare or wheal disappearance (k(out)) and bilastine IC(50) values were 0.44 ng/mL/h (14.60%), 1.09 h(-1) (15.14%) and 5.15 ng/mL (16.16%), respectively, for wheal inhibition, and 11.10 ng/mL/h (8.48%), 1.03 h(-1) (8.35%) and 1.25 ng/mL (14.56%), respectively, for flare inhibition. The simulation results revealed that bilastine plasma concentrations do not remain over the IC(50) value throughout the inter-dose period for doses of 5 and 10 mg. However, with a dose of 20 mg of bilastine administered every 24 hours, plasma concentrations remained over the IC(50) value during the considered period for the flare effect, and up to 20 hours for the wheal effect. Pharmacokinetic and pharmacodynamic relationships of bilastine were reliably described with the use of an indirect response pharmacodynamic model; this led to an accurate prediction of the pharmacodynamic activity of bilastine.

Use of a pharmacokinetic/pharmacodynamic approach in the cat to determine a dosage regimen for the COX‐2 selective drug robenacoxib

This study investigated the analgesic, anti-inflammatory and antipyretic efficacy of the new COX-2 selective inhibitor robenacoxib in the cat and established pharmacodynamic (PD) parameters for these effects. Robenacoxib, at a dosage of 2 mg/kg administered subcutaneously, was evaluated in a kaolin-induced paw inflammation model in 10 cats, using both clinically relevant endpoints (lameness scoring, locomotion tests) and other indicators of inflammation (body and skin temperature, thermal pain threshold) to establish its pharmacological profile. A pharmacokinetic/pharmacodynamic (PK/PD) modelling approach, based on indirect response models, was used to describe the time course and magnitude of the responses to robenacoxib. All endpoints demonstrated good responsiveness to robenacoxib administration and both the magnitude and time courses of responses were well described by the indirect pharmacodynamic response models. Pharmacokinetic and clinically relevant pharmacodynamic parameters were used to simulate dosage regimens that will assist the planning of clinical trials and the selection of an optimal dosage regimen for robenacoxib in the cat.

Population PK–PD model for Fc-osteoprotegerin in healthy postmenopausal women

Osteoporosis is a metabolic bone disease resulting from increased bone resorption and characterized by low bone mass that leads to increased bone fragility and risk of fracture, particularly of the hip, spine and wrist. Bone resorption is dependent on receptor activator of NF-kappa B ligand (RANKL), which binds to RANK receptor on preosteoclasts to initiate osteoclastogenesis and maintains osteoclast function and survival. To neutralize the effects of RANKL, the body naturally produces the protein osteoprotegerin (OPG), which acts as a decoy receptor for RANKL and contributes to bone homeostasis. We describe the piecewise development of a three-compartment pharmacokinetic model with both linear and Michaelis-Menten eliminations, and an indirect pharmacodynamic response model to describe the pharmacokinetics and pharmacodynamics, respectively, of the fusion protein, Fc-osteoprotegerin (Fc-OPG), in healthy postmenopausal women. Subsequently, model verification was performed and used to address study design questions via simulation. The model was developed using data from eight cohorts (n = 13 subjects/cohort; Fc-OPG:placebo = 10:3) classified by dose level (0.1, 0.3, 1.0, or 3.0 mg/kg) and route of administration (intravenous [IV] or subcutaneous [SC]). Fc-OPG serum concentrations and urinary N-telopeptide/creatinine ratios (NTX) following both IV and SC administration were available. The model provided an adequate fit to the observed data and physiologically plausible parameter estimates. Model robustness was tested via a posterior predictive check with the model performing well in most cases. Subsequent clinical trial simulations demonstrated that a single 3.0-mg/kg SC dose of Fc-OPG would be expected to produce, at 14 days post-dose, a median NTX percentage change from baseline of -45% (with a 95% prediction interval ranging from -34% to -60%). Lastly, model ruggedness was evaluated using local and global sensitivity analysis methods. In conclusion, the model selection and simulation strategies we applied were rigorous, useful, and easily generalizable.

Pharmacokinetic-pharmacodynamic modeling of telmisartan using an indirect response model in spontaneously hypertensive rats

To investigate the pharmacokinetic (PK) and the pharmacodynamic (PD) properties of telmisartan in spontaneously hypertensive (SH) rats using an indirect response and effect-compartment link models, and compare two PK-PD models fitting quality. The SH rats received a single oral dose of 2, 4, and 8 mg/kg of telmisartan. The plasma concentrations of telmisartan were determined by the liquid chromatography-mass spectrum method. The mean arterial blood pressure was measured to characterize the pharmacodynamics of telmisartan by tail-cuff manometry. The relationship for the telmisartan concentration-hypotensive effect in the SH rats was characterized using an indirect response model. The PK parameters showed dose proportionality, with a long terminal half-life of 16 h, a clearance of 0.15 Lxkg( -1) xh( -1), and a volume of distribution of 5.36 Lxkg( -1) in the study. For the indirect response PD model, the estimated K(in) were 36.6, 34.1, and 32.8 %.h( -1), K(out) were 36.7, 34.6, and 31.9 h( -1); the IC(50) values were 86.2, 95.8, and 91.1 ngxmL( -1); and the area under the effect curve (AUEC) were 762.8, 1490.5, and 2086.2 mmHg.h at three doses, respectively. For the effect-compartment model, the K(eo) were 29.4, 33.8, and 28.7 h( -1); the IC(50) values were 78.2, 85.7, and 80.9 ngxmL(-1), and the AUEC were 781.5, 1602.8, and 2215.7 mmHg.h at three doses, respectively. According to Akaike's information criterion values, the proposed indirect response model provided a more appropriate and good-fitting PK/PD characterization of telmisartan than the effect-compartment link model in SH rats.

Pharmacodynamic Models for Agents that Alter Production of Natural Cells with Various Distributions of Lifespans

Indirect pharmacodynamic response (IDR) models were developed for agents which alter the generation of cell populations with arbitrary lifespan distributions. These models extend lifespan based IDR models introduced previously [J. Pharmacokinet. Biopharm. 27: 467, 1999] for cell populations with the same lifespan ("delta" distribution). Considered are cell populations exhibiting time-invariant lifespan distributions described by the probability density function l(tau). It is assumed that cell response (R) is produced at a zero-order rate (kin(t)) and is eliminated from the population when the cell lifespan expires. The cell loss rate is calculated as kin*l(t), where '*' denotes the convolution operator. Therapeutic agents can stimulate or inhibit production rates according to the Hill function: 1 +/- H(C(t)) where H(C(t)) contains the capacity (Smax) and potency (SC50) parameters and C(t) is a pharmacokinetic function. The production rate is kin(t) = kin.[ 1+/-H(C(t))]. The operational model is dR/dt = kin(t)-kin*l(t) with the baseline condition R0 = kin.TR, where TR is the mean lifespan. Single populations as well as populations with precursors were examined by simulation to establish the role of lifespan distribution parameters (mean and standard deviation) in controlling the response vs. time profile. Estimability of parameters was assessed. Numerical techniques of solving differential equations with the convolution integral were proposed. In addition, the models were applied to literature data to describe the stimulatory effects of single doses of recombinant human erythropoietin on reticulocytes in blood. The estimates of Smax and SC50 for these agents were obtained along with means and standard deviations for reticulocyte lifespan distributions. The proposed models can be used to analyze the pharmacodynamics of agents which alter natural cell production yielding parameters describing their efficacy and potency as well as means and standard deviations for cell lifespan distributions.

Assessment of Basic Indirect Pharmacodynamic Response Models with Physiological Limits

Many physiological factors are regulated by homeostatic mechanisms to maintain normal body function. Empirical lower Rl (Model I and IV) or upper Rh limits (Model II and III) were included in current basic indirect response (IDR) models to account for the additional role of physiological limits (IDRPL). Various characteristics of these models were evaluated with simulations and explicit equations. The simulations reveal that the expanded models exhibit most properties of basic indirect response models, such as slow response initiation, lag time between the kinetic and dynamic peaks, a large dose plateau, and shift in Tmax with dose. The proposed models always produce lesser net responses than predicted by basic IDR models. Simulations demonstrate that addition of a parameter limit which is close to the baseline has a great influence on the overall and maximum responses and fitted model parameters. Only stimulatory IDRPL Models III and IV allow resolution of all model parameters in the absence of clear indications or predetermined values of the lower or upper limits. However, all four models are able to resolve model parameters when subgroups with different baselines are simultaneously fitted. These models create new interpretations of the determinants of baseline conditions which can be important in assessing inter-subject variability in responses. The applicability of IDRPL models is demonstrated using several examples from the published literature. Indirect response models with physiological limits will be useful in characterizing drug responses for turnover systems which are maintained within a certain range.

Explicit solutions for a class of indirect pharmacodynamic response models

Explicit solutions for four, ordinary differential equation (ODE)-based, types of indirect response models are presented. These response models were introduced by Dayneka et al. in 1993 [J. Pharmacokinet. Biopharm. 21 (1993) 457] to describe pharmacodynamic responses utilizing inhibitory or stimulatory E(max) type functions. The explicit solutions are expressed in terms of hypergeometric 2F1 functions and their analytical continuations. A practical application is demonstrated for modeling the kinetics of drug action for ibandronate, a potent bisphosphonate that suppresses bone turnover resulting in a reduction in the markers of bone turnover. Ten times shorter model evaluation times, with the explicit solution compared with the differential equation implementation, may enhance situations where a large number of model evaluations are needed, such as clinical trial simulations and parameter estimation.

D‐optimal designs for parameter estimation for indirect pharmacodynamic response models

Clinical Pharmacology & Therapeutics (2003) 73, P23–P23; doi:

Viral pharmacodynamic model for (-)-beta-2',3'-dideoxy-5-fluoro-3'-thiacytidine (emtricitabine) in chronically infected woodchucks.

There is a need for adequate models of virus depletion in animals and humans as a function of drug dose in order to plan starting dose regimens in the clinic for new antiretroviral nucleoside agents. An indirect response pharmacodynamic model was fitted to link the plasma pharmacokinetics from a 28 day treatment with the nucleoside reverse transcription inhibitor emtricitabine [(-)-FTC], with the resulting virus depletion and recovery profiles in woodchucks chronically infected with woodchuck hepatitis B virus. In this approach it is assumed that the virus is eliminated from serum in a first order fashion and that the fraction of serum virus load produced per day is inhibited by the accumulation of nucleoside triphosphate in a manner that could be described using a Hill equation. Nadir virus load values were inversely related to pretreatment virus load levels within each dose group. A median inhibitory concentration value of 1.5 microM for (-)-FTC triphosphate, previously measured against the isolated viral polymerase of woodchuck hepatitis, was used in model fitting. The fitted value for concentration exponent eta of 3.46 indicated a greater than linear sensitivity of virus inhibition with dose. Since the post-treatment virus rebound was much greater than predictions of an initial model, a dose-dependent rebound factor was incorporated in the final model. The rebound factor was maximal at the end of (-)-FTC treatment and decayed mono-exponentially with a rate constant Kreb of 0.11/day. The model inferred decay half-life of (-)-FTC triphosphate in the apparent 'effect compartment' of the model was similar to the half-life value previously estimated for human hepatitis B virus-infected hepatocytes. The model described adequately the virus depletion and recovery profiles for the dose range tested and could be adapted for the selection of starting doses for future animal and human studies with emtricitabine and other nucleoside analogues in development.

Cocaine and alcohol interactions in the rat: Effect of cocaine and alcohol pretreatments on cocaine pharmacokinetics and pharmacodynamics

This experiment was designed to investigate the effect of pretreatment with cocaine and alcohol on cocaine pharmacokinetics and pharmacodynamics. Four groups of rats (n = 8 per group) received one of the following pretreatments for two weeks: none, alcohol (10% v/v in drinking water), cocaine (15 mg/kg/day ip), and alcohol+cocaine (10% v/v in drinking water+15 mg/kg/day ip). On the day of the experiment, cocaine was administered (30 mg/kg, ip) to each rat, either alone or in combination with alcohol (5 g/kg, po), in a balanced crossover experimental design. Plasma and brain ECF concentrations of cocaine and its three metabolites: benzoylecgonine, norcocaine, and cocaethylene were assayed by HPLC–UV. The percent change in brain dopamine concentration, mean arterial blood pressure, and heart rate were determined simultaneously. A sigmoid-Emax model was used to describe the brain cocaine concentration–neurochemical effect (dopamine) relationship, and an indirect phar-macodynamic response model was used to describe the plasma cocaine concentration–cardiovascular effect relationships. Alcohol pretreatment led to significant increase in cocaine AUCp, αt1/2, and βt1/2. Cocaine pretreatment significantly increased cocaine bioavail-ability, absorption rate constant, TBC, and the formation clearance of cocaethylene. Acute alcohol coadministration with cocaine increased cocaine AUCp and bioavailability, reduced the fraction of cocaine dose converted to benzoylecgonine, and increased the formation of norcocaine. These results indicate that the pharmacokinetics of cocaine, either administered alone or in combination with alcohol, is significantly altered due to prior cocaine and/or alcohol use. Both cocaine and alcohol pretreatments increased the Emax for dopamine, with no effect on the EC50. Acute alcohol coadministration with cocaine significantly increased the Emax for dopamine and reduced the EC50. Cocaine pretreatment significantly decreased the Imax for blood pressure, IC50, and Rmax. For the heart rate response, both alcohol and cocaine pretreatments significantly increased the IC50, with no effect on Imax. These results indicate that both cocaine and alcohol pretreatments as well as acute alcohol coadministration lead to significant alterations in cocaine pharmacodynamics that are due, at least in part, to the changes in cocaine pharmacokinetics. If similar effects occur in humans, chronic cocaine and alcohol abusers may respond differently to cocaine administration compared to naïve users and may be at higher risks of cocaine central nervous system toxicity.

Clinical Pharmacokinetics and Pharmacodynamics of a New Squalene Synthase Inhibitor, BMS‐188494, in Healthy Volunteers

A double-blind, placebo-controlled, parallel-group, ascending, multiple-dose study was completed in 45 healthy male volunteers to assess the maximum tolerated dose, pharmacokinetics, and pharmacodynamics of BMS-187745, a squalene synthase inhibitor, administered as multiple oral doses of its prodrug BMS-188494. Participants received a daily oral dose of 10 mg for 2 weeks, or a daily oral dose of 25, 50, 100, or 200 mg for 4 weeks. The absorption rate constant (ka) and bioavailability (F) values were estimated by fitting the plasma BMS-187745 concentration-time data to a biexponential function with a first-order ka. Values for F were similar for all five dose levels, and thus were independent of dose. The ka values also were similar for all dose groups except the 50-mg group, for which ka values were somewhat higher. The change in urinary excretion rate of farnesyl pyrophosphate metabolite (dioic acid) was determined to be a pharmacodynamic measure. There was no significant change in dioic acid excretion at doses of less than 100 mg given for 4 weeks. An indirect pharmacodynamic response model with threshold concentration (CT) and based on inhibition of squalene synthase was proposed to describe the effect versus time data. The pharmacodynamic data from all dose levels were fitted simultaneously to the proposed model and the fitted parameters estimated as CT = 3.9 micrograms/mL, kout = 0.47 hr-1, IC50 = 4.1 micrograms/mL, and Imax = 1.0. The proposed indirect response model requiring a threshold concentration provides a useful means of quantitating responses for a new type of therapeutic agent.