Three-compartment Pharmacokinetic Model Research Articles

Clinical Pharmacology of Brigatinib: A Next-Generation Anaplastic Lymphoma Kinase Inhibitor.

Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor designed to overcome mechanisms of resistance associated with crizotinib, is approved for the treatment of ALK-positive advanced or metastatic non-small cell lung cancer. After oral administration of single doses of brigatinib 30-240 mg, the median time to reach maximum plasma concentration ranged from 1 to 4 h. In patients with advanced malignancies, brigatinib showed dose linearity over the dose range of 60-240 mg once daily. A high-fat meal had no clinically meaningful effect on systemic exposures of brigatinib (area under the plasma concentration-time curve); thus, brigatinib can be administered with or without food. In a population pharmacokinetic analysis, a three-compartment pharmacokinetic model with transit absorption compartments was found to adequately describe brigatinib pharmacokinetics. In addition, the population pharmacokinetic analyses showed that no dose adjustment is required based on body weight, age, race, sex, total bilirubin (<1.5× upper limit of normal), and mild-to-moderate renal impairment. Data from dedicated phase I trials have indicated that no dose adjustment is required for patients with mild or moderate hepatic impairment, while a dose reduction of approximately 40% (e.g., from 180 to 120 mg) is recommended for patients with severe hepatic impairment, and a reduction of approximately 50% (e.g., from 180 to 90 mg) is recommended when administering brigatinib to patients with severe renal impairment. Brigatinib is primarily metabolized by cytochrome P450 (CYP) 3A, and results of clinical drug-drug interaction studies and physiologically based pharmacokinetic analyses have demonstrated that coadministration of strong or moderate CYP3A inhibitors or inducers with brigatinib should be avoided. If coadministration with a strong or moderate CYP3A inhibitor cannot be avoided, the dose of brigatinib should be reduced by approximately 50% (strong CYP3A inhibitor) or approximately 40% (moderate CYP3A inhibitor), respectively. Brigatinib is a weak inducer of CYP3A in vivo; data from a phase I drug-drug interaction study showed that coadministration of brigatinib 180 mg once daily reduced the oral midazolam area under the plasma concentration-time curve from time zero to infinity by approximately 26%. Brigatinib did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations in vitro. Exposure-response analyses based on data from the ALTA (ALK in Lung Cancer Trial of AP26113) and ALTA-1L pivotal trials of brigatinib confirm the favorable benefit versus risk profile of the approved titration dosing regimen of 180 mg once daily (after a 7-day lead-in at 90 mg once daily).

Evaluating the indotecan-neutropenia relationship in patients with solid tumors by population pharmacokinetic modeling and sigmoidal Emax regressions.

This study aimed at characterizing indotecan population pharmacokinetics and explore the indotecan-neutropenia relationship in patients with solid tumors. Population pharmacokinetics were assessed using nonlinear mixed-effects modeling of concentration data from two first-in-human phase 1 trials evaluating different dosing schedules of indotecan. Covariates were assessed in a stepwise manner. Final model qualification included bootstrap simulation, visual and quantitative predictive checks, and goodness-of-fit. A sigmoidal Emax model was developed to describe the relationship between average concentration and maximum percent neutrophil reduction. Simulations at fixed doses were conducted to determine the mean predicted decrease in neutrophil count for each schedule. 518 concentrations from 41 patients supported a three-compartment pharmacokinetic model. Body weight and body surface area accounted for inter-individual variability of central/peripheral distribution volume and intercompartmental clearance, respectively. Estimated typical population values were CL 2.75 L/h, Q3 46.0 L/h, and V3 37.9 L. The estimated value of Q2 for a typical patient (BSA = 1.96 m2) was 17.3 L/h, while V1 and V2 for a typical patient (WT = 80kg) was 33.9 L and 132 L. The final sigmoidal Emax model estimated that half-maximal ANC reduction occurs at an average concentration of 1416µg/L and 1041µg/L for the daily and weekly regimens, respectively. Simulations of the weekly regimen demonstrated lower percent reduction in ANC compared to the daily regimen at equivalent cumulative fixed doses. The final PK model adequately describes indotecan population pharmacokinetics. Fixed dosing may be justified based on covariate analysis and the weekly dosing regimen may have a reduced neutropenic effect.

Modeling of factors affecting late gadolinium enhancement kinetics in MRI of cardiac amyloid

BackgroundLate gadolinium enhancement (LGE) is a valuable part of cardiac magnetic resonance imaging (CMR). In particular, inversion-recovery imaging of LGE, with nulling of the signal from reference areas of myocardium, can have a distinctive pattern in some patients with cardiac amyloid, including both diffuse (relatively faint) subendocardial LGE and a relatively dark appearance of the blood. However, the underlying reasons for this distinctive appearance have not previously been well investigated. Pharmacokinetic modeling of myocardial contrast enhancement kinetics can potentially provide insight into the mechanisms of the distinctive LGE appearance that can be seen in cardiac amyloid, as well as why it may be unreliable in some patients. MethodsAn interactive three-compartment pharmacokinetic model of the dynamics of myocardial contrast enhancement in CMR was implemented, and used to simulate LGE dynamics in normal, scar, and cardiac amyloid myocardium; the results were compared with previously published values. ResultsThe three-compartment model is able to capture the qualitative features of LGE, in patients with cardiac amyloid. In particular, the characteristic “dark blood” appearance of PSIR images of LGE in cardiac amyloid is seen to likely primarily reflect expansion of the extravascular extracellular space (EES) by amyloid in the “reference” myocardium; the cardiac amyloid contrast enhancement dynamics also reflect expansion of the body EES. ConclusionThe distinctive appearance of LGE in cardiac amyloid is likely due to a combination of diffuse expansion by amyloid of the EES of the reference myocardium and of the body EES.

Reversal of rocuronium-induced intense neuromuscular blockade by sugammadex in Korean children: A pharmacokinetic and pharmacodynamic analysis.

Sugammadex, a selective antagonist of steroidal non-depolarizing neuromuscular blocking agents, has been used in children in limited circumstances. However, neither pharmacokinetics (PKs) nor recovery profile of sugammadex for intense neuromuscular blockade reversal in children have been reported. This prospective study aimed to obtain a PK model of sugammadex and evaluate its efficacy and safety for intense neuromuscular blockade reversal in children. Forty children (age, 2-17 years) who underwent surgery that required early neuromuscular blockade reversal were enrolled. After neuromuscular blockade with 1mg∙kg-1 of rocuronium, sugammadex (2, 4, and 8mg∙kg-1 ) or a conventional dose of neostigmine (0.03 mg∙kg-1 ) was administered randomly after confirmation of zero post-tetanic count. The plasma concentrations of rocuronium and sugammadex were measured 2min after rocuronium injection; immediately before, 2, 5, 15, 60, 120, 240, and 480 min after the study drug injection. Response to train-of-four stimulation was continuously recorded. Noncompartmental analysis and population PK modeling were performed. For pharmacodynamics, the recovery profile was measured. Three-compartment PK model was established for sugammadex. The median (interquartile range [IQR]) time from injection of 8mg∙kg-1 of sugammadex to recovery of T4 /T1 greater than or equal to 0.9 at train-of-four stimulation was 1.1 (IQR: 0.88-1.8) min. No adverse events related to sugammadex were observed. We present a PK analysis of sugammadex for rocuronium-induced intense neuromuscular blockade reversal in children with its recovery profile. The time to recover T4 /T1 greater than or equal to 0.9 at train-of-four stimulation with 8mg∙kg-1 of sugammadex was less than 3min and comparable to that in adults.

Predicting Antibiotic Effect of Vancomycin Using Pharmacokinetic/Pharmacodynamic Modeling and Simulation: Dense Sampling versus Sparse Sampling.

This study aimed to investigate the effect of a structural pharmacokinetic (PK) model with fewer compartments developed following sparse sampling on the PK parameter estimation and the probability of target attainment (PTA) prediction of vancomycin. Two- and three-compartment PK models of vancomycin were used for the virtual concentration–time profile simulation. Datasets with reduced blood sampling times were generated to support a model with a lesser number of compartments. Monte Carlo simulation was conducted to evaluate the PTA. For the two-compartment PK profile, the total clearance (CL) of the reduced one-compartment model showed a relative bias (RBias) and relative root mean square error (RRMSE) over 90%. For the three-compartment PK profile, the CL of the reduced one-compartment model represented the largest RBias and RRMSE, while the steady-state volume of distribution of the reduced two-compartment model represented the largest absolute RBias and RRMSE. A lesser number of compartments corresponded to a lower predicted area under the concentration–time curve of vancomycin. The estimated PK parameters and predicted PK/PD index from models built with sparse sampling designs that cannot support the PK profile can be significantly inaccurate and unprecise. This might lead to the misprediction of the PTA and selection of improper dosage regimens when clinicians prescribe antibiotics.

Development and optimization of a fentanyl pharmacokinetic model for target-controlled infusion in anaesthetized dogs

ObjectiveTo investigate pharmacokinetics (PK) of fentanyl administered by target-controlled infusion (TCI), and to develop a PK model optimized by covariates for TCI in anaesthetized dogs. Study designProspective clinical study. AnimalsA group of 20 client-owned dogs with spinal pain undergoing anaesthesia for magnetic resonance imaging. MethodsFentanyl was administered as an infusion to 20 anaesthetized dogs using a TCI system incorporating a previously described fentanyl two-compartment PK. Arterial blood samples were collected at specific time points during the infusion and over 60 minutes post-infusion for measurement of fentanyl plasma concentrations. The predictive performance of the Sano PK model was assessed by comparing predicted and measured plasma concentrations. A population PK analysis was then performed using a nonlinear mixed-effect modelling approach, allowing inter- and intra-individual variability estimation. Finally, a quantitative stepwise evaluation of the influence of various covariates such as weight, body condition score, size, size-related age, sex and type of premedication on the PK model was considered. ResultsOverall predictive performance of the Sano PK set of variables was not clinically acceptable in anaesthetized dogs. Fentanyl PK was best described by a three-compartment model. Weight and sex were found to affect the volume of distribution of the central compartment. Addition of these two covariate/variable associations resulted in a reduction of the objective function value (OFV) from –340.18 to –448.34, and of the median population weighted residual and the median population absolute weighted residual from 16.1% and 38.6% to 3.9% and 20.3%, respectively. Fentanyl infusions at measured concentrations up to 5.4 ng mL–1 in sevoflurane-anaesthetized dogs resulted in stable anaesthesia and smooth recoveries without complications. Conclusions and clinical relevanceA population three-compartment PK model for fentanyl TCI in anaesthetized dogs was developed. Weight and sex have been detected and incorporated as significant covariates.

This Month in Anesthesiology

This Month in Anesthesiology

Model of drug delivery to populations composed of two cell types

The rate of drug delivery to cells and the subsequent rate of drug metabolism are dependent on the cell membrane permeability to the drug. In some cases, tissue may be composed of different types of cells that exhibit order of magnitude differences in their membrane permeabilities. This paper presents a brief review of the components of the tissue scale three-compartment pharmacokinetic model of drug delivery to single–cell–type populations. The existing model is extended to consider tissue composed of two different cell types. A case study is presented of infusion mediated delivery of doxorubicin to a tumor that is composed of a drug reactive cell type and of a drug resistive cell type. The membrane permeabilities of the two cell types differ by an order of magnitude. A parametric investigation of the population composition is conducted and it is shown that the drug metabolism of the low permeability cells are negatively influenced by the fraction of the tissue composed of the permeable drug reactive cells. This is because when the population is composed mostly of drug permeable cells, the extracellular space is rapidly depleted of the drug. This has two compounding effects: (i) locally there is simply less drug available to the neighboring drug resistant cells, and (ii) the depletion of the drug from the extracellular space near the vessel-tissue interface leaves less drug to be transported to both cell types farther away from the vessel.

Glomerular filtration rate in children and young adults with haemato‐oncological disease and infection is best described by three‐compartment iohexol model

Children with cancer and infection may develop glomerular hyperfiltration. With the aim to determine the prevalence of glomerular hyperfiltration in children and young adults with haemato-oncological disease and infection, we developed population pharmacokinetic model of iohexol. We further aimed to assess the accuracy of estimated glomerular filtration rate (eGFR) equations and single- or two-point measured GFR (mGFR) formulas compared with GFR based on iohexol clearance from our population pharmacokinetic model (iGFR). Hospitalised patients (0.5-25years) with haemato-oncological disease and infection were included if their eGFR was ≥80ml/min/1.73m2 at the screening visit. Iohexol plasma concentrations were described by population pharmacokinetic model. Bias, precision and accuracy of 23 eGFR equations and 18 mGFR formulas were calculated. Total of 32 iohexol administrations were performed in 28 patients. Median (range) eGFR was 136ml/min/1.73m2 (74-234) and age 15.1years (0.8-26.0). Three-compartment model with allometric scaling of central, one peripheral compartment and clearance (with power 0.75) to weight fitted the best. Median (range) iGFR was 103ml/min/1.73m2 (68-140). All except one eGFR equation overestimated GFR. Lund-Malmö revised eGFR equation performed the best, followed by Gao equation. Of single- or two-point mGFR formulas, 15 overestimated iGFR. Modified Jacobsson formula at 5.5hours performed the best, followed by Fleming formula at 3hours. In children and young adults with haemato-oncological disease and infection, renal function is best described by iohexol clearance from three-compartment pharmacokinetic model, while eGFR equations and single- and two-point mGFR formulas overestimate iGFR.

Optimal control for colistin dosage selection.

Optimization of antibiotic administration helps minimizing cases of bacterial resistance. Dosages are often selected by trial and error using a pharmacokinetic (PK) model. However, this is limited to the range of tested dosages, restraining possible treatment choices, especially for the loading doses. Colistin is a last-resort antibiotic with a narrow therapeutic window; therefore, its administration should avoid subtherapeutic or toxic concentrations. This study formulates an optimal control problem for dosage selection of colistin based on a PK model, minimizing deviations of colistin concentration to a target value and allowing a specific dosage optimization for a given individual. An adjoint model was used to provide the sensitivity of concentration deviations to dose changes. A three-compartment PK model was adopted. The standard deviation between colistin plasma concentrations and a target set at 2 mg/L was minimized for some chosen treatments and sample patients. Significantly lower deviations from the target concentration are obtained for shorter administration intervals (e.g. every 8 h) compared to longer ones (e.g. every 24 h). For patients with normal or altered renal function, the optimal loading dose regimen should be divided into two or more administrations to attain the target concentration quickly, with a high first loading dose followed by much lower ones. This regimen is not easily obtained by trial and error, highlighting advantages of the method. The present method is a refined optimization of antibiotic dosage for the treatment of infections. Results for colistin suggest significant improvement in treatment avoiding subtherapeutic or toxic concentrations.

Influence of ABC transporters on the excretion of ciprofloxacin assessed with PET imaging in mice

Ciprofloxacin is a commonly prescribed fluoroquinolone antibiotic which is cleared by active tubular secretion and intestinal excretion. Ciprofloxacin is a known substrate of the ATP-binding cassette (ABC) transporters breast cancer resistance protein (BCRP) and multidrug resistance-associated protein 4 (MRP4). In this work, we used positron emission tomography (PET) imaging to investigate the influence of BCRP, MRP4, MRP2 and P-glycoprotein (P-gp) on the excretion of [18F]ciprofloxacin in mice. Dynamic 90-min PET scans were performed after intravenous injection of [18F]ciprofloxacin in wild-type mice without and with pre-treatment with the broad-spectrum MRP inhibitor MK571. Moreover, [18F]ciprofloxacin PET scans were performed in Abcc4(-/-), Abcc2(-/-), Abcc4(-/-)Abcg2(-/-) and Abcb1a/b(-/-)Abcg2(-/-) mice. In addition to non-compartmental pharmacokinetic (PK) analysis, a novel three-compartment PK model was developed for a detailed assessment of the renal disposition of [18F]ciprofloxacin. In MK571 pre-treated mice, a significant increase in the blood exposure to [18F]ciprofloxacin was observed along with a significant reduction in the renal and intestinal clearances. PK modelling revealed a significant reduction in renal radioactivity uptake (CL1) and in the rate constants for transfer of radioactivity from the corticomedullary renal region into blood (k2) and urine (k3), respectively, after MK571 administration. No changes in the renal clearance or in the estimated kidney PK model parameters were observed in any of the studied knockout models, while a significant reduction in the intestinal clearance was observed in Abcc2(-/-) and Abcc4(-/-)Abcg2(-/-) mice. Our data failed to reveal a role of any of the studied ABC transporters in the tubular secretion of ciprofloxacin. This may indicate that ciprofloxacin is handled in the kidneys by more than one transporter family, most likely with a great degree of mutual functional redundancy. Our study highlights the potential of PET imaging for an assessment of transporter-mediated renal excretion of radiolabelled drugs.

Study of Parameters Estimation of The Three-Compartment Pharmacokinetic Model using Particle Swarm Optimization Algorithm

The accuracy of the numerical solution of the three-compartment pharmacokinetic model is generally related to the rate parameter. Therefore, in this research, the numerical solution will be applied to the pharmacokinetic model which is shaped by the nonlinear coupled ordinary differential equations. Then the particle swarm optimization (PSO) algorithm which used random numbers is used to estimate the parameters of the pharmacokinetic model. The accuracy of the estimation parameters can be predicted using the experimental data of the drug absorption concentration by using the shape suitability of the curve. Based on these study results, the PSO algorithm is very simple but provides accurate parameter estimates for predicting drug concentrations in the central compartment over the entire time span after oral drug administration. This numerical method has been tried in experimental literature data for the drug atenolol. The prediction accuracy of the drug absorption indicates that the R 2 value of all numerical results has reached above 90 %.

A Universal Pharmacokinetic Model for Dexmedetomidine in Children and Adults.

A universal pharmacokinetic model was developed from pooled paediatric and adult data (40.6 postmenstrual weeks, 70.8 years, 3.1–152 kg). A three-compartment pharmacokinetic model with first-order elimination was superior to a two-compartment model to describe these pooled dexmedetomidine data. Population parameter estimates (population parameter variability%) were clearance (CL) 0.9 L/min/70 kg (36); intercompartmental clearances (Q2) 1.68 L/min/70 kg (63); Q3 0.62 L/min/70 kg (90); volume of distribution in the central compartment (V1) 25.2 L/70 kg (103.9); rapidly equilibrating peripheral compartment (V2) 34.4 L/70 kg (41.8); slow equilibrating peripheral compartment (V3) 65.4 L/70 kg (62). Obesity was best described by fat-free mass for clearances and normal fat mass for volumes with a factor for fat mass (FfatV) of 0.293. Models describing dexmedetomidine pharmacokinetics in adults can be applied to children by accounting for size (allometry) and age (maturation). This universal dexmedetomidine model is applicable to a broad range of ages and weights: neonates through to obese adults. Lean body weight is a better size descriptor for dexmedetomidine clearance than total body weight. This parameter set could be programmed into target-controlled infusion pumps for use in a broad population.

Pharmacokinetic-Pharmacodynamic Modeling of the Antioxidant Activity of Quzhou Fructus Aurantii Decoction in a Rat Model of Hyperlipidemia

BackgroundQuzhou Fructus Aurantii (QFA) is an herb that is commonly used to alleviate inflammation in individuals dealing with obesity.To date, however, no systematic pharmacokinetic (PK) or pharmacodynamic (PD) analyses of the clinical efficacy of QFA under hyperlipemia-associated oxidative stress conditions have been conducted. The present study, was therefore designed to construct a PK-PD model for this herb, with the goal of linking QFA PK profiles to key therapeutic outlines to guide the therapeutic use of this herb in clinical settings. MethodsRats were fed a high-fat diet in order to establish a model of hyperlipidemia, after which they were randomized into a normal control group (NCG), a normal treatment group (NTG), a model control group (MCG), and a model treated group (MTG) (n = 6 each). QAF decoction was used to treat rats in the NTG and MTG groups (25 g/kg), while equivalent volumes of physiological saline were administered to rats in the NCG and MCG groups. Plasma samples were collected from the mandibular vein for animals at appropriate time points and analyzed via high-performance liquid chromatography (HPLC). We evaluated PK properties for three QAF components and compared these dynamics between the NTG and MTG groups, while also measuring levels of lipid peroxidation (LPO) in the plasma of rats in all four treatment groups. We then constructed a PK-PD model based upon plasma neohesperidin, luteolin, and nobiletin concentrations and LPO levels using a three-compartment PK model together with a Sigmoid Emax PD model. This model thereby enabled us to assess the antioxidative impact of neohesperidin, luteolin, and nobiletin on hyperlipidemia in rats. ResultsWhen comparing the NTG and MTG groups, we detected significant differences in the following parameters pertaining to neohesperidin, luteolin, and nobiletin:t1/2β, V1, t1/2γ, CL1 (p < 0.01) and AUC0-t, Tmax, Cmax (p < 0.05). Relative to NTG group rats, AUC0-t, TmaxandCmaxvalues significantly higher for MTG group rats (p < 0.01), while t1/2β, V1, and t1/2γ values were significantly lower in MTG group rats (p < 0.01) in MTG rats. QAF decoction also exhibited excellent PD efficacy in MTG rats, with significant reductions in plasma LPO levels relative to NTG rats (p < 0.01) following treatment. This therapeutic efficacy may be attributable to the activity of neohesperidin, luteolin, and nobiletin, as LPO levels and plasma concentrations of these compounds were negatively correlated in treated rats. Based upon Akaike Information Criterion (AIC) values, we determined that neohesperidin, luteolin, and nobiletin PK processes were consistent with a three-compartment model. Together, these findings indicated that three active components in QAF decoction (neohesperidin, luteolin, and nobiletin) may exhibit antioxidant activity in vivo. ConclusionOur in vivo data indicated that neohesperidin, luteolin and nobiletin components of QAF decoctions exhibit distinct PK and PD properties. Together, these findings suggest that hyperlipidemia-related oxidative stress can significantly impact QFA decoction PK and PD parameters. Our data additionally offer fundamental insights that can be used to design appropriate dosing regimens for individualized clinical QAF decoction treatment.

Serum concentrations, pharmacokinetic/pharmacodynamic modeling, and effects of dexamethasone on inflammatory mediators following intravenous and oral administration to exercised horses

Corticosteroids are potent anti-inflammatory drugs and as such are commonly administered to performance and racehorses. The objectives of the current study were to describe blood and urine concentrations and the pharmacokinetics and effects on cortisol and inflammatory mediator concentrations, following intravenous and oral administration to 12 exercised horses. Horses received an intravenous administration of 40 mg of dexamethasone sodium phosphate and 20 mg of dexamethasone tablets with a 4 week washout in between administrations. Blood and urine samples were collected prior to and for up to 96 hours post drug administration. Whole blood samples were collected at various time points and challenged with lipopolysaccharide or calcium ionophore to induce ex vivo synthesis of eicosanoids. The concentrations of dexamethasone and eicosanoids were measured using LC-MS/MS and the concentrations from both routes of administration fit simultaneously using a three-compartment pharmacokinetic model. A turnover model with inhibition of Kin gave an adequate fit to the dexamethasone-cortisol PKPD data. Serum and urine dexamethasone concentrations were at the limit of quantitation at 96 and 48 hours post administration, respectively. The volume of distribution, systemic clearance, and terminal half-life was 0.907 L/kg, 7.89 mL/h/kg, and 1.34 h, respectively. The IC50 for cortisol suppression was 0.007 ng/mL. Stimulation of dexamethasone treated blood with lipopolysaccharide and calcium ionophore resulted in an inhibition of inflammatory biomarker production for a prolonged period of time post drug administration. The results of this study suggest that dexamethasone has a prolonged anti-inflammatory effect following intravenous or oral administration to horses.

Kinetic modeling and analysis of dynamic bioluminescence imaging of substrates administered by intraperitoneal injection.

Bioluminescence imaging (BLI) has been found to have diverse applications in the life sciences and medical research due to its ease of use and high sensitivity. From kinetics analysis, dynamic imaging studies have significant advantages for diagnosis when compared to traditional static imaging studies. This work focuses on modeling and quantitatively analyzing the dynamic data produced from the intraperitoneal (IP) injection of D-luciferin in longitudinal BLI, aiming to provide a powerful tool for monitoring the growth of tumors. We constructed a three-compartment pharmacokinetic (PK) model and employed the standard Michaelis-Menten (M-M) kinetics to investigate the dynamic BLI data produced from the IP injection of D-luciferin. The 3 compartments were the plasma compartment, the non-specific compartment, and the specific compartment. The validity of this PK model was tested by the dynamic BLI data of MKN28M-luc xenograft mice, along with the published longitudinal dynamic BLI data of B16F10-luc xenograft mice. The R-squares between the simulated lines and the measurement were 1 and 0.99, respectively, for the mice data and the published data. In addition, the 2 kinetic macroparameters obtained reflected the rate of tumor growth in vivo. In particular, the values of macroparameters A showed a significant dependence on tumor surface area. The proposed PK model may be an effective tool for use in drug development programs and for monitoring the response of tumors to treatment.

Measurement of Hepatic ABCB1 and ABCG2 Transport Activity with [11C]Tariquidar and PET in Humans and Mice.

P-Glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) in the canalicular membrane of hepatocytes mediate the biliary excretion of drugs and drug metabolites. To measure hepatic ABCB1 and ABCG2 activity, we performed positron emission tomography (PET) scans with the ABCB1/ABCG2 substrate [11C]tariquidar in healthy volunteers and wild-type, Abcb1a/b(-/-), Abcg2(-/-), and Abcb1a/b(-/-)Abcg2(-/-) mice without and with coadministration of unlabeled tariquidar. PET data were analyzed with a three-compartment pharmacokinetic model. [11C]Tariquidar underwent hepatobiliary excretion in both humans and mice, and tariquidar coadministration caused a significant reduction in the rate constant for the transfer of radioactivity from the liver into bile (by -74% in humans and by -62% in wild-type mice), suggesting inhibition of canalicular efflux transporter activity. Radio-thin-layer chromatography analysis revealed that the majority of radioactivity (>87%) in the mouse liver and bile was composed of unmetabolized [11C]tariquidar. PET data in transporter knockout mice revealed that both ABCB1 and ABCG2 mediated biliary excretion of [11C]tariquidar. In vitro experiments indicated that tariquidar is not a substrate of major hepatic basolateral uptake transporters (SLCO1B1, SLCO1B3, SLCO2B1, SLC22A1, and SLC22A3). Our data suggest that [11C]tariquidar can be used to measure hepatic canalicular ABCB1/ABCG2 transport activity without a confounding effect of uptake transporters.

Pharmacokinetic and Pharmacodynamic Characterization of Tetrahydrocannabinol-Induced Cannabinoid Dependence After Chronic Passive Cannabis Smoke Exposure in Rats.

Introduction: Cannabis is the most widely used illicit drug in the US, and cannabis use among young adults continues to rise. Previous studies have shown that chronic administration of delta 9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis, induces dependence in animal models. Because smoking is the most frequent route of THC self-administration, it is critical to investigate the effects of cannabis smoke inhalation. The goal of the current study was to develop a rat model to characterize the pharmacokinetics (PKs) of THC after cannabis smoke inhalation, and to determine if chronic cannabis smoke inhalation leads to the development of cannabis dependence. Materials and Methods: For the PK study, male Wistar rats were administered THC intravenously (1 mg/kg) or exposed to smoke from 5 or 10 sequentially smoked cannabis cigarettes (5.3% THC) in an automated smoking machine. Plasma samples were collected from 10 min to 10 hours post smoke exposure (or intravenous administration) and analyzed using liquid chromatography-mass spectrometry to characterize the PK of THC. A three-compartment PK model was used to characterize the PKs. In a separate study, three groups of male Wistar rats were trained in an intracranial self-stimulation (ICSS) procedure, and exposed to smoke from burning 5 or 10 cannabis cigarettes (or clean air control conditions), 5 days/week for 4 weeks. Discussion and Conclusions: Across exposure days, the change from baseline in ICSS thresholds for cannabis smoke-exposed groups was significantly lower and response latencies were significantly faster in the cannabis smoke-exposed groups compared to controls, suggesting that chronic cannabis smoke exposure has rewarding properties. Acute administration of the CB1 receptor antagonist rimonabant (0.3, 1.0, 3.0 mg/kg) induced a dose-dependent increase in ICSS thresholds in the smoke-exposed rats, suggestive of dependence and withdrawal. Finally, an effect compartment PK-pharmacodynamic model was used to describe the relationship between THC concentrations and changes in ICSS thresholds after cannabis smoke exposure.

Three-compartment pharmacokinetic models of radiotracers used in the GFR-determination - estimation of their parameters using the time-concentration curves.

In GFR measurements with radiotracers, there is evidence that a two-compartment model is unable to describe the full plasma curve, including early time points, but analyses generally focus on two-compartment models. To analyze both the mammillary and catenary three-compartment model and to determine empirical relations between model constants and the overall GFR and ECV (extra-cellular volume). Mathematical analysis of the three-compartment model. Full-curve patient data from 32 adults and 7 children were used to relate model parameters to GFR and ECV. Model volumes were found to be roughly proportional to ECV. In both models, the central (plasma) volume was V1 = 0.24 × ECV and elimination rate from V1 was k10 = 4.2 × GFR/ECV. In the mammillary model, the two parallel volumes were V2 = 0.28 × ECV, V3 = 0.48 × ECV, and intercompartmental clearances were Cl12 [mL/min] = 0.0058 × ECV [mL], Cl13 = 0.042 × ECV. In the catenary model, the serial volumes were V2 = 0.60 × ECV, V3 = 0.16 × ECV, with clearances Cl12 = 0.048 × ECV, Cl23 = 0.0036 × ECV. Insight into the three-compartment model was achieved, and empirical relations to ECV and GFR/ECV were determined.

Ant Colony Optimization PID Control of Hypnosis With Propofol Using Renyi Permutation Entropy as Controlled Variable

General anesthesia is a critical procedure in clinical surgery. To offer a closed control of depth of hypnosis, we establish a closed-loop anesthetic delivery system for propofol anesthesia. The system consists of three components: 1) three-compartment pharmacokinetic model; 2) a pharmacodynamics model obtained by identifying the relationship of effect–site concentration and Renyi permutation entropy via particle swarm optimization; and 3) ant colony optimization proportion integration differentiation controller. The performance of Renyi permutation entropy and bispectral index in tracking the effect–site concentration is evaluated by the prediction probability. The assessments of the performance of the controller are using: 1) the rising time, percent overshoot, and settling time and 2) median performance error, median absolute performance error, wobble, divergence, and integral absolute error. The results show that the prediction probability of Renyi permutation entropy (0.79±0.13 and mean±standard deviation) is higher than the bispectral index (0.74±0.15). The ant colony optimization proportion integration differentiation controller is quick to respond to sudden changes and maintains the stabilty at the desired depth of hypnosis (rise time and overshoot are 4.53±1.96 min and 3.48±1.49 (%), respectively). In conclusion, the proposed closed-loop anesthetic delivery system has potential value for accurate anesthetic administration.