Joost DeJongh

THE PHARMACOKINETICS OF GLYCYRRHIZIC ACID EVALUATED BY PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELING

Glycyrrhizic acid is widely applied as a sweetener in food products and chewing tobacco. In addition, it is of clinical interest for possible treatment of chronic hepatitis C. In some highly exposed subjects, side effects such as hypertension and symptoms associated with electrolyte disturbances have been reported. To analyze the relationship between the pharmacokinetics of glycyrrhizic acid in its toxicity, the kinetics of glycyrrhizic acid and its biologically active metabolite glycyrrhetic acid were evaluated. Glycyrrhizic acid is mainly absorbed after presystemic hydrolysis as glycyrrhetic acid. Because glycyrrhetic acid is a 200–1000 times more potent inhibitor of 11-β-hydroxysteroid dehydrogenase compared to glycyrrhizic acid, the kinetics of glycyrrhetic acid are relevant in a toxicological perspective. Once absorbed, glycyrrhetic acid is transported, mainly taken up into the liver by capacity-limited carriers, where it is metabolized into glucuronide and sulfate conjugates. These conjugates are transported efficiently into the bile. After outflow of the bile into the duodenum, the conjugates are hydrolyzed to glycyrrhetic acid by commensal bacteria; glycyrrhetic acid is subsequently reabsorbed, causing a pronounced delay in the terminal plasma clearance. Physiologically based pharmacokinetic modeling indicated that, in humans, the transit rate of gastrointestinal contents through the small and large intestines predominantly determines to what extent glycyrrhetic acid conjugates will be reabsorbed. This parameter, which can be estimated noninvasively, may serve as a useful risk estimator for glycyrrhizic-acid-induced adverse effects, because in subjects with prolonged gastrointestinal transit times, glycyrrhetic acid might accumulate after repeated intake.

Morphine glucuronidation in preterm neonates, infants and children younger than 3 years

Background and objectiveA considerable amount of drug use in children is still unlicensed or off-label. In order to derive rational dosing schemes, the influence of aging on glucuronidation capacity in newborns, including preterms, infants and children under the age of 3 years was studied using morphine and its major metabolites as a model drug.MethodsA population pharmacokinetic model was developed with the nonlinear mixed-effects modelling software NONMEM® V, on the basis of 2159 concentrations of morphine and its glucuronides from 248 infants receiving intravenous morphine ranging in bodyweight from 500 g to 18 kg (median 2.8 kg). The model was internally validated using normalized prediction distribution errors.ResultsFormation clearances of morphine to its glucuronides and elimination clearances of the glucuronides were found to be primarily influenced by bodyweight, which was parameterized using an allometric equation with an estimated exponential scaling factor of 1.44. Additionally, a postnatal age of less than 10 days was identified as a covariate for formation clearance to the glucuronides, independent of birthweight or postmenstrual age. Distribution volumes scaled linearly with bodyweight.ConclusionsModel-based simulations show that in newborns, including preterms, infants and children under the age of 3 years, a loading dose in µg/kg and a maintenance dose expressed in µg/kg1.5/h, with a 50% reduction of the maintenance dose in newborns younger than 10 days, results in a narrow range of morphine and metabolite serum concentrations throughout the studied age range. Future pharmacodynamic investigations are needed to reveal target concentrations in this population, after which final dosing recommendations can be made.

A Mechanism-based Disease Progression Model for Comparison of Long-term Effects of Pioglitazone, Metformin and Gliclazide on Disease Processes Underlying Type 2 Diabetes Mellitus

Effective long-term treatment of Type 2 Diabetes Mellitus (T2DM) implies modification of the disease processes that cause this progressive disorder. This paper proposes a mechanism-based approach to disease progression modeling of T2DM that aims to provide the ability to describe and quantify the effects of treatment on the time-course of the progressive loss of β-cell function and insulin-sensitivity underlying T2DM. It develops a population pharmacodynamic model that incorporates mechanism-based representations of the homeostatic feedback relationships between fasting levels of plasma glucose (FPG) and fasting serum insulin (FSI), and the physiological feed-forward relationship between FPG and glycosylated hemoglobin A1c (HbA1c). This model was developed on data from two parallel one-year studies comparing the effects of pioglitazone relative to metformin or sulfonylurea treatment in 2408 treatment-naïve T2DM patients. It was found that the model provided accurate descriptions of the time-courses of FPG and HbA1c for different treatment arms. It allowed the identification of the long-term effects of different treatments on loss of β-cell function and insulin-sensitivity, independently from their immediate anti-hyperglycemic effects modeled at their specific sites of action. Hence it avoided the confounding of these effects that is inherent in point estimates of β-cell function and insulin-sensitivity such as the widely used HOMA-%B and HOMA-%S. It was also found that metformin therapy did not result in a reduction in FSI levels in conjunction with reduced FPG levels, as expected for an insulin-sensitizer, whereas pioglitazone therapy did. It is concluded that, although its current implementation leaves room for further improvement, the mechanism-based approach presented here constitutes a promising conceptual advance in the study of T2DM disease progression and disease modification.

Disease System Analysis: Basic Disease Progression Models in Degenerative Disease

PurposeTo describe the disease status of degenerative diseases (i.e., type 2 diabetes mellitus, Parkinson’s disease) as function of disease process and treatment effects, a family of disease progression models is introduced.MethodsDisease progression is described using a progression rate (Rdp) acting on the synthesis or elimination parameters of the indirect response model. Symptomatic effects act as disease-dependent or -independent effects on the synthesis or elimination parameters. Protective drug effects act as disease dependent or -independent effects on Rdp.ResultsSimulations with the ten disease models show distinctly different signature profiles of treatment effects on disease status. Symptomatic effects result in improvement of disease status with a subsequent deterioration. Treatment cessation results in a disease status equal to the situation where treatment had not been applied. Protective effects result in a lasting reduction, or even reversal, of the disease progression rate and the resulting disease status during the treatment period. After cessation of treatment the natural disease course will continue from the disease status at that point.ConclusionDisease system analysis constitutes a scientific basis for the distinction between symptomatic versus protective drug effects in relation to specific disease processes as well as the identification of the exposure-response relationship during the time-course of disease.

Propofol Pharmacokinetics and Pharmacodynamics for Depth of Sedation in Nonventilated Infants after Major Craniofacial Surgery

Background: To support safe and effective use of propofol in nonventilated children after major surgery, a model for propofol pharmacokinetics and pharmacodynamics is described. Methods: After craniofacial surgery, 22 of the 44 evaluated infants (aged 3–17 months) in the pediatric intensive care unit received propofol (2–4 mg · kg−1 · h−1) during a median of 12.5 h, based on the COMFORT-Behavior score. COMFORT-Behavior scores and Bispectral Index values were recorded simultaneously. Population pharmacokinetic and pharmacodynamic modeling was performed using NONMEM V (GloboMax LLC, Hanover, MD). Results: In the two-compartment model, body weight (median, 8.9 kg) was a significant covariate. Typical values were Cl = 0.70 · (BW/8.9)0.61 l/min, Vc = 18.8 l, Q = 0.35 l/min, and Vss = 146 l. In infants who received no sedative, depth of sedation was a function of baseline, postanesthesia effect (Emax model), and circadian night rhythm. In agitated infants, depth of sedation was best described by baseline, postanesthesia effect, and propofol effect (Emax model). The propofol concentration at half maximum effect was 1.76 mg/l (coefficient of variation = 47%) for the COMFORT-Behavior scale and 3.71 mg/l (coefficient of variation = 145%) for the Bispectral Index. Conclusions: Propofol clearance is two times higher in nonventilated healthy children than reported in the literature for ventilated children and adults. Based on the model, the authors advise a propofol dose of 30 mg/h in a 10-kg infant to achieve values of 12–14 on the COMFORT-Behavior scale and 70–75 on the Bispectral Index during the night. Wide pharmacodynamic variability emphasizes the importance of dose titration.

Population pharmacokinetic and pharmacodynamic modeling of propofol for long‐term sedation in critically ill patients: A comparison between propofol 6% and propofol 1%

A population pharmacokinetic and pharmacodynamic model of propofol for long‐term sedation in critically ill patients is described, because limited information is available in these patients. In the models the influence of time‐independent covariates, in particular, the propofol formulation (propofol 6% versus propofol 1%), and of time‐dependent covariates was investigated.

Disease severity is a major determinant for the pharmacodynamics of propofol in critically ill patients

As oversedation is still common and significant variability between and within critically ill patients makes empiric dosing difficult, the population pharmacokinetics and pharmacodynamics of propofol upon long‐term use are characterized, particularly focused on the varying disease state as determinant of the effect. Twenty‐six critically ill patients were evaluated during 0.7–9.5 days (median 1.9 days) using the Ramsay scale and the bispectral index as pharmacodynamic end points. NONMEM V was applied for population pharmacokinetic and pharmacodynamic modeling. Propofol pharmacokinetics was described by a two‐compartment model, in which cardiac patients had a 38% lower clearance. Severity of illness, expressed as a Sequential Organ Failure Assessment (SOFA) score, particularly influenced the pharmacodynamics and to a minor degree the pharmacokinetics. Deeper levels of sedation were found with an increasing SOFA score. With severe illness, critically ill patients will need downward titration of propofol. In patients with cardiac failure, the propofol dosages should be reduced by 38%.

Predictive Performance of a Recently Developed Population Pharmacokinetic Model for Morphine and its Metabolites in New Datasets of (Preterm) Neonates, Infants and Children

Background and ObjectiveModel validation procedures are crucial when models are to be used to develop new dosing algorithms. In this study, the predictive performance of a previously published paediatric population pharmacokinetic model for morphine and its metabolites in children younger than 3 years (original model) is studied in new datasets that were not used to develop the original model.MethodsSix external datasets including neonates and infants up to 1 year were obtained from four different research centres. These datasets contained postoperative patients, ventilated patients and patients on extracorporeal membrane oxygenation (ECMO) treatment. Basic observed versus predicted plots, normalized prediction distribution error analysis, model refitting, bootstrap analysis, subpopulation analysis and a literature comparison of clearance predictions were performed with the new datasets to evaluate the predictive performance of the original morphine pharmacokinetic model.ResultsThe original model was found to be stable and the parameter estimates were found to be precise. The concentrations predicted by the original model were in good agreement with the observed concentrations in the four datasets from postoperative and ventilated patients, and the model-predicted clearances in these datasets were in agreement with literature values. In the datasets from patients on ECMO treatment with continuous venovenous haemofiltration (CVVH) the predictive performance of the model was good as well, whereas underprediction occurred, particularly for the metabolites, in patients on ECMO treatment without CVVH.ConclusionThe predictive value of the original morphine pharmacokinetic model is demonstrated in new datasets by the use of six different validation and evaluation tools. It is herewith justified to undertake a proof-of-principle approach in the development of rational dosing recommendations — namely, performing a prospective clinical trial in which the model-based dosing algorithm is clinically evaluated.

Pharmacokinetics and pharmacodynamics of midazolam and metabolites in nonventilated infants after craniofacial surgery.

Background:Because information on the optimal dose of midazolam for sedation of nonventilated infants after major surgery is scant, a population pharmacokinetic and pharmacodynamic model is developed for this specific group. Methods:Twenty-four of the 53 evaluated infants (aged 3–24 months) admitted to the Pediatric Surgery Intensive Care Unit, who required sedation judged necessary on the basis of the COMFORT-Behavior score and were randomly assigned to receive midazolam, were included in the analysis. Bispectral Index values were recorded concordantly. Population pharmacokinetic and pharmacodynamic modeling was performed using NONMEM V (GloboMax LLC, Hanover, MD). Results:For midazolam, total clearance was 0.157 l/min, central volume was 3.8 l, peripheral volume was 30.2 l, and intercompartmental clearance was 0.30 l/min. Assuming 60% conversion of midazolam to 1-OH-midazolam, the volume of distribution for 1-OH-midazolam and 1-OH-midazolamglucuronide was 6.7 and 1.7 l, and clearance was 0.21 and 0.047 l/min, respectively. Depth of sedation using COMFORT-Behavior could adequately be described by a baseline, postanesthesia effect (Emax model) and midazolam effect (Emax model).The midazolam concentration at half maximum effect was 0.58 &mgr;m with a high interindividual variability of 89%. Using the Bispectral Index, in 57% of the infants the effect of midazolam could not be characterized. Conclusion:In nonventilated infants after major surgery, midazolam clearance is two to five times higher than in ventilated children. From the model presented, the recommended initial dosage is a loading dose of 1 mg followed by a continuous infusion of 0.5 mg/h during the night for a COMFORT-Behavior of 12–14 in infants aged 1 yr. Large interindividual variability warrants individual titration of midazolam in these children.

A human physiologically-based model for glycyrrhzic acid, a compound subject to presystemic metabolism and enterohepatic cycling.

AbstractPurpose. To analyze the role of the kinetics of glycyrrhizic acid (GD) in its toxicity. A physiologically-based pharmacokinetic (PBPK) model that has been developed for humans. Methods. The kinetics of GD, which is absorbed as glycyrrhetic acid (GA), were described by a human PBPK model, which is based on a rat model. After rat to human extrapolation, the model was validated on plasma concentration data after ingestion of GA and GD solutions or licorice confectionery, and an additional data derived from the literature. Observed interindividual variability in kinetics was quantified by deriving an optimal set of parameters for each individual. Results. The a-priori defined model successfully forecasted GA kinetics in humans, which is characterized by a second absorption peak in the terminal elimination phase. This peak is subscribed to enterohepatic cycling of GA metabolites. The optimized model explained most of the interindividual variance, observed in the clinical study, and adequately described data from the literature. Conclusions. Preclinical information on GD kinetics could be incorporated in the human PBPK model. Model simulations demonstrate that especially in subjects with prolonged gastrointestinal residence times, GA may accumulate after repeated licorice consumption, thus increasing the health risk of this specific subgroup of individuals.