Pharmacokinetic simulations and AUC: center specificity in the limited sampling model.
Explore the source record for details and available documents.
Antihypertensive Agents↗
Biomedical subjects
J H Proost
Publications and source records attributed to J H Proost.
Renal targeting of captopril using subcutaneous administration of captopril-lysozyme conjugate.
Explore the source record for details and available documents.
Absorption↗
Decreased number of acetylcholine receptors is the mechanism that alters the time course of muscle relaxants in myasthenia gravis: a study in a rat model.
BACKGROUND: In myasthenic patients, the time course of action of non-depolarizing neuromuscular blocking agents is prolonged and the sensitivity is increased. We used our antegrade perfused rat peroneal nerve anterior tibialis muscle model to investigate if this altered time course of effect and sensitivity can be explained by the decreased acetylcholine receptor concentration that is caused by the disease. METHODS: Functional acetylcholine receptors were reduced by administration of alpha-bungarotoxin or by injecting monoclonal antibodies against rat acetylcholine receptors (experimental autoimmune myasthenia gravis). After induction of anaesthesia, the model was set up and perfusion of the tibialis anterior muscle with blood was started. After stabilization of the twitch, rocuronium or pancuronium were infused until 90% block was obtained. Twitch data and infusion data were recorded and used to calculate the time course of effect and potency. RESULTS: The potency of neuromuscular blocking agents was increased and the offset of the neuromuscular block was prolonged in both the alpha-bungarotoxin groups and the experimental autoimmune myasthenia gravis groups compared to controls. CONCLUSION: This study shows that the increased sensitivity to neuromuscular-blocking agents in myasthenia gravis can be accounted for by a decreased number of acetylcholine receptors. It also shows that the antegrade perfused rat peroneal nerve anterior tibialis muscle model is a suitable model to study the effects of myasthenia gravis on the time course of effect of neuromuscular blocking agents.
Androstanols↗
Absorption kinetics and pharmacodynamics of two oral dosage forms of flecainide in patients with an episode of paroxysmal atrial fibrillation.
OBJECTIVES: The objectives were to study the absorption kinetics and pharmacodynamics of two oral formulations of flecainide in patients with atrial fibrillation (AF) and to assess the relationship between pharmacokinetic parameters and the efficacy in restoring sinus rhythm. METHODS: The data of 54 patients included in a randomised, open, parallel-group study were used. Patients received an oral solution containing 300 mg flecainide and 20 mg cisapride or three tablets each containing 100 mg flecainide. The pharmacokinetic profile of flecainide was fitted using a one-compartment model with lag-time and first-order absorption. RESULTS: The tablets gave a maximum concentration (C (max\ fit)) of 0.43+/-0.14 mg/l at 2.37+/-1.20 h. The oral solution resulted in a much faster peak concentration at 1.05+/-0.71 h (P<0.0001). The C (max\ fit) of the oral solution of 0.60+/-0.17 mg/l was higher (P=0.0002) than that of the tablets, and interindividual variabilities of C (max\ fit) were 28% and 33%, respectively. The absorption rate constant (ka) of the oral solution was twofold larger (P<0.0001). A higher ka (P=0.04) and a duration of AF less than 24 h (P=0.006) increased the probability of cardioversion. If atrial fibrillation lasted less than 24 h, only ka (P=0.016) was obtained as a significant variable in multivariate analysis. The linear models of QRS interval changes versus flecainide concentrations of both formulations had similar slopes with similar interindividual variabilities. CONCLUSIONS: The probability of cardioversion after an oral loading dose of flecainide in patients with AF is dependent on ka. Rapid loading of the effect compartment, i.e. the atria, appears to be critical to reach cardioversion. Higher flecainide serum concentrations and a more rapid absorption does not increase interindividual variability of pharmacokinetics and pharmacodynamics, which is important when safety is considered.
Administration, Oral↗
Model to describe the degree of twitch potentiation during neuromuscular monitoring.
BACKGROUND: Neuromuscular block is estimated by comparing the evoked peak twitch with a control value measured in the absence of neuromuscular block. In practice, this control value is often difficult to determine because repeated motor nerve stimulation enhances the evoked mechanical response of the corresponding muscle, resulting in an increased twitch response. This is known as twitch potentiation or the staircase phenomenon. It is probably the result of myosin light chain phosphorylation creating an increased twitch force for a given amount of Ca(2+) released at each action potential. Modelling of potentiation may improve studies of neuromuscular blocking agents using mechanomyography or accelerometry. METHODS: We used one- and two-exponential models to describe the degree of myosin light chain phosphorylation and associated twitch potentiation. These models were fitted to accelerographic twitch force measurements for various stimulation patterns and frequencies used in neuromuscular monitoring. RESULTS: Fitting a two-exponential model to twitch data for various stimulation rates and patterns provides better prediction than a one-exponential model. A one-exponential model performs poorly when the stimulation rate varies during measurement. CONCLUSIONS: We conclude that a two-exponential model can predict the degree of twitch potentiation for the stimulation patterns and frequencies tested more accurately than a one-exponential model. However, if only one stimulation frequency is used, a one-exponential model can provide good accuracy. We illustrate that such a potentiation model can improve the ability of pharmacodynamic-pharmacokinetic neuromuscular block models to predict twitch response in the presence of a neuromuscular blocking agent.
Electric Stimulation↗
Pharmacokinetic studies in children with cancer.
We reviewed the current status of our knowledge of pharmacokinetics and pharmacodynamics of some anti-neoplastic drugs, used in the treatment of childhood cancer. Extrapolation of data from pharmacokinetic studies in adults to the paediatric population is often not feasible. Specific studies in children are needed. Of all reviewed anti-neoplastic drugs methotrexate appears to be most extensively studied. Methotrexate pharmacokinetics is correlated with toxicity and response to therapy, and it has been shown that individualized adaptive dosing of methotrexate is correlated with a better response to therapy without increasing toxicity in children with ALL and osteosarcoma. Of most of the other reviewed anti-neoplastic drugs it is demonstrated that pharmacokinetics is correlated with toxicity, and of some drugs a relationship of pharmacokinetics with response to therapy is demonstrated as well. In case of cytarabine, etoposide, and teniposide, individualized dosing also appears to be feasible. However, there is no evidence that this strategy improves response to therapy. Specifically data on pharmacokinetic and pharmacodynamic correlations and effect of pharmacokinetically guided, individualized dosing are important for the design of optimal cancer chemotherapy for individual patients. Unfortunately for a considerable number of anti-neoplastic drugs these specific data are lacking in children and future research is needed.
Antineoplastic Agents↗
An interstitial compartment is necessary to link the pharmacokinetics and pharmacodynamics of mivacurium.
BACKGROUND AND OBJECTIVE: The time course of action of mivacurium does not correlate with its rapid breakdown by plasma cholinesterase. Pharmacokinetic-pharmacodynamic (PK-PD) modelling was applied to obtain more insight in the concentration-effect relationship. METHODS: Fourteen patients between 25 and 55yr, undergoing non-major surgery, American Society of Anesthesiologists Grade I-II, were included. All patients received thiopentone/fentanyl/isoflurane/oxygen/nitrous oxide anaesthesia. Neuromuscular block was monitored mechanomyographically using single twitch stimulation (0.1 Hz). Mivacurium was administered as a short-term infusion, mean (standard deviation) duration 4.7 (1.0) min and dose 145 (33) microg kg(-1). Arterial blood samples were obtained, and plasma was analysed using high performance liquid chromatography. PK-PD modelling was performed using an iterative Bayesian two-stage approach, assuming that the trans-trans and cis-trans isomers are equally potent. RESULTS: A PK-PD model with an effect compartment linked to plasma did not fit to the data satisfactorily. A model using an interstitial space compartment between plasma and effect compartment fitted significantly better. Parameters (mean (percentage coefficient of variation)) of the best fitting model were: k(ip) 0.374 min(-1) (46%), k(ei) 0.151 min(-1) (36%), EC50 98 microg L(-1) (29%) and gamma 3.7 (22%). CONCLUSIONS: The PK-PD behaviour of mivacurium could be described using a model with an interstitial space compartment interposed between plasma and effect compartment. This model shows that the time course of mivacurium is mainly governed by the concentration decline in this interposed compartment and only indirectly related to the rapid plasma clearance.
Adult↗
Prediction of whole-body metabolic clearance of drugs through the combined use of slices from rat liver, lung, kidney, small intestine and colon.
1: The aim was to investigate whether precision-cut rat tissue slices could be used to predict metabolic drug clearance in vivo. To obtain a complete picture, slices not only from liver, but also from lung, kidney, small intestine and colon were included. 2: The metabolic clearances of 7-ethoxycoumarin, 7-hydroxycoumarin, testosterone, methyltestosterone and warfarin were determined by measuring the disappearance of these compounds during incubation with slices prepared from liver, lung, kidney, small intestine and colon. 3: The total in vitro metabolic clearance was determined by adding the individual in vitro organ clearances from the slices. Prediction based on the in vitro clearance was within an order of magnitude to the corresponding in vivo values. Interestingly, the relative contribution of extrahepatic metabolic clearance of the studied compounds to total clearance was remarkably high, ranging from 35 to 72% of the total metabolic clearance. 4: It is concluded that the model of multi-organ precision-cut slices is a useful in vitro tool for prediction of in vivo metabolic clearance. In addition, it provides information about the relative contribution of the liver, lung, kidney, small intestine and colon to the total metabolic clearance.
Animals↗
Dose individualization in PharmDIS-e+.
Individualized dosage regimen calculations require knowledge on the pharmacokinetic and pharmacodynamic properties of the drug and the characteristics of the patient. A PK-PD-based dosage regimen is not easily and generally applicable, mainly because the combination of available PK parameters and therapeutic target levels may be inappropriate for the purpose of predicting a plausible dosage regimen. Within the project PharmDIS-e+, an alternative approach was chosen, and this "PK and standard dose"-based principle is well suited for computerized dosing advice. PharmDIS-e+ aims at the development of several applications for dosing regimen advice for general practitioners, hospital physicians and pharmacists.
Aged↗
Pharmacokinetics and whole body distribution of elastase derived angiostatin (K1-3) in rats.
In the current study, we determined short-term pharmacokinetics and whole body distribution of elastase derived angiostatin [angiostatin(k1-3)] in rats after i.v. injection of radiolabelled protein. Since in gamma-camera studies, no tumor specific angiostatin(k1-3) accumulation was observed, general pharmacokinetics were studied in tumor free rats. By one-compartment model fitting of the data, Km 7.3 +/- 1.7 microg x ml(-1), Vmax 0.94 +/- 0.19 microg x min(-1), V, 10.9 +/- 2.5 ml and intrinsic clearance (Vmax/Km) 0.128 ml x min(-1) were calculated. Of the injected dose (I.D.) of angiostatin(k1-3), 12.1 +/- 2.1% per gram tissue was present in the kidneys 10 min after injection. Accumulation of angiostatin(k1-3) was detectable in spleen, liver, lungs and heart 10 min after injection. Sixty minutes after injection, kidney associated angiostatin(k1-3) had decreased, whereas in stomach and small intestines a small increase was seen. Immunohistochemical analysis demonstrated specific staining of interstitial cells of the kidney, liver Kupffer cells and endothelium of larger blood vessels of the lungs. Renal clearance of angiostatin(k1-3) and/or fragments is a major route of elimination, whereas lack of accumulation of radioactivity in the faeces indicates little hepatic elimination or hepatic elimination followed by enterohepatic cycling of the protein's degradation products. Instant blood coagulation at the site of vascular activation and the occurrence of respiratory problems upon administration of higher doses of angiostatin(k1-3) warrants further investigation of the protein's potential side effects. The data presented can be applied to study the relation between angiostatin(k1-3) treatment regimens, blood concentration levels, anti-tumor activity and harmful effects.
Angiostatins↗
Gentamicin pharmacokinetics in preterm infants with a patent and a closed ductus arteriosus.
BACKGROUND AND AIM: A patent ductus arteriosus (PDA) may influence renal and hepatic blood flow and hence pharmacokinetics of drugs in neonates compared to neonates with a closed ductus arteriosus (CDA). A 10-percent difference of gentamicin pharmacokinetic parameters between PDA and CDA has been reported; but its implications are unclear. The relevance of this difference relative to the variability within the neonatal population was investigated. METHODS: Twenty-four neonates (12 with a PDA and 12 with a CDA) treated with gentamicin were retrospectively included. Before closing treatment of the PDA, serum levels were drawn and analysed for regular therapeutic drug monitoring of gentamicin. Data were analysed using the standard two-stage approach (STS) and an iterative 2-stage Bayesian population analysis approach (It2B). RESULTS: Both types of analysis showed no significant differences between both populations for gentamicin total body clearance per kg bodyweight (CL/kg). Volume of distribution per kg bodyweight (Vd/kg) tended to be larger and elimination rate (Kel) tended to be smaller in neonates with PDA. Multiple regression analysis showed for both populations highly significant correlations between total body clearance and body weight (p < 0.0001) or gestational age (p < 0.0001), and between volume of distribution and body weight (p < 0.0001) or gestational age (p < 0.0001). CONCLUSION: Although neonates with a PDA may have small differences in gentamicin pharmacokinetics compared to neonates with a CDA, this is not relevant for clinical practice taking the variability within that population into account.
Anti-Bacterial Agents↗
Effect of hypothermia on the hepatic uptake and biliary excretion of vecuronium in the isolated perfused rat liver.
BACKGROUND: Hypothermia prolongs the time course of action of nondepolarizing muscle relaxants. It is not known whether this prolongation is caused by a reduced rate of extrahepatic distribution or elimination, liver uptake, metabolic clearance, or biliary excretion. Therefore, the authors studied the effects of hypothermia on the net hepatic uptake, metabolism, and biliary excretion of vecuronium in isolated perfused rat liver. METHODS: Livers of Wistar rats were perfused with Krebs Ringer solution (1% albumin, 3.3% carbon dioxide in oxygen, pH 7.36-7.42, 38 degrees C). Each perfusion experiment (recirculatory perfusion system) was divided into three phases. In phase 1, a bolus dose of vecuronium (950 microg) was followed by a continuous infusion of vecuronium (63 microg/min) throughout the perfusion experiment. In phase 2, the temperature was reduced to 28 degrees C. In phase 3, temperature was restored. In controls, the temperature was kept constant throughout the perfusion. Concentrations of vecuronium and its metabolites were measured in perfusion medium, bile, and liver homogenate. Parameters of a multicompartmental liver model were fitted to the concentration patterns in perfusion medium and in bile. RESULTS: Hypothermia increased vecuronium concentrations in the perfusion medium from 4.0 microg/ml (range, 2.5-6.6) to 15.6 microg/ml (11.5-18.4 microg/ml; P = 0.018). Hypothermia reduced the biliary excretion rate of 3-desacetyl vecuronium from 18% (range, 6-37%) to 16% (range, 4-19%) of that of vecuronium (P = 0.018). Pharmacokinetic analysis confirmed that hypothermia reduced the rate constants of hepatic uptake and metabolism from 0.219 to 0.053 and from 0.059 to 0.030, respectively. CONCLUSIONS: Hypothermia significantly and reversibly reduced the net hepatic uptake of vecuronium. Hypothermia reduced the metabolism of vecuronium and the biliary excretion rate of 3-desacetyl vecuronium.
Animals↗
Predictability of processed electroencephalography effects on the basis of pharmacokinetic-pharmacodynamic modeling during repeated propofol infusions in patients with extradural analgesia.
BACKGROUND: Pharmacokinetic-pharmacodynamic (PKPD) modeling can be used to characterize the concentration-effect relation of drugs. If the concentration-effect relation of a hypnotic drug is stable over time, an effect parameter derived from the processed electroencephalographic signal may be used to control the infusion for hypnosis. Therefore, the stability of the propofol concentration-electroencephalographic effect relation over time was investigated under non-steady state conditions. METHODS: Three propofol infusions (25 mg x kg(-1) x h(-1) for 10 min, 22 mg x kg(-1) x h(-1) for 10 min, and 12.5 mg x kg(-1) x h(-1) for 20 min) were administered to 10 patients during extradural analgesia. Each successive infusion was started immediately after the patient had regained responsiveness after termination of the preceding infusion. Electroencephalography was recorded from bilateral prefrontal to mastoid leads. Electroencephalographic amplitude in the 11- to 15-Hz band and the Bispectral Index were used as electroencephalographic effect variables. PKPD parameters were calculated with use of parametric and nonparametric models based on electroencephalographic data and arterial propofol concentrations derived during the initial infusion, and these were used to predict electroencephalographic effect during the subsequent infusions. The predictability of the electroencephalographic effects was determined by the coefficient of determination (R2) and of the -2 log likelihood of the sequential infusions. RESULTS: The direction of electroencephalographic changes in response to the infusions was reproducible. Although PKPD parameters could be estimated well during the initial infusion (median [range] parametric R2 = 0.74 [0.56-0.95] for electroencephalographic amplitude and 0.90 [0.27-0.99] for Bispectral Index), none of the modeling techniques could predict accurately the electroencephalographic effect during subsequent infusions (R2 = 0.00 [-0.31-0.46] for electroencephalographic amplitude and 0.15 [-.46-0.57] for Bispectral Index; P < 0.01). CONCLUSIONS: The relation between blood propofol concentrations and the electroencephalographic effect under non-steady state conditions is not stable over time and is too complex to be modeled by any of the applied PKPD models.
Adult↗
A pharmacokinetic-dynamic explanation of the rapid onset-offset of rapacuronium.
The rapid onset and offset of rapacuronium can be explained from its pharmacokinetic and pharmacodynamic characteristics. A unique property of rapacuronium is its high value for ke0, indicating a rapid access to the receptor site. The reason for this high ke0 may be related to the low intrinsic potency of rapacuronium, but this is not yet fully clarified.
Humans↗
Clinical efficacy, safety and pharmacokinetics of a newly developed controlled release morphine sulphate suppository in patients with cancer pain.
OBJECTIVE: To compare the efficacy, safety and pharmacokinetics of a newly developed controlled-release suppository (MSR) with MS Contin tablets (MSC) in cancer patients with pain. METHODS: In a double-blind, randomised, two-way cross-over trial, 25 patients with cancer pain were selected with a morphine (M) demand of 30 mg every 12 h. Patients were divided into two groups. Group 1 received active MSC (30 mg) and placebo MSR, followed by placebo MSC and active MSR (30 mg) each for a period of 5 days. Group 2 started with active MSR and placebo MSC, followed by active MSC and placebo MSR, each for a period of 5 days. Blood for determination of plasma concentration of morphine (M) and its 3- and 6-glucuronides (M3G, M6G) was collected, and area under the plasma concentration-time curve (AUC)0-12 h, peak plasma concentration (Cmax), time to reach Cmax (tmax), and CO and C12 of M, M6G and M3G were determined on day 5 and day 10. Intensity of pain experienced by each patient was assessed every 2 h on a 0-10 scale, while side effects and rescue medication were recorded. RESULTS: Twenty patients (ten patients in each group) completed the study. A pronounced inter-patient variability in plasma concentrations of M, M3G and M6G was observed after administration of both forms. Apart from the C0 and C12, no significant differences in AUC0-12 h, tmax and Cmax of morphine between the rectal and oral route of administration were found. In the case of the metabolites, it was found that AUC0-12 h and Cmax of M6G, and AUC0-12 h, Cmax, C0 and C12 of M3G after rectal administration were significantly lower than after oral administration. However, apart from the tmax of M6G, none of the pharmacokinetic parameters of M, M6G or M3G met the criteria for bioequivalence. There were no significant (P = 0.44) differences in pain intensity score between the oral and rectal forms within the two groups, regardless of the treatment sequence. No treatment differences in nausea, sedation or the demand on escape medication (acetaminophen tablets) between the rectal and oral forms were observed. CONCLUSION: The newly developed controlled-release M suppository is safe and effective and may be a useful alternative for oral morphine administration in patients with cancer pain.
Adult↗
Pharmacokinetic studies of neuromuscular blocking agents: good clinical research practice (GCRP).
In September 1997, an international consensus conference on standardization of studies of neuromuscular blocking agents was held in Copenhagen, Denmark. Based on the conference, a set of guidelines for good clinical research practice (GCRP) in pharmacokinetic studies of neuromuscular blocking agents is presented. Guidelines include: design of the study; relevant patient groups to investigate; test drug administration, sampling and analysis; pharmacokinetic analysis; pharmacokinetic/pharmacodynamic modeling; population pharmacokinetics; statistics; and presentation of pharmacokinetic data. The guidelines are intended to aid those working in this research area; it is hoped that they will assist researchers, editors of scientific papers, and pharmaceutical companies in improving the quality of pharmacokinetic studies.
Body Temperature↗
Urinary, biliary and faecal excretion of rocuronium in humans.
The excretion of rocuronium and its potential metabolites was studied in 38 anaesthetized patients, ASA I-III and 21-69 yr old. Rocuronium bromide was administered as an i.v. bolus dose of 0.3 or 0.9 mg kg-1. In Part A of the study, the excretion into urine and bile, and the liver content were studied. Plasma kinetics (n = 19) were similar to those reported previously. Urinary recovery within 48 h after administration was 26 (8)% (mean (SD)) (n = 8) of the dose. In bile obtained from T-drains, the recovery within 48 h was 7 (6)% (n = 11). The rocuronium concentration in bile declined bi-exponentially, with half-lives of 2.3 (0.7) and 16 (11) h respectively (n = 6). In three patients from whom stoma fluid was collected, the amount of rocuronium recovered ranged from 0.04 to 12.0% of the dose. In liver tissue obtained from four patients undergoing hemihepatectomy, the estimated amount of rocuronium at 2-5 h after administration ranged between 6.3 and 13.2% (n = 4). In the second part of the study (Part B), urine and faeces were collected over 4-8 days and the recovery was 27 (13)% and 31 (23)% of the dose respectively (n = 10). In most samples, irrespective of the type of biological material, only small amounts of the metabolite 17-desacetyl-rocuronium was found. The results demonstrate that rocuronium is taken up by the liver and excreted into bile in high concentrations. The faecal and urinary excretion of unchanged rocuronium are the major routes of rocuronium elimination.
Adult↗
Structure-pharmacokinetics relationship of series of aminosteroidal neuromuscular blocking agents in the cat.
To obtain more insight in the relationship between physicochemical properties of neuromuscular blocking agents (NMBAs) and their pharmacokinetic characteristics, a series of 12 aminosteroidal NMBAs, supplemented with data on five related NMBAs from the literature, was investigated in anaesthetized cats. After i.v. bolus injection, plasma concentration decreased very rapidly, showing a biphasic pattern, with half-lives ranging from 0.4 to 1.4 min, and from 3 to 10 min, respectively. Clearance was in the range from 24 to 58 ml. min(-1). kg(-1). Compounds containing an acetyl-ester group at position 3 were partly metabolized to the 3-OH derivative. The urinary excretion of the parent drug and metabolites amounted to <10% for each of the compounds. The parent drugs were excreted in large amounts into bile, along with smaller amounts of 3-OH derivatives. The terminal half-life of the urinary and biliary excretion rate were markedly longer than the apparent terminal half-life in plasma, ranging from 11 to 40 min, and from 119 to 489 min in urine and bile, respectively. Lipophilicity of the NMBAs, expressed as the partition coefficient octanol/Krebs (log P), was found to be correlated positively with unbound plasma clearance and unbound initial plasma clearance, and negatively with plasma half-life, volume of distribution at steady state, and mean residence time. The increase of the unbound plasma clearance with increasing lipophilicity is counteracted by the concurrent increase in plasma protein binding.
Animals↗