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1.
J Clin Monit Comput ; 35(4): 815-825, 2021 08.
Article in English | MEDLINE | ID: mdl-32488680

ABSTRACT

This prospective study evaluates haemodynamic and electroencephalographic effects observed when administering four combinations of effect-site concentrations of propofol (CePROP) and remifentanil (CeREMI), all yielding a single predicted probability of tolerance of laryngoscopy of 90% (PTOL = 90%) according to the Bouillon interaction model. We aimed to identify combinations of CePROP and CeREMI along a single isobole of PTOL that result in favourable hypnotic and haemodynamic conditions. This knowledge could be of advantage in the development of drug advisory monitoring technology. 80 patients (18-90 years of age, ASA I-III) were randomized into four groups and titrated towards CePROP (Schnider model, ug⋅ml-1) and CeREMI (Minto model, ng⋅ml-1) of respectively 8.6 and 1, 5.9 and 2, 3.6 and 4 and 2.0 and 8. After eleven minutes of equilibration, baseline measurements of haemodynamic endpoints and bispectral index were compared with three minutes of responsiveness measurements after laryngoscopy. Before laryngoscopy, bispectral index differed significantly (p < 0.0001) between groups in concordance with CePROP. Heart rate decreased with increasing CeREMI (p = 0.001). The haemodynamic and arousal responses evoked by laryngoscopy were not significantly different between groups, but CePROP = 3.6 µg⋅ml-1 and CeREMI = 4 ng⋅ml-1 evoked the lowest median value for ∆HR and ∆SAP after laryngoscopy. This study provides clinical insight on the haemodynamic and hypnotic consequences, when a model based predicted PTOL is used as a target for combined effect-site controlled target- controlled infusion of propofol and remifentanil. Heart rate and bispectral index were significantly different between groups despite a theoretical equipotency for PTOL, suggesting that each component of the anaesthetic state (immobility, analgesia, and hypnotic drug effect) should be considered as independent neurophysiological and pharmacological phenomena. However, claims of (in)accuracy of the predicted PTOL must be considered preliminary because larger numbers of observations are required for that goal.


Subject(s)
Propofol , Anesthetics, Intravenous/pharmacology , Electroencephalography , Hemodynamics , Humans , Laryngoscopy , Piperidines/pharmacology , Propofol/pharmacology , Prospective Studies , Remifentanil/pharmacology
2.
Article in English | MEDLINE | ID: mdl-28137814

ABSTRACT

Ertapenem is a broad-spectrum carbapenem antibiotic whose activity against Mycobacterium tuberculosis is being explored. Carbapenems have antibacterial activity when the plasma concentration exceeds the MIC at least 40% of the time (40% TMIC). To assess the 40% TMIC in multidrug-resistant tuberculosis (MDR-TB) patients, a limited sampling strategy was developed using a population pharmacokinetic model based on data for healthy volunteers. A two-compartment population pharmacokinetic model was developed with data for 42 healthy volunteers using an iterative two-stage Bayesian method. External validation was performed by Bayesian fitting of the model developed with data for volunteers to the data for individual MDR-TB patients (in which the fitted values of the area under the concentration-time curve from 0 to 24 h [AUC0-24, fit values] were used) using the population model developed for volunteers as a prior. A Monte Carlo simulation (n = 1,000) was used to evaluate limited sampling strategies. Additionally, the 40% TMIC with the free fraction (f 40% TMIC) of ertapenem in MDR-TB patients was estimated with the population pharmacokinetic model. The population pharmacokinetic model that was developed was shown to overestimate the area under the concentration-time curve from 0 to 24 h (AUC0-24) in MDR-TB patients by 6.8% (range, -17.2 to 30.7%). The best-performing limited sampling strategy, which had a time restriction of 0 to 6 h, was found to be sampling at 1 and 5 h (r2 = 0.78, mean prediction error = -0.33%, root mean square error = 5.5%). Drug exposure was overestimated by a mean percentage of 4.2% (range, -15.2 to 23.6%). When a free fraction of 5% was considered and the MIC was set at 0.5 mg/liter, the minimum f 40% TMIC would have been exceeded in 9 out of 12 patients. A population pharmacokinetic model and limited sampling strategy, developed using data from healthy volunteers, were shown to be adequate to predict ertapenem exposure in MDR-TB patients.


Subject(s)
Antitubercular Agents/pharmacokinetics , Models, Statistical , Mycobacterium tuberculosis/drug effects , beta-Lactams/pharmacokinetics , Adolescent , Adult , Antitubercular Agents/blood , Area Under Curve , Bayes Theorem , Drug Administration Schedule , Drug Dosage Calculations , Ertapenem , Female , Healthy Volunteers , Humans , Male , Microbial Sensitivity Tests , Monte Carlo Method , Mycobacterium tuberculosis/growth & development , Tuberculosis, Multidrug-Resistant/drug therapy , Tuberculosis, Multidrug-Resistant/microbiology , beta-Lactams/blood
3.
Br J Anaesth ; 118(1): 44-57, 2017 Jan.
Article in English | MEDLINE | ID: mdl-28039241

ABSTRACT

This review describes the basics of pharmacokinetic and pharmacodynamic drug interactions and methodological points of particular interest when designing drug interaction studies. It also provides an overview of the available literature concerning interactions, with emphasis on graphic representation of interactions using isoboles and response surface models. It gives examples on how to transform this knowledge into clinically and educationally applicable (bedside) tools.


Subject(s)
Anesthetics/pharmacology , Anesthetics/pharmacokinetics , Anesthetics/administration & dosage , Drug Design , Drug Interactions , Humans
4.
Br J Clin Pharmacol ; 81(1): 101-12, 2016 Jan.
Article in English | MEDLINE | ID: mdl-27099877

ABSTRACT

AIMS: Intrathecal baclofen (ITB) has proven to be an effective and safe treatment for severe spasticity. However, although ITB is used extensively, clinical decisions are based on very scarce pharmacokinetic-pharmacodynamic (PKPD) data. The aim of this study was to measure baclofen CSF concentrations and clinical effects after administration of various ITB boluses in patients with spasticity and to create a PKPD model for ITB. METHODS: Twelve patients with severe spasticity received four different bolus doses of ITB (0, 25, 50, 75 µg and an optional dose of 100 µg), administered via a catheter with the tip at thoracic level (Th) 10. After each bolus, 10 CSF samples were taken at fixed time intervals, using a catheter with the tip located at Th12. Clinical effect was assessed by measuring spasticity with the Modified Ashworth Scale (MAS). These data were used to develop a PKPD model. RESULTS: All patients achieved an adequate spasmolytic effect with ITB doses varying from 50 to 100 µg. No serious side effects were observed. CSF baclofen concentrations, as well as the clinical effects, correlated significantly with ITB doses. The PK model predicted a steep spinal concentration gradient of ITB along the spinal axis. The clinical effect could be predicted using a delayed-effect model. CONCLUSIONS: ITB is an effective and safe therapy with, however, a steep concentration gradient along the spinal axis. This means that the administered baclofen is staying mainly around the catheter tip, which stresses the importance to position the ITB catheter tip closely to the targeted spinal level.


Subject(s)
Baclofen/pharmacokinetics , Muscle Relaxants, Central/pharmacokinetics , Muscle Spasticity/drug therapy , Adult , Baclofen/administration & dosage , Baclofen/pharmacology , Female , Humans , Injections, Spinal , Male , Middle Aged , Models, Biological
5.
Br J Anaesth ; 116(5): 624-31, 2016 May.
Article in English | MEDLINE | ID: mdl-27106965

ABSTRACT

BACKGROUND: The probability to tolerate laryngoscopy (PTOL) and its derivative, the noxious stimulation response index (NSRI), have been proposed as measures of potency of a propofol-remifentanil drug combination. This study aims at developing a triple drug interaction model to estimate the combined potency of sevoflurane, propofol, and remifentanil in terms of PTOL. We compare the predictive performance of PTOL and the NSRI with various anaesthetic depth monitors. METHODS: Data from three previous studies (n=120) were pooled and reanalysed. Movement response after laryngoscopy was observed with different combinations of propofol-remifentanil, sevoflurane-propofol, and sevoflurane-remifentanil. A triple interaction model to estimate PTOL was developed. The NSRI was derived from PTOL. The ability of PTOL and the NSRI to predict observed tolerance of laryngoscopy (TOL) was compared with the following other measures: (i) effect-site concentrations of sevoflurane, propofol, and remifentanil (CeSEVO, CePROP, and CeREMI); (ii) bispectral index; (iii) two measures of spectral entropy; (iv) composite variability index; and (v) surgical pleth index. RESULTS: Sevoflurane and propofol interact additively, whereas remifentanil interacts in a strongly synergistic manner. The effect-site concentrations of sevoflurane and propofol at a PTOL of 50% (Ce50; se) were 2.59 (0.13) vol % and 7.58 (0.49) µg ml(-1). A CeREMI of 1.36 (0.15) ng ml(-1) reduced the Ce50 of sevoflurane and propofol by 50%. The common slope factor was 5.22 (0.52). The PTOL and NSRI predict the movement response to laryngoscopy best. CONCLUSIONS: The triple interaction model estimates the potency of any combination of sevoflurane, propofol, and remifentanil expressed as either PTOL or NSRI.


Subject(s)
Anesthetics, Combined/pharmacology , Laryngoscopy , Adolescent , Adult , Anesthetics, Combined/administration & dosage , Anesthetics, Inhalation/administration & dosage , Anesthetics, Inhalation/pharmacology , Anesthetics, Intravenous/administration & dosage , Anesthetics, Intravenous/pharmacology , Drug Administration Schedule , Drug Interactions , Drug Monitoring/methods , Drug Synergism , Electroencephalography/drug effects , Female , Humans , Male , Methyl Ethers/administration & dosage , Methyl Ethers/pharmacology , Middle Aged , Models, Biological , Movement/drug effects , Piperidines/administration & dosage , Piperidines/pharmacology , Propofol/administration & dosage , Propofol/pharmacology , Remifentanil , Sevoflurane , Young Adult
6.
Ann Oncol ; 26(11): 2305-10, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26347114

ABSTRACT

BACKGROUND: The success of cisplatin-based (Platinol, Bristol-Myers Squibb Company, New York, NY, USA) chemotherapy for testicular cancer comes at the price of long-term and late effects related to healthy tissue damage. We assessed and modelled serum platinum (Pt) decay after chemotherapy and determined relationships between long-term circulating Pt levels and known late effects. PATIENTS AND METHODS: In 99 testicular cancer survivors, treated with cisplatin-based chemotherapy, serum and 24-h urine samples were collected during follow-up (1-13 years after treatment). To build a population pharmacokinetic model, measured Pt data were simultaneously analysed, together with cisplatin dose, age, weight and height using the NONMEM software. Based on this model, area under the curve between 1 and 3 years after treatment (Pt AUC1-3 years) was calculated for each patient. Predicted long-term Pt exposure was related to renal function and to late effects of treatment assessed median 9 (3-15) years after chemotherapy. RESULTS: Decay of Pt was best described by a two-compartment model. Mean terminal T1/2 was 3.7 (range 2.5-5.2) years. Pt AUC1-3 years correlated with cumulative cisplatin dose, and creatinine clearance before and 1 year after treatment. Patients with paraesthesia had higher Pt AUC1-3 years (30.9 versus 27.0 µg/l month) compared with those without paraesthesia (P = 0.021). Patients with hypogonadism, elevated LDL-cholesterol levels or hypertension also had higher Pt AUC1-3 years. CONCLUSIONS: Renal function before and after cisplatin treatment is an important determinant of long-term Pt exposure. Known long-term effects of testicular cancer treatment, such as paraesthesia, hypogonadism, hypercholesterolaemia and hypertension, are associated with long-term circulating Pt exposure.


Subject(s)
Cisplatin/therapeutic use , Platinum/blood , Testicular Neoplasms/blood , Testicular Neoplasms/drug therapy , Adult , Cisplatin/adverse effects , Follow-Up Studies , Humans , Hypercholesterolemia/blood , Hypercholesterolemia/congenital , Hypercholesterolemia/diagnosis , Hypertension/blood , Hypertension/chemically induced , Hypertension/diagnosis , Male , Middle Aged , Testicular Neoplasms/diagnosis , Treatment Outcome , Young Adult
7.
Eur J Clin Pharmacol ; 71(12): 1493-500, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26416100

ABSTRACT

PURPOSE: Clomipramine is one of the drugs for depression during pregnancy; however, pharmacokinetic data of clomipramine and its active metabolite desmethylclomipramine in this vulnerable period are lacking. In this study, we describe clomipramine and desmethylclomipramine concentrations including their ratios during pregnancy. Second, we describe Center for Epidemiologic Studies Depression scale (CES-D) scores during pregnancy. METHODS: During 13 pregnancies, every trimester and 3 months after pregnancy, the clomipramine and desmethylclomipramine concentrations were measured with LC-MSMS and the severity of depression was assessed by taking the CES-D score. All concentrations used in our calculations were in fact the ratio between actual plasma concentration (µg/l) and the actual dose (mg). We compared differences in ratios between trimesters by using the Friedman test. RESULTS: Studying 12 women and 13 pregnancies, we found no changes in mean clomipramine concentrations, a statistically significant decrease in mean desmethylclomipramine concentrations (p = 0.014) and a significant decrease in the ratio of desmethylclomipramine/clomipramine mean concentrations during pregnancy (p = 0.014) compared to the post-partum period. Sub-therapeutic concentrations of clomipramine and desmethylclomipramine were found in three patients during whole pregnancy. CONCLUSIONS: The mean concentrations of the pharmacologically active metabolite of clomipramine and desmethylclomipramine changes during pregnancy, where a decrease in mean concentrations was found during pregnancy. In case of recurrent disease, we recommend to control clomipramine and its metabolite concentrations, while both are active.


Subject(s)
Antidepressive Agents, Tricyclic/pharmacokinetics , Clomipramine/analogs & derivatives , Depression/drug therapy , Pregnancy Complications/drug therapy , Adult , Antidepressive Agents, Tricyclic/therapeutic use , Chromatography, Liquid/methods , Clomipramine/pharmacokinetics , Clomipramine/therapeutic use , Depression/complications , Depression/physiopathology , Female , Humans , Pregnancy , Pregnancy Complications/physiopathology , Psychiatric Status Rating Scales , Severity of Illness Index , Tandem Mass Spectrometry/methods
8.
Int J Antimicrob Agents ; 46(3): 332-7, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26228464

ABSTRACT

Amikacin and kanamycin are considered important and effective drugs in the treatment of multidrug-resistant tuberculosis (MDR-TB). Unfortunately, the incidence of toxicity is high and is related to elevated drug exposure. In order to achieve a balance between efficacy and toxicity, a population pharmacokinetic (PPK) model may help to optimise drug exposure. Patients with MDR-TB who had received amikacin or kanamycin as part of their treatment and who had routinely received therapeutic drug monitoring were evaluated. A PPK model was developed and subsequently validated. Using this model, a limited sampling model was developed. Eleven patients receiving amikacin and nine patients receiving kanamycin were included in this study. The median observed 24-h area under the concentration-time curve (AUC0-24h) was 77.2 mg h/L [interquartile range (IQR) 64.7-96.2 mg h/L] for amikacin and 64.1 mg h/L (IQR 55.6-92.1 mg h/L) for kanamycin. The PPK model was developed and validated using n-1 cross-validation. A robust population model was developed that is suitable for predicting the AUC0-24h of amikacin and kanamycin. This model, in combination with the limited sampling strategy developed, can be used in daily routine to guide dosing but also to assess AUC0-24h in phase 3 studies.


Subject(s)
Amikacin/therapeutic use , Antitubercular Agents/therapeutic use , Drug Monitoring/methods , Kanamycin/therapeutic use , Specimen Handling/methods , Tuberculosis, Multidrug-Resistant/drug therapy , Adult , Amikacin/pharmacokinetics , Antitubercular Agents/pharmacokinetics , Biostatistics , Female , Humans , Kanamycin/pharmacokinetics , Male , Models, Statistical , Retrospective Studies , Young Adult
9.
Article in English | MEDLINE | ID: mdl-23835881

ABSTRACT

A major problem in the treatment of schizophrenic patients with current antipsychotic drugs, mainly acting as dopamine-2 receptor antagonists, is the occurrence of side effects such as extrapyramidal symptoms (EPS). Meta-analyses of summary data of EPS occurrence, and receptor occupancies inferred from mean plasma concentrations, have shown the incidence of EPS to rise when receptor occupancy is above ~80%. In this analysis, individual longitudinal EPS data from 2,630 patients participating in one of seven different trials and treated with haloperidol, paliperidone, ziprasidone, olanzapine, JNJ-37822681, or placebo were analyzed using a continuous time probability model with Markov elements. The developed pharmacokinetic-pharmacodynamic model describes the longitudinal changes of spontaneously reported EPS-related adverse events and their severity levels rated by clinicians. Individual steady-state concentrations and occupancy levels were found to be predictors for EPS. The results confirm 80% occupancy as a level of increased EPS occurrence rates, also at the individual level.CPT: Pharmacometrics & Systems Pharmacology (2012) 1, e1; doi:10.1038/psp.2012.9; advance online publication 26 September 2012.

10.
Eur J Anaesthesiol ; 25(7): 572-80, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18400136

ABSTRACT

BACKGROUND AND OBJECTIVES: For neuromuscular blocking agents, an inverse relationship between potency and time to peak effect has been observed. To test the hypothesis that this relationship is due to buffered diffusion, we investigated the influence of dose on time to peak effect. Pharmacokinetic-pharmacodynamic simulations were performed to support the expected relationships between potency, dose, peak effect and time to peak effect. METHODS: Pigs (20-28 kg body weight) were anaesthetized with ketamine and midazolam, followed by pentobarbital and fentanyl intravenously. Neuromuscular block was measured by stimulating the peroneal nerve supramaximally at 0.1 Hz and measuring the response of the tibialis anterior muscle mechanomyographically. After an initial dose to establish the individual ED90 of a neuromuscular blocking agent (rocuronium, vecuronium, pipecuronium or d-tubocurarine), five different doses of the same compound were administered to each animal, aiming at 20%, 40%, 60%, 75% or 90% block, in a random order. Doses were given 45 min after complete recovery of the twitch response. RESULTS: For rocuronium and pipecuronium, time to peak effect increased with dose, whereas dose did not affect time to peak effect of vecuronium and d-tubocurarine. Simulations predict that time to peak effect decreases with dose if buffered diffusion is taken into account. CONCLUSIONS: The results suggest that buffered diffusion does not play a dominant role in the time to peak effect of neuromuscular blocking agents. Therefore it is unlikely that the observed inverse relationship between potency and time to peak effect of neuromuscular blocking agents in the clinical range is due to buffered diffusion.


Subject(s)
Neuromuscular Blocking Agents/administration & dosage , Animals , Buffers , Diffusion/drug effects , Dose-Response Relationship, Drug , Male , Swine , Time Factors
12.
Int J Clin Pharmacol Ther ; 45(7): 402-9, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17725247

ABSTRACT

OBJECTIVE: Limited sampling models (LSM) for estimating AUC in therapeutic drug monitoring are usually validated in a separate group of patients, according to published guidelines. The aim of this study is to evaluate the validation of LSM by comparing independent validation with cross-validation using the patient data from the development group. METHODS: The design of the Monte Carlo simulation study was similar to a study described in the literature, i.e. a development group of 20 patients receiving cyclosporine orally every 12 h. Blood samples were taken at 10 fixed time points. In total 20,000 patient data sets were generated by Monte Carlo simulation, taking into account interindividual variability and measurement errors. Accuracy (mean error, ME) and precision (root mean squared error, RMSE) were calculated for evaluation of the validation procedures, varying the time points of the samples used for the estimation of AUC to identify the optimal sampling time points. In addition, the influence of the number of samples and the number of subjects was investigated. RESULTS: Cross-validation resulted in values for ME and RMSE almost identical to values using a separate validation group with the same number of subjects as the development group. CONCLUSION: A separate validation group is not needed. The most efficient method is to use all patient data for the development of the LSM, and to assess the accuracy and precision by cross-validation.


Subject(s)
Area Under Curve , Models, Biological , Research Design , Computer Simulation , Cyclosporine/pharmacokinetics , Drug Monitoring , Humans , Immunosuppressive Agents/pharmacokinetics , Monte Carlo Method , Reproducibility of Results
14.
Eur J Anaesthesiol ; 22(8): 591-6, 2005 Aug.
Article in English | MEDLINE | ID: mdl-16119595

ABSTRACT

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.


Subject(s)
Myasthenia Gravis, Autoimmune, Experimental/metabolism , Neuromuscular Nondepolarizing Agents/pharmacology , Neuromuscular Nondepolarizing Agents/pharmacokinetics , Receptors, Cholinergic/metabolism , Androstanols/pharmacokinetics , Androstanols/pharmacology , Animals , Antibodies, Blocking/pharmacology , Bungarotoxins/pharmacology , Immunization, Passive , In Vitro Techniques , Male , Muscle Contraction/drug effects , Muscle Relaxation/drug effects , Muscle, Skeletal/drug effects , Pancuronium/pharmacokinetics , Pancuronium/pharmacology , Rats , Rats, Wistar , Receptors, Cholinergic/drug effects , Rocuronium
16.
Eur J Clin Pharmacol ; 60(10): 693-701, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15619132

ABSTRACT

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.


Subject(s)
Anti-Arrhythmia Agents/therapeutic use , Atrial Fibrillation/drug therapy , Flecainide/therapeutic use , Administration, Oral , Anti-Arrhythmia Agents/pharmacokinetics , Anti-Arrhythmia Agents/pharmacology , Anti-Ulcer Agents/administration & dosage , Anti-Ulcer Agents/pharmacology , Area Under Curve , Chemistry, Pharmaceutical , Cisapride/administration & dosage , Cisapride/pharmacology , Drug Combinations , Electrocardiography , Female , Flecainide/pharmacokinetics , Flecainide/pharmacology , Humans , Intestinal Absorption , Male , Middle Aged , Tablets
17.
Crit Rev Oncol Hematol ; 52(3): 173-97, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15582785

ABSTRACT

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.


Subject(s)
Antineoplastic Agents/pharmacokinetics , Neoplasms/metabolism , Antineoplastic Agents/administration & dosage , Child , Dose-Response Relationship, Drug , Humans , Metabolic Clearance Rate , Neoplasms/pathology , Therapeutic Equivalency
18.
Xenobiotica ; 34(3): 229-41, 2004 Mar.
Article in English | MEDLINE | ID: mdl-15204696

ABSTRACT

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.


Subject(s)
Coumarins/metabolism , Coumarins/pharmacokinetics , Pharmaceutical Preparations/metabolism , Umbelliferones/metabolism , Umbelliferones/pharmacokinetics , Animals , Biotransformation , Colon/metabolism , In Vitro Techniques , Intestine, Small/metabolism , Kidney/metabolism , Liver/metabolism , Lung/metabolism , Male , Microtomy , Organ Specificity , Predictive Value of Tests , Rats , Rats, Wistar
19.
Br J Anaesth ; 92(3): 373-80, 2004 Mar.
Article in English | MEDLINE | ID: mdl-14742345

ABSTRACT

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.


Subject(s)
Evoked Potentials, Motor/drug effects , Models, Biological , Monitoring, Intraoperative/methods , Neuromuscular Blockade , Neuromuscular Junction/drug effects , Electric Stimulation , Evoked Potentials, Motor/physiology , Humans , Muscle, Skeletal/drug effects , Muscle, Skeletal/physiology , Myosin Light Chains/metabolism , Neuromuscular Blocking Agents/pharmacology , Neuromuscular Junction/physiology , Phosphorylation/drug effects
20.
Eur J Anaesthesiol ; 21(11): 882-91, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15717705

ABSTRACT

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.


Subject(s)
Body Fluid Compartments/physiology , Extracellular Space/physiology , Isoquinolines/pharmacology , Isoquinolines/pharmacokinetics , Neuromuscular Nondepolarizing Agents/pharmacology , Neuromuscular Nondepolarizing Agents/pharmacokinetics , Adult , Chromatography, High Pressure Liquid/methods , Female , Humans , Isoquinolines/blood , Male , Middle Aged , Mivacurium , Models, Biological , Neuromuscular Nondepolarizing Agents/blood , Time Factors
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