Population Pharmacokinetics of Piritramide in Surgical Patients 

1999 ◽  
Vol 90 (1) ◽  
pp. 7-15 ◽  
Author(s):  
Thomas Bouillon ◽  
Daniela Kietzmann ◽  
Rudiger Port ◽  
Ingolf Meineke ◽  
Andreas Hoeft
Keyword(s):  
Population Pharmacokinetics ◽  
Venous Blood ◽  
Compartment Model ◽  
Mixed Effects ◽  
Pharmacokinetic Parameters ◽  
Effect Compartment ◽  
Bolus Administration ◽  
Time Data ◽  
Intermittent Bolus ◽  
Patient Consent

Background Piritramide is a synthetic opioid used for postoperative analgesia in several European countries. The authors present a mixed-effects model of its population pharmacokinetics in patients undergoing surgery. Methods After institutional approval and informed patient consent was obtained, 29 patients who were classified as American Society of Anesthesiologists physical status I or II and aged 21-82 yr were enrolled in the study. They received 0.2 mg/kg piritramide as an intravenous bolus before anesthesia was induced. Central venous blood samples were drawn for as long as 48 h after administration of the drug. The plasma concentration of piritramide was determined by gas chromatography. The concentration-time data were analyzed by mixed-effects modeling. Target-controlled infusions and intermittent bolus regimens were simulated to identify a regimen suitable for patient-controlled analgesia based on population pharmacokinetics and published pharmacodynamic data. Results The pharmacokinetics of piritramide were described adequately by a linear three-compartment model. Patient age and weight were significant covariates. The values of the pharmacokinetic parameters are: V1 = 50.5 [1], V2 = 150 x (1 + 9.32 x 10(-3) x (age - 47 yr)) [l], V3 = 212 x (1 + 6.37 x 10(-3) x (age - 47 yr)) [l], Cl1 = 0.56 x (1 - 6.14 x 10(-3) x (age - 47 yr)) [l/min], Cl2 = 8.25 x (1 + 2.02 x 10(-2) x (Wt - 74 kg)) [l/min], Cl3 = 0.80 [l/min]. The age of 47 yr and the weight of 74 kg refer to the median values for these factors in the patients studied. Rapid distribution, slow distribution, and elimination half-lives for the median patient are 0.05, 1.34, and 10.43 h, respectively. The context-sensitive half-time after a 24-h infusion is predicted at 10.5 h in a 75-yr-old patient compared with 7 h for the median patient. Conclusions Piritramide is distributed extensively and eliminated slowly. The pharmacokinetic profile of the drug allows for intermittent bolus administration even when constant effect compartment concentrations are desirable, e.g., for PLA.

Mixed-effects Modeling of the Influence of Alfentanil on Propofol Pharmacokinetics

2004 ◽  
Vol 100 (4) ◽  
pp. 795-805 ◽  
Author(s):  
Martijn J. Mertens ◽  
Erik Olofsen ◽  
Anton G. L. Burm ◽  
James G. Bovill ◽  
Jaap Vuyk
Keyword(s):  
Heart Rate ◽  
Cardiac Output ◽  
Venous Blood ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Mixed Effects ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Elimination Clearance ◽  
End Tidal

Background The influence of alfentanil on the pharmacokinetics of propofol is poorly understood. Therefore, the authors studied the effect of a pseudo-steady state concentration of alfentanil on the pharmacokinetics of propofol. Methods The pharmacokinetics of propofol were studied on two occasions in eight male volunteers in a randomized crossover manner with a 3-week interval. While volunteers breathed 30% O2 in air, 1 mg/kg intravenous propofol was given in 1 min, followed by 3 mg.kg(-1).h(-1) for 59 min (sessions A and B). During session B, a target-controlled infusion of alfentanil (target concentration, 80 ng/ml) was given from 10 min before the start until 6 h after termination of the propofol infusion. Blood pressure, cardiac output, electrocardiogram, respiratory rate, oxygen saturation, and end-tidal carbon dioxide were monitored. Venous blood samples for determination of the blood propofol and plasma alfentanil concentration were collected until 6 h after termination of the propofol infusion. Nonlinear mixed-effects population pharmacokinetic models examining the influence of alfentanil and hemodynamic parameters on propofol pharmacokinetics were constructed. Results A two-compartment model, including a lag time accounting for the venous blood sampling, adequately described the concentration-time curves of propofol. Alfentanil decreased the elimination clearance of propofol from 2.1 l/min to 1.9 l/min, the distribution clearance from 2.7 l/min to 2.0 l/min, and the peripheral volume of distribution from 179 l to 141 l. Scaling the pharmacokinetic parameters to cardiac output, heart rate, and plasma alfentanil concentration significantly improved the model. Conclusions Alfentanil alters the pharmacokinetics of propofol. Cardiac output and heart rate have an important influence on the pharmacokinetics of propofol.

scholarly journals The Population Pharmacokinetics of Rifampicin in Japanese Pulmonary Tuberculosis Patients

Drug Research ◽  
2020 ◽  
Vol 70 (05) ◽  
pp. 199-205
Author(s):  
Takahiro Nishimura ◽  
Haruichi Kohno ◽  
Hideaki Nagai ◽  
Daisuke Maruoka ◽  
Yuichi Koike ◽  
...  
Keyword(s):  
Population Pharmacokinetics ◽  
Japanese Patients ◽  
Morbidity Rate ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
High Morbidity ◽  
Power Model ◽  
Time Data ◽  
Nonlinear Mixed Effects Model ◽  
High Morbidity Rate

AbstractIn Japan, tuberculosis has been recognized as one of the major infections requiring urgent measures because of its high morbidity rate even now especially in elderly people suffering from tuberculosis during the past epidemic and its reactivation. Hence, many Japanese clinicians have made efforts to suppress the onset of tuberculosis and treat it effectively. The objectives of this study are to (1) identify covariate(s) that may explain the variation of rifampicin, which is the key antitubercular agent, under the steady-state by evaluating its population pharmacokinetics and (2) to propose an appropriate dosing method of rifampicin to Japanese patients. For this purpose, serum concentration–time data were obtained from 138 patients receiving rifampicin (300–450 mg) and isoniazid (300–400 mg) every day over 14 days, and analyzed using nonlinear mixed effects model. Thereby, population pharmacokinetic parameters were estimated followed by elucidating relations between the parameters and statistical factors. The analysis adopted one-compartment model including Lag-time by assuming that the absorption process is 0+1st order. The analyses demonstrate that meal affected the bioavailability, primary absorption rate constant, and zero order absorption time in the constructed model. A body weight calculated from the power model was selected as the covariate by the Stepwise Covariate Model method and found to highly affect the clearance in the range from −31.6% to 47.4%. We conclude that the dose in Japanese tuberculous patients can be well estimated by the power model formula and should be taken into consideration when rifampicin is administered.

Zalcitabine Population Pharmacokinetics: Application of Radioimmunoassay

1998 ◽  
Vol 42 (2) ◽  
pp. 409-413 ◽  
Author(s):  
John M. Adams ◽  
Mark J. Shelton ◽  
Ross G. Hewitt ◽  
Mary DeRemer ◽  
Robin DiFrancesco ◽  
...  
Keyword(s):  
Population Pharmacokinetics ◽  
Information Age ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Oral Clearance ◽  
Standard Curve ◽  
Immunodeficiency Virus ◽  
Traditional Approaches

ABSTRACT Zalcitabine population pharmacokinetics were evaluated in 44 human immunodeficiency virus-infected patients (39 males and 5 females) in our immunodeficiency clinic. Eighty-one blood samples were collected during routine clinic visits for the measurement of plasma zalcitabine concentrations by radioimmunoassay (1.84 ± 1.24 samples/patient; range, 1 to 6 samples/patient). These data, along with dosing information, age (38.6 ± 7.13 years), sex, weight (79.1 ± 15.0 kg), and estimated creatinine clearance (89.1 ± 21.5 ml/min), were entered into NONMEM to obtain population estimates for zalcitabine pharmacokinetic parameters (4). The standard curve of the radioimmunoassay ranged from 0.5 to 50.0 ng/ml. The observed concentrations of zalcitabine in plasma ranged from 2.01 to 8.57 ng/ml following the administration of doses of either 0.375 or 0.75 mg. A one-compartment model best fit the data. The addition of patient covariates did not improve the basic fit of the model to the data. Oral clearance was determined to be 14.8 liters/h (0.19 liter/h/kg; coefficient of variation [CV] = 23.8%), while the volume of distribution was estimated to be 87.6 liters (1.18 liters/kg; CV = 54.0%). We were also able to obtain individual estimates of oral clearance (range, 8.05 to 19.8 liters/h; 0.11 to 0.30 liter/h/kg) and volume of distribution (range, 49.2 to 161 liters; 0.43 to 1.92 liters/kg) of zalcitabine in these patients with the POSTHOC option in NONMEM. Our value for oral clearance agrees well with other estimates of oral clearance from traditional pharmacokinetic studies of zalcitabine and suggests that population methods may be a reasonable alternative to these traditional approaches for obtaining information on the disposition of zalcitabine.

scholarly journals Population Pharmacokinetics of Rifapentine and Its Primary Desacetyl Metabolite in South African Tuberculosis Patients

2005 ◽  
Vol 49 (11) ◽  
pp. 4429-4436 ◽  
Author(s):  
Grant Langdon ◽  
Justin Wilkins ◽  
Lynn McFadyen ◽  
Helen McIlleron ◽  
Peter Smith ◽  
...  
Keyword(s):  
Population Pharmacokinetics ◽  
South African ◽  
Parent Drug ◽  
Tuberculosis Patient ◽  
Pharmacokinetic Parameters ◽  
Oral Clearance ◽  
Time Data ◽  
Primary Metabolite ◽  
Mixed Effect ◽  
Tuberculosis Patients

ABSTRACT This study was designed to describe the population pharmacokinetics of rifapentine (RFP) and 25-desacetyl RFP in a South African pulmonary tuberculosis patient population. Special reference was made to studying the influence of previous exposure to rifampin (RIF) and the variability in pharmacokinetic parameters between patients and between occasions and the influence of different covariates. Patients were included in the study if they had been receiving first-line antimycobacterial therapy (rifampin, isoniazid, pyrazinamide, and ethambutol) for not less than 4 weeks and not more than 6 weeks and were divided into three RFP dosage groups based on weight: 600 mg, <45 kg; 750 mg, 46 to 55 kg; and 900 mg, >55 kg. Participants received a single oral dose of RFP together with concomitant antimycobacterial agents, excluding RIF, on study days 1 and 5 after they ingested a soup-based meal. The RFP and 25-desacetyl RFP concentration-time data were analyzed by nonlinear mixed-effect modeling using NONMEM. The pharmacokinetics of the parent drug were modeled separately, and the individual pharmacokinetic parameters were used as inputs for the 25-desacetyl RFP pharmacokinetic model. A one-compartment disposition model was found to best describe the data for both the parent and the metabolite, and the metabolite was assumed to be formed only from the central compartment of the parent drug. Prior treatment with RIF did not alter the pharmacokinetics of RFP but appeared to increase the excretion of 25-desacetyl RFP in a nonlinear fashion. The RFP oral clearance and volume of distribution were found to increase by 0.049 liter/h and 0.691 liter, respectively, with a 1-kg increase from the median weight of 50 kg. The oral clearance of 25-desacetyl RFP was found to be 35% lower in female patients. The model developed here describes the population pharmacokinetics of RFP and its primary metabolite in tuberculosis patients and includes the effects of prior administration with RIF and covariate factors.

scholarly journals Population Pharmacokinetics of Arbekacin in Patients Infected with Methicillin-Resistant Staphylococcus aureus

2006 ◽  
Vol 50 (11) ◽  
pp. 3754-3762 ◽  
Author(s):  
Yusuke Tanigawara ◽  
Reiko Sato ◽  
Kunihiko Morita ◽  
Mitsuo Kaku ◽  
Naoki Aikawa ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Population Pharmacokinetics ◽  
Elderly Subjects ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Time Data ◽  
Mixed Effect ◽  
Methicillin Resistant

ABSTRACT Arbekacin, a derivative of dibekacin, is an aminoglycoside developed and widely used in Japan for the treatment of patients infected with methicillin-resistant Staphylococcus aureus (MRSA). The population pharmacokinetics of arbekacin was investigated in the Japanese, using 353 patients infected with MRSA and 50 healthy or renally impaired volunteers. The age of the study population ranged from 8 to 95 years, and weight ranged from 10.8 to 107 kg. In total, 1,581 serum arbekacin concentrations were measured (primarily from routine patient care) and used to perform the present pharmacokinetic analysis. Drug concentration-time data were well described by a two-compartment open model. Factors influencing arbekacin pharmacokinetics were investigated using a nonlinear mixed-effect model analysis. The best-developed model showed that drug clearance (CL) was related to creatinine clearance (CLCR), age, and body weight (WT), as expressed by CL (liter/h) = 0.0319CLCR + (26.5/age) (CLCR < 80 ml/min) and CL (liter/h) = 0.0130 CLCR + 0.0342WT + (26.5/age) (CLCR ≥ 80 ml/min). The volume of distribution for the central and peripheral compartments was different in healthy subjects and infected patients, and this difference was more pronounced among disease types. The elderly subjects (aged 80 years or over) exhibited, on average, a 19% greater volume for the central compartment. The volumes for the peripheral compartment were 50.6 liters in patients with pneumonia and 24.3 liters in patients with sepsis. The population pharmacokinetic parameters of arbekacin obtained here are useful for optimal use of this aminoglycoside in the treatment of MRSA-infected patients.

Propofol Alters the Pharmacokinetics of Alfentanil in Healthy Male Volunteers

2001 ◽  
Vol 94 (6) ◽  
pp. 949-957 ◽  
Author(s):  
Martijn J. Mertens ◽  
Jaap Vuyk ◽  
Erik Olofsen ◽  
James G. Bovill ◽  
Anton G. L. Burm
Keyword(s):  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Venous Blood ◽  
Compartment Model ◽  
Lag Time ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Male Volunteers ◽  
Elimination Clearance ◽  
End Tidal

Background The influence of propofol on the pharmacokinetics of alfentanil is poorly understood. The authors therefore studied the effect of a pseudo-steady state concentration of propofol on the pharmacokinetics of alfentanil. Methods The pharmacokinetics of alfentanil was studied on two occasions in eight male volunteers in a randomized crossover manner with a 3-week interval. While breathing 30% O2 in air, 12.5 microg/kg intravenous alfentanil was given in 2 min, followed by 25 microg.kg(-1).h(-1) for 58 min (sessions A and B). During session B, a target controlled infusion of propofol (target concentration, 1.5 microg/ml) was given from 10 min before the start until 6 h after termination of the alfentanil infusion. Blood pressure, cardiac output, electrocardiogram, respiratory rate, oxygen saturation, and end-tidal carbon dioxide were monitored. Venous blood samples for determination of the plasma alfentanil concentration were collected until 6 h after termination of the alfentanil infusion. Nonlinear mixed-effects population pharmacokinetic models examining the influence of propofol and mean arterial pressure were constructed. Results A three-compartment model, including a lag time accounting for the venous blood sampling, adequately described the concentration-time curves of alfentanil Propofol decreased the elimination clearance of alfentanil by 15%, rapid distribution clearance by 68%, slow distribution clearance by 51%, and lag time by 62%. Mean arterial pressure and systemic vascular resistance were significantly lower in the presence of propofol. Scaling the pharmacokinetic parameters to the mean arterial pressure instead of propofol improved the model. Conclusions Propofol alters the pharmacokinetics of alfentanil. Hemodynamic changes induced by propofol may have an important influence on the pharmacokinetics of alfentanil.

Fentanyl Pharmacokinetics in Hemorrhagic Shock 

1999 ◽  
Vol 91 (1) ◽  
pp. 156-166 ◽  
Author(s):  
Talmage D. Egan ◽  
Suma Kuramkote ◽  
Guoqing Gong ◽  
Jie Zhang ◽  
Scott W. McJames ◽  
...  
Keyword(s):  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Hemorrhagic Shock ◽  
Population Model ◽  
Compartment Model ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Time Data ◽  
Arterial Blood ◽  
Final Population

Background It is common clinical practice to administer reduced doses of opioid to patients suffering from hemorrhagic shock to minimize adverse hemodynamic consequences and to prevent prolonged opioid effect However, the scientific foundation supporting this practice is not well established. The aim of this study was to test the hypothesis that hemorrhagic shock alters both the distribution and clearance of opioids using fentanyl in a porcine isobaric hemorrhage model. Methods Eighteen pigs were randomized to shock or control groups. The animals in the shock group were subjected to hemorrhage using an isobaric method. Pigs in both groups received fentanyl (50 microg/kg) intravenously over 5 min. Frequent arterial blood samples were obtained for radioimmunoassay. Each animal's pharmacokinetic parameters were estimated by fitting a three-compartment model to the concentration versus time data Nonlinear mixed-effects population pharmacokinetic models examining the influence of mean arterial pressure and cardiac index were also constructed. Clinical simulations using the final population model were performed. Results The shock cohort reached substantially higher fentanyl concentrations. The shock group's central clearance and central- and second-compartment distribution volumes were significantly reduced. The most useful population model scaled all pharmacokinetic parameters to mean arterial pressure. The simulations illustrated that hemorrhagic shock results in higher fentanyl concentrations for any given dosage scheme. Conclusion The essential finding of the study is that fentanyl pharmacokinetics are substantially altered by hemorrhagic shock. The reduced opioid requirement commonly observed during hemorrhagic shock is at least partially attributable to pharmacokinetic mechanisms.

scholarly journals Determination of Pharmacokinetic Parameters by the Application of Noncompartmental Analysis

2017 ◽  
Vol II (I) ◽  
pp. 42-47
Author(s):  
Sidra Altaf ◽  
Asma Kaleem ◽  
Syeda Komal Fatima ◽  
Ayesha Sabir ◽  
Imran Khan
Keyword(s):  
Drug Exposure ◽  
Compartment Model ◽  
The Body ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Noncompartmental Analysis ◽  
Time Data ◽  
Moment Theory ◽  
Concentration Time

Pharmacokinetic models utilize mathematical terms to do pharmacokinetic analysis. Pharmacokinetic analysis of drug is defined as an experimental method to find drug exposure once administered or how does drug behave inside the body. Pharmacokinetic parameters determined include drug absorption, distribution, metabolism and elimination after its administration. These two types of models are used compartment and non -compartment models. A compartment is defined as space inside the body that a drug occupies upon its administration. When there is linear kinetics, it is desirable to use a simple non-compartment model with lesser assumptions, while when a compound follows non-linear kinetic, it is preferred to use a compartment model. Noncompartment model utilizes concentration-time data to predict C max, t max, AUC and AUMC for the administered compound. AUC and AUMC can be calculated using the trapezoidal rule. Pharmacokinetic parameters can also be predicted using statistical moment theory.

scholarly journals Population Pharmacokinetics of Pyrimethamine and Sulfadoxine in Children Treated for Congenital Toxoplasmosis

2004 ◽  
Vol 48 (10) ◽  
pp. 3794-3800 ◽  
Author(s):  
Stéphane Corvaisier ◽  
Bruno Charpiat ◽  
Cyril Mounier ◽  
Martine Wallon ◽  
Gilles Leboucher ◽  
...  
Keyword(s):  
Body Weight ◽  
Population Pharmacokinetics ◽  
Rate Constants ◽  
High Performance ◽  
Structural Model ◽  
Elimination Rate ◽  
Congenital Toxoplasmosis ◽  
Compartment Model ◽  
Pharmacokinetic Parameters ◽  
Drug Concentrations

ABSTRACT The population pharmacokinetics of pyrimethamine (PYR) and sulfadoxine (SDX) for a group of 32 children with congenital toxoplasmosis was investigated by nonparametric modeling analysis. A one-compartment model was used as the structural model, and individual pharmacokinetic parameters were estimated by Bayesian modeling. PYR (1.25 mg/kg of body weight) and SDX (25 mg/kg) were administered orally every 10 days for 1 year, with adjustment of the dose to body weight every 3 months. Drug concentrations were measured by high-performance liquid chromatography. A total of 101 measurements in serum were available for both drugs. Mean absorption rate constants, volumes of distribution, elimination rate constants, and half-lives were 0.915 h−1, 4.379 liters/kg, 0.00839 h−1, and 5.5 days for PYR and 1.659 h−1, 0.392 liters/kg, 0.00526 h−1, and 6.6 days for SDX, respectively. Wide interindividual variability was observed. The estimated minimum and maximum concentrations of PYR in serum differed 8- and 25-fold among patients, respectively, and those of SDX differed 4- and 5-fold, respectively. Increases in the concentration of PYR were observed for eight children, and increases in the SDX concentration were observed for seven children. Serum PYR-SDX concentrations are unpredictable even when the dose is standardized for body weight. The concentrations of the PYR-SDX combination that are most efficacious for children have not yet been established. A model such as ours, associated with long-term follow-up, is needed to study the correlation between exposure to these two drugs and clinical outcome in children.

scholarly journals Pharmacokinetics and Molecular Modeling Indicate nAChRα4-Derived Peptide HAEE Goes through the Blood–Brain Barrier

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 909
Author(s):  
Yurii A. Zolotarev ◽  
Vladimir A. Mitkevich ◽  
Stanislav I. Shram ◽  
Alexei A. Adzhubei ◽  
Anna P. Tolstova ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Mouse Model ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Laboratory Animals ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Data ◽  
Bolus Administration ◽  
Blood Brain ◽  
The Brain

One of the treatment strategies for Alzheimer’s disease (AD) is based on the use of pharmacological agents capable of binding to beta-amyloid (Aβ) and blocking its aggregation in the brain. Previously, we found that intravenous administration of the synthetic tetrapeptide Acetyl-His-Ala-Glu-Glu-Amide (HAEE), which is an analogue of the 35–38 region of the α4 subunit of α4β2 nicotinic acetylcholine receptor and specifically binds to the 11–14 site of Aβ, reduced the development of cerebral amyloidogenesis in a mouse model of AD. In the current study on three types of laboratory animals, we determined the biodistribution and tissue localization patterns of HAEE peptide after single intravenous bolus administration. The pharmacokinetic parameters of HAEE were established using uniformly tritium-labeled HAEE. Pharmacokinetic data provided evidence that HAEE goes through the blood–brain barrier. Based on molecular modeling, a role of LRP1 in receptor-mediated transcytosis of HAEE was proposed. Altogether, the results obtained indicate that the anti-amyloid effect of HAEE, previously found in a mouse model of AD, most likely occurs due to its interaction with Aβ species directly in the brain.

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