Population pharmacokinetic model development and its relationship with adverse events of oxcarbazepine in adult patients with epilepsy

AbstractThis study aimed to develop a pharmacokinetic (PK) model of oxcarbazepine (OXC) and analyse the relationship between monohydroxylated derivative (MHD), an active metabolite of OXC, and the adverse events of OXC. We obtained 711 OXC samples from 618 patients with epilepsy who were enrolled in the Epilepsy Registry Cohort of Seoul National University Hospital from February 2011 to January 2014. The plasma PK model was developed using a nonlinear mixed-effect modelling method with NONMEM (ver 7.3). A one-compartment model with a first-order absorption model and proportional residual error adequately described the MHD concentration–time profiles. The only covariate incorporated for CL/F and V/F was body weight. Of the 447 patients analysed, 28 (6.26%) had dose-related adverse events (DRAEs), which were dizziness, somnolence, headache, and diplopia. For DRAE occurrence, the cut-off values of the MHD trough and AUC were 12.27 mg/L (specificity 0.570, sensitivity 0.643) and 698.5 mg h/L (specificity, sensitivity 0.571), respectively. Multivariate analysis showed the sole dizziness symptom was significantly associated with both the MHD trough and the AUC (p = 0.013, p = 0.038, respectively). We newly developed a population PK model using sparse sampling data from patients with epilepsy, and the model better reflects the actual clinical situation.

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Population pharmacokinetic model development and its relationship with adverse events of oxcarbazepine in adult patients with epilepsy

10.21203/rs.3.rs-138619/v1 ◽

2021 ◽

Author(s):

Yoonhyuk Jang ◽

Seonghae Yoon ◽

Tae-Joon Kim ◽

SeungHwan Lee ◽

Kyung-Sang Yu ◽

...

Keyword(s):

Adverse Events ◽

Model Development ◽

Compartment Model ◽

Clinical Situation ◽

University Hospital ◽

Population Pharmacokinetic ◽

Mixed Effect ◽

National University ◽

Seoul National University ◽

Patients With Epilepsy

Abstract This study aimed to develop a pharmacokinetic (PK) model of oxcarbazepine (OXC) and analyse the relationship between monohydroxylated derivative (MHD), an active metabolite of OXC, and the adverse events of OXC. We obtained 711 OXC samples from 618 patients with epilepsy who were enrolled in the Epilepsy Registry Cohort of Seoul National University Hospital from February 2011 to January 2014. The plasma PK model was developed using a nonlinear mixed-effect modelling method with NONMEM (ver 7.3). A one-compartment model with a first-order absorption model and proportional residual error adequately described the MHD concentration–time profiles. The only covariate incorporated for CL/F and V/F was body weight. Of the 447 patients analysed, 28 (6.26%) had dose-related adverse events (DRAEs), which were dizziness, somnolence, headache, and diplopia. For DRAE occurrence, the cut-off values of the MHD trough and AUC were 12.27 mg/L (specificity 0.570, sensitivity 0.643) and 698.5 mg⋅h/L (specificity, sensitivity 0.571), respectively. Multivariate analysis showed the sole dizziness symptom was significantly associated with both the MHD trough and the AUC (p = 0.013, p = 0.038, respectively). We newly developed a population PK model using sparse sampling data from patients with epilepsy, and the model better reflects the actual clinical situation.

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Pharmacokinetics of intravenous sildenafil in children with palliated single ventricle heart defects: effect of elevated hepatic pressures

Cardiology in the Young ◽

10.1017/s1047951115000359 ◽

2015 ◽

Vol 26 (2) ◽

pp. 354-362 ◽

Cited By ~ 8

Author(s):

Kevin D. Hill ◽

Mario R. Sampson ◽

Jennifer S. Li ◽

Robert D. Tunks ◽

Scott R. Schulman ◽

...

Keyword(s):

Drug Exposure ◽

Structural Model ◽

Single Ventricle ◽

Heart Defects ◽

Model Development ◽

Area Under The Curve ◽

Compartment Model ◽

Population Pharmacokinetic ◽

Mixed Effect ◽

The Impact

AbstractAimsSildenafil is frequently prescribed to children with single ventricle heart defects. These children have unique hepatic physiology with elevated hepatic pressures, which may alter drug pharmacokinetics. We sought to determine the impact of hepatic pressure on sildenafil pharmacokinetics in children with single ventricle heart defects.MethodsA population pharmacokinetic model was developed using data from 20 single ventricle children receiving single-dose intravenous sildenafil during cardiac catheterisation. Non-linear mixed effect modelling was used for model development, and covariate effects were evaluated based on estimated precision and clinical significance.ResultsThe analysis included a median (range) of 4 (2–5) pharmacokinetic samples per child. The final structural model was a two-compartment model for sildenafil with a one-compartment model for des-methyl-sildenafil (active metabolite), with assumed 100% sildenafil to des-methyl-sildenafil conversion. Sildenafil clearance was unaffected by hepatic pressure (clearance=0.62 L/hour/kg); however, clearance of des-methyl-sildenafil (1.94×(hepatic pressure/9)−1.33 L/hour/kg) was predicted to decrease ~7-fold as hepatic pressure increased from 4 to 18 mmHg. Predicted drug exposure was increased by ~1.5-fold in subjects with hepatic pressures ⩾10 versus <10 mmHg (median area under the curve=533 versus 792 µg*h/L).DiscussionElevated hepatic pressure delays clearance of the sildenafil metabolite – des-methyl-sildenafil – and increases drug exposure. We speculate that this results from impaired biliary clearance. Hepatic pressure should be considered when prescribing sildenafil to children. These data demonstrate the importance of pharmacokinetic assessments in patients with unique cardiovascular physiology that may affect drug metabolism.

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Population Pharmacokinetics of Oxycodone and Metabolites in Patients with Cancer-Related Pain

Cancers ◽

10.3390/cancers13112768 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2768

Author(s):

Bram C. Agema ◽

Astrid W. Oosten ◽

Sebastiaan D. T. Sassen ◽

Wim J. R. Rietdijk ◽

Carin C. D. van der Rijt ◽

...

Keyword(s):

Adverse Events ◽

Pharmacokinetic Model ◽

Compartment Model ◽

Hospitalized Patients ◽

Population Pharmacokinetic ◽

Patients With Cancer ◽

Pain Scores ◽

Starting Point ◽

Patient Reported ◽

Pharmacodynamic Data

Oxycodone is frequently used for treating cancer-related pain, while not much is known about the factors that influence treatment outcomes in these patients. We aim to unravel these factors by developing a population-pharmacokinetic model to assess the pharmacokinetics of oxycodone and its metabolites in cancer patients, and to associate this with pain scores, and adverse events. Hospitalized patients with cancer-related pain, who were treated with oral oxycodone, could participate. Pharmacokinetic samples and patient-reported pain scores and occurrence and severity of nine adverse events were taken every 12 h. In 28 patients, 302 pharmacokinetic samples were collected. A one-compartment model for oxycodone and each metabolite best described oxycodone, nor-oxycodone, and nor-oxymorphone pharmacokinetics. Furthermore, oxycodone exposure was not associated with average and maximal pain scores, and oxycodone, nor-oxycodone, and nor-oxymorphone exposure were not associated with adverse events (all p > 0.05). This is the first model to describe the pharmacokinetics of oxycodone including the metabolites nor-oxycodone and nor-oxymorphone in hospitalized patients with cancer pain. Additional research, including more patients and a more timely collection of pharmacodynamic data, is needed to further elucidate oxycodone (metabolite) pharmacokinetic/pharmacodynamic relationships. This model is an important starting point for further studies to optimize oxycodone dosing regiments in patients with cancer-related pain.

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Screening for early detection of lung cancer: results from Seoul National University Hospital.

Tuberculosis and Respiratory Diseases ◽

10.4046/trd.1991.38.2.119 ◽

1991 ◽

Vol 38 (2) ◽

pp. 119-127

Author(s):

Yong Chol Han ◽

Chul Gyu Yoo ◽

Young Whan Kim ◽

Sung Koo Han ◽

Young Soo Shim ◽

...

Keyword(s):

Lung Cancer ◽

Early Detection ◽

University Hospital ◽

National University ◽

Seoul National University

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Radioiodine Treatment of Differentiated Thyroid Carcinoma: The Experience at Seoul National University Hospital

Current Medical Imaging Formerly Current Medical Imaging Reviews ◽

10.2174/157340510790694081 ◽

2010 ◽

Vol 6 (1) ◽

pp. 2-7

Author(s):

Ho Lee ◽

June-Key Chung ◽

Jong Lee ◽

So Oh ◽

Keon Kang ◽

...

Keyword(s):

Thyroid Carcinoma ◽

Differentiated Thyroid Carcinoma ◽

University Hospital ◽

Radioiodine Treatment ◽

National University ◽

Seoul National University

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Abstract TMP45: Usefulness of Susceptibility Vessel Sign With Bright Vessel Appearance in Acute Ischemic Stroke

Stroke ◽

10.1161/str.47.suppl_1.tmp45 ◽

2016 ◽

Vol 47 (suppl_1) ◽

Author(s):

Han-Gil Jeong ◽

Beom-Joon Kim ◽

Chi Kyung Kim ◽

Jun Yup Kim ◽

Dong-Wan Kang ◽

...

Keyword(s):

Ischemic Stroke ◽

Arterial Occlusion ◽

University Hospital ◽

Large Artery ◽

Peripheral Arteries ◽

Inclusion Criteria ◽

Arterial Segment ◽

Susceptibility Effect ◽

National University ◽

Seoul National University

Background: Red thrombi, composed of fibrin and trapped erythrocytes, have magnetic susceptibility effect. Susceptibility vessel sign (SVS) is visualized more sensitively using susceptibility weighted imaging (SWI) than T2*-weighted imaging. Bright vessel appearance (BVA) on arterial spin labeling (ASL) imaging can visualize occluded arterial segment by arterial transit artifact, more sensitively in small and peripheral branches. We investigated the usefulness of SWI-SVS with BVA to visualize different thrombus and predict stroke mechanisms. Methods: From a total of 564 stroke cases who admitted to Seoul National University Hospital in 2014, the authors collected eligible cases with the following inclusion criteria; (1) Lesion-documented ischemic stroke (N=425); (2) SWI and ASL MRI performed (N=407); (3) Symptomatic arterial occlusion with BVA (N=141). All images were analyzed for the presence and location of SWI-SVS and BVA. The location of SWI-SVS and BVA were classified into (1) proximal, large arteries; distal ICA, M1/2, A1, P1, basilar artery, V4 and (2) peripheral, small arteries; M3/4, P2/3, A2/3, lenticulostriate arteries, three cerebellar arteries. The relationships between SWI-SVS in the presence of BVA and stroke etiologies are explored. Results: Male was 58.2% (n=82) and mean age was 65.7±14.3. Thirty-four percent (n=48/141) of BVA and 30.3% (n=30/99) of SVS was located within small, peripheral arteries. SWI-SVS was more commonly associated with other determined etiology (20.2% vs. 4.8%) and cardioembolism (39.4% vs. 14.3%), but less with large artery atherosclerosis (26.3% vs. 69.0%, P <0.01) compared to the patients without SWI-SVS. Cancer-related hypercoagulability (60%, n=12/20) was most common in other determined cases with SWI-SVS. Multivariate analysis showed that SWI-SVS was an independent predictor of other determined etiology (adjusted OR, 7.20; 95% CI, 1.48-34.99) and cardioembolism (adjusted OR, 5.76; 95% CI, 1.27-26.02) Conclusions: SWI-SVS with BVA may predict ischemic stroke of cardioembolism and other determined etiology. Occlusions of small, peripheral arteries are well visualized with BVA and composition of thrombus can be identified by SWI-SVS.

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