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

2015 ◽  
Vol 26 (2) ◽  
pp. 354-362 ◽  
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.

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

2021 ◽  
Vol 11 (1) ◽  
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

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.

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

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.

scholarly journals Population Pharmacokinetics of Intravenous Isavuconazole in Solid-Organ Transplant Recipients

2019 ◽  
Vol 64 (2) ◽  
Author(s):  
Xuemei Wu ◽  
Raman Venkataramanan ◽  
Ryan M. Rivosecchi ◽  
Chenxiao Tang ◽  
Rachel V. Marini ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Treatment Effectiveness ◽  
Organ Transplant ◽  
Compartment Model ◽  
Solid Organ Transplant ◽  
Population Pharmacokinetic ◽  
Target Area ◽  
Solid Organ ◽  
Mixed Effect ◽  
Content Type

ABSTRACT Isavuconazole (ISA) is a triazole antifungal with activity against yeasts and molds. We established a population pharmacokinetic (pop PK) model of intravenous (i.v.) ISA to identify covariates that affect pharmacokinetics, using plasma samples from solid-organ transplant (SOT) recipients receiving peritransplant prophylaxis. Samples (n = 471) from 79 SOT recipients were utilized for pop PK analysis using nonlinear mixed-effect modeling NONMEM software. ISA (i.v.) PK parameters were best described by a two-compartment model. Significant covariates were sex on clearance (∼53% higher in women than men) and body mass index on peripheral volume of distribution. Incorporating drug exposure into Monte Carlo simulations, we demonstrated that standard ISA dosing is likely to attain the PK-pharmacodynamic (PD) target (area under the concentration curve/MIC ratio [AUC/MIC]) for treatment effectiveness against almost all infections caused by Aspergillus fumigatus isolates exhibiting MICs of ≤0.5 μg/ml (modal MIC). In contrast, standard dosing is predicted to attain PK-PD targets against <20% of infections caused by Candida albicans and Candida glabrata isolates exhibiting MICs of ≥0.016 and ≥0.5 μg/ml, respectively (modal MICs). These data are consistent with our SOT program’s experience with ISA breakthrough infections, where 3 of 4 were caused by C. glabrata for which probabilities of PK-PD target attainment (PTA) were only 70% and 0% for isolates with MICs of 0.25 μg/ml and 1 μg/ml. Our findings provide important new insights into how ISA use might be optimized following SOT.

scholarly journals Population Pharmacokinetic Analysis of Voriconazole and Anidulafungin in Adult Patients with Invasive Aspergillosis

2014 ◽  
Vol 58 (8) ◽  
pp. 4718-4726 ◽  
Author(s):  
Ping Liu ◽  
Diane R. Mould
Keyword(s):  
Invasive Aspergillosis ◽  
Area Under The Curve ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Institutional Review Boards ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
First Order ◽  
Two Compartment Model

ABSTRACTTo assess the pharmacokinetics (PK) of voriconazole and anidulafungin in patients with invasive aspergillosis (IA) in comparison with other populations, sparse PK data were obtained for 305 adults from a prospective phase 3 study comparing voriconazole and anidulafungin in combination versus voriconazole monotherapy (voriconazole, 6 mg/kg intravenously [IV] every 12 h [q12h] for 24 h followed by 4 mg/kg IV q12h, switched to 300 mg orally q12h as appropriate; with placebo or anidulafungin IV, a 200-mg loading dose followed by 100 mg q24h). Voriconazole PK was described by a two-compartment model with first-order absorption and mixed linear and time-dependent nonlinear (Michaelis-Menten) elimination; anidulafungin PK was described by a two-compartment model with first-order elimination. For voriconazole, the normal inverse Wishart prior approach was implemented to stabilize the model. Compared to previous models, no new covariates were identified for voriconazole or anidulafungin. PK parameter estimates of voriconazole and anidulafungin are in agreement with those reported previously except for voriconazole clearance (the nonlinear clearance component became minimal). At a 4-mg/kg IV dose, voriconazole exposure tended to increase slightly as age, weight, or body mass index increased, but the difference was not considered clinically relevant. Estimated voriconazole exposures in IA patients at 4 mg/kg IV were higher than those reported for healthy adults (e.g., the average area under the curve over a 12-hour dosing interval [AUC0–12] at steady state was 46% higher); while it is not definitive, age and concomitant medications may impact this difference. Estimated anidulafungin exposures in IA patients were comparable to those reported for the general patient population. This study was approved by the appropriate institutional review boards or ethics committees and registered on ClinicalTrials.gov (NCT00531479).

scholarly journals Population Pharmacokinetics of Fluconazole in Young Infants

2008 ◽  
Vol 52 (11) ◽  
pp. 4043-4049 ◽  
Author(s):  
K. C. Wade ◽  
D. Wu ◽  
D. A. Kaufman ◽  
R. M. Ward ◽  
D. K. Benjamin ◽  
...  
Keyword(s):  
Fixed Effects ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Relative Standard Error ◽  
Data Set ◽  
Mixed Effect ◽  
Young Infants ◽  
Relative Standard ◽  
Population Pk ◽  
The Impact

ABSTRACT Fluconazole is being increasingly used to prevent and treat invasive candidiasis in neonates, yet dosing is largely empirical due to the lack of adequate pharmacokinetic (PK) data. We performed a multicenter population PK study of fluconazole in 23- to 40-week-gestation infants less than 120 days of age. We developed a population PK model using nonlinear mixed effect modeling (NONMEM) with the NONMEM algorithm. Covariate effects were predefined and evaluated based on estimation precision and clinical significance. We studied fluconazole PK in 55 infants who at enrollment had a median (range) weight of 1.02 (0.440 to 7.125) kg, a gestational age at birth (BGA) of 26 (23 to 40) weeks, and a postnatal age (PNA) of 2.3 (0.14 to 12.6) weeks. The final data set contained 357 samples; 217/357 (61%) were collected prospectively at prespecified time intervals, and 140/357 (39%) were scavenged from discarded clinical specimens. Fluconazole population PK was best described by a one-compartment model with covariates normalized to median values. The population mean clearance (CL) can be derived for this population by the equation CL (liter/h) equals 0.015 · (weight/1)0.75 · (BGA/26)1.739 · (PNA/2)0.237 · serum creatinine (SCRT)−4.896 (when SCRT is >1.0 mg/dl), and using a volume of distribution (V) (liter) of 1.024 · (weight/1). The relative standard error around the fixed effects point estimates ranged from 3 to 24%. CL doubles between birth and 28 days of age from 0.008 to 0.016 and from 0.010 to 0.022 liter/kg/h for typical 24- and 32-week-gestation infants, respectively. This population PK model of fluconazole discriminated the impact of BGA, PNA, and creatinine on drug CL. Our data suggest that dosing in young infants will require adjustment for BGA and PNA to achieve targeted systemic drug exposures.

scholarly journals Population pharmacokinetics of levodopa gel infusion in Parkinson’s disease: effects of entacapone infusion and genetic polymorphism

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
M. Senek ◽  
D. Nyholm ◽  
E. I. Nielsen
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Population Pharmacokinetics ◽  
Drug Exposure ◽  
Population Level ◽  
Compartment Model ◽  
Concentration Data ◽  
Comt Genotype ◽  
Double Blind ◽  
The Impact

Abstract Levodopa-entacapone-carbidopa intestinal gel (LECIG) provides continuous drug delivery through intrajejunal infusion. The aim of this study was to characterize the population pharmacokinetics of levodopa following LECIG and levodopa-carbidopa intestinal gel (LCIG) infusion to investigate suitable translation of dose from LCIG to LECIG treatment, and the impact of common variations in the dopa-decarboxylase (DDC) and catechol-O-methyltransferase (COMT) genes on levodopa pharmacokinetics. A non-linear mixed-effects model of levodopa pharmacokinetics was developed using plasma concentration data from a double-blind, cross-over study of LCIG compared with LECIG in patients with advanced Parkinson’s disease (n = 11). All patients were genotyped for rs4680 (polymorphism of the COMT gene), rs921451 and rs3837091 (polymorphisms of the DDC gene). The final model was a one compartment model with a high fixed absorption rate constant, and a first order elimination, with estimated apparent clearances (CL/F), of 27.9 L/h/70 kg for LCIG versus 17.5 L/h/70 kg for LECIG, and apparent volume of distribution of 74.4 L/70 kg. Our results thus suggest that the continuous maintenance dose of LECIG, on a population level, should be decreased by approximately 35%, to achieve similar drug exposure as with LCIG. An effect from entacapone was identified on all individuals, regardless of COMT rs4680 genotype. The individuals with higher DDC and COMT enzyme activity showed tendencies towards higher levodopa CL/F. The simultaneous administration of entacapone to LCIG administration results in a 36.5% lower apparent levodopa clearance, and there is a need for lower continuous maintenance doses, regardless of patients’ COMT genotype.

scholarly journals Milrinone Pharmacokinetics and Pharmacodynamics in Neonates with Persistent Pulmonary Hypertension of the Newborn

2017 ◽  
Vol 34 (08) ◽  
pp. 749-758 ◽  
Author(s):  
Annie Giaccone ◽  
Athena Zuppa ◽  
Beena Sood ◽  
Meryl Cohen ◽  
Michael O'Byrne ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pilot Study ◽  
Drug Exposure ◽  
Structural Model ◽  
Standard Dose ◽  
Oxygenation Index ◽  
Persistent Pulmonary Hypertension ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Open Label ◽  
The Impact

Objective To describe the pharmacokinetics and pharmacodynamics of milrinone in infants with persistent pulmonary hypertension of the newborn (PPHN) and to explore the impact of age on milrinone disposition. Design Randomized, open label pilot study. Setting Multicenter; level 3 and level 4 neonatal intensive care units. Patients Six infants ≥34 weeks' gestational age and <10 days of life with persistent hypoxemia receiving inhaled nitric oxide. Intervention Intravenous milrinone lactate in one of two dosing regimens: (1) low dose, 20 mcg/kg bolus followed by 0.2 mcg/kg/minute, and (2) standard dose, 50 mcg/kg bolus followed by 0.5 mcg/kg/minute. Measurements and Main Results The final structural model was a two-compartment disposition model with interindividual variability estimated on clearance (CL). The estimated value of CL is 7.65 mL/minute/3.4 kg (3.05 mL/minute/kg). The addition of age improved the precision of the CL estimate, and CL increased with chronological age in days. The oxygenation index was highly variable within each participant and improved with time. There were no observed safety concerns in either dosing group. Conclusion The CL of milrinone in newborns with PPHN is reduced and increases with age. In this pilot study, we did not see significant pharmacodynamic or safety effects associated with drug exposure.

scholarly journals Use of Pharmacokinetic and Pharmacodynamic Principles To Determine Optimal Administration of Daptomycin in Patients Receiving Standardized Thrice-Weekly Hemodialysis

2011 ◽  
Vol 55 (4) ◽  
pp. 1677-1683 ◽  
Author(s):  
Nimish Patel ◽  
Katie Cardone ◽  
Darren W. Grabe ◽  
Shari Meola ◽  
Christopher Hoy ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Monte Carlo ◽  
Body Weight ◽  
Infective Endocarditis ◽  
Population Model ◽  
Area Under The Curve ◽  
Compartment Model ◽  
Population Pharmacokinetic ◽  
Exposure Profile ◽  
Trough Concentrations

ABSTRACTThis study identified optimal daptomycin dosing for patients receiving thrice-weekly hemodialysis (HD). Twelve adult patients on HD received daptomycin at 6 mg/kg of body weight intravenously (i.v.) one time; plasma and dialysate samples were collected over 3 days. A 2-compartment model with separate HD and non-HD clearance terms was fit to the data. A series of 9,999-subject Monte Carlo simulations (MCS) was performed to identify HD dosing schemes providing efficacy and toxicity profiles comparable to those obtained for MCS employing the daptomycin population pharmacokinetic (PK) model derived from patients in theStaphylococcus aureusbacteremia-infective endocarditis (SAB-IE) study. For efficacy, we selected the HD dosing scheme which generated an area-under-the-curve (AUC) exposure profile comparable to that for the SAB-IE population model. For toxicity, we selected HD dosing schemes that minimized trough concentrations of ≥24.3 mg/liter. Separate HD dosing schemes were developed for each FDA-approved regimen and for two weekly interdialytic periods (48 and 72 h). Administration of the same parent daptomycin dose intra-HD and post-HD resulted in AUC, maximum concentration of drug in serum (Cmax), andCminvalues most comparable to those for SAB-IE simulations for the 48-hour interdialytic period. In contrast, all candidate HD dosing schemes provided AUC48-72values that were at least 50% lower than the SAB-IE AUC48-72values. Increasing the parent dose by 50% provided more comparable AUC48-72values while maintaining acceptableCminvalues. Administration of the daptomycin parent dose intra-HD or post-HD was optimal for the 48-h interdialytic period. For the 72-h interdialytic period, clinicians should consider increasing the dose by 50% to achieve more comparable AUC48-72values.

scholarly journals Population Pharmacokinetic/Pharmacogenetic Model for Optimization of Efavirenz Therapy in Caucasian HIV-Infected Patients

2011 ◽  
Vol 55 (11) ◽  
pp. 5314-5324 ◽  
Author(s):  
Almudena Sánchez ◽  
Salvador Cabrera ◽  
Dolores Santos ◽  
M. Paz Valverde ◽  
Aurelio Fuertes ◽  
...  
Keyword(s):  
High Performance ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Population Pharmacokinetic ◽  
Nucleotide Polymorphisms ◽  
Mixed Effect ◽  
Factors Affecting ◽  
Nonlinear Mixed Effect ◽  
Study Population ◽  
Major Factors

ABSTRACTDespite extensive clinical experience with efavirenz (EFV), unpredictable interindividual variabilities in efficacy and toxicity remain important limitations associated with the use of this antiretroviral. The purpose of this study was to determine the factors affecting EFV pharmacokinetics and to develop a pharmacokinetic/pharmacogenetic (PK/PG) model in a Caucasian population of HIV-infected patients. In total, 869 EFV plasma concentrations from 128 HIV-infected patients treated with EFV were quantitatively assessed using a validated high-performance liquid chromatography technique. All patients were genotyped for 90 single nucleotide polymorphisms (SNPs) in genes coding for proteins involved in the metabolism and transport of EFV, using a MassArray platform provided by Sequenom. The influence of these polymorphisms on EFV pharmacokinetics and the effects of demographic, clinical, biochemical, lifestyle, and concurrent drug covariates were evaluated. Plasma concentrations were fitted by a one-compartment model, with first-order absorption and elimination using nonlinear mixed-effect modeling (NONMEM program). The CYP2B6*6 allele, multidrug resistance-associated protein 4 (MRP4) 1497C→T, and gamma-glutamyltranspeptidase (GGT) were identified as major factors influencing the apparent EFV oral clearance (CL/F), reducing the initial interindividual variability by 54.8%, according to the model CL/F = (12.2 − 0.00279·GGT)·0.602CYP2B6*6 [G/T]·0.354CYP2B6*6 [T/T]·0.793MRP4 1497C→T, where CYP2B6*6 [G/T], CYP2B6*6 [T/T], and MRP4 1497C→T take values of 0 or 1 to indicate the absence or presence of polymorphisms. The detailed genetic analysis conducted in this study identified two of 90 SNPs that significantly impacted CL/F, which might indicate that the remaining SNPs analyzed do not influence this PK parameter, at least in Caucasian populations with characteristics similar to those of our study population.

scholarly journals Assessment of the nlmixr R-package for population pharmacokinetic modeling: A metformin case study

2021 ◽  
Author(s):  
Wen Yao Mak ◽  
Qing Xi Ooi ◽  
Cintia Cruz ◽  
Irene Looi ◽  
Kah Hay Yuen ◽  
...  
Keyword(s):  
Compartment Model ◽  
Stochastic Simulations ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Mixed Effect ◽  
Flip Flop ◽  
Final Model ◽  
Elimination Phase ◽  
Transit Compartment ◽  
Terminal Elimination Phase

Aim: nlmixr offers first-order conditional estimation with or without interaction (FOCE or FOCEi) and stochastic approximation estimation-maximisation (SAEM) to fit nonlinear mixed-effect models (NLMEM). We modelled metformin’s population pharmacokinetics with flip-flop characteristics within nlmixr framework and investigated SAEM and FOCEi’s performance with respect to bias, precision, and robustness. Method: Compartmental pharmacokinetic models were fitted. The final model was determined based on the lowest objective function value and visual inspection of goodness-of-fit plots. To examine flip-flop pharmacokinetics, k_a values of a typical concentration-time profile based on the final model were perturbed and changes in the steepness of the terminal elimination phase were evaluated. The bias and precision of parameter estimates were compared between SAEM and FOCEi using stochastic simulations and estimations. For robustness, parameters were re-estimated as the initial estimates were perturbed 100-times and resultant changes evaluated. Results: A one-compartment model with transit compartment for absorption best described the data. At low n, Stirling’s approximation of n! over-approximated plasma concentration unlike the log-gamma function. Flip-flop pharmacokinetics were evident as the steepness of the terminal elimination phase changed with k_a. Mean rRMSE for fixed-effect parameters was 0.932. When initial estimates were perturbed, FOCEi estimates of k_a and food effect on k_a appeared bimodal and were upward biased. Discussion: nlmixr is reliable for NLMEM even if flip-flop is present but caution should be exercised when using Stirling’s approximation for n! in the transit compartment model. SAEM was marginally superior to FOCEi in bias and precision, but SAEM was superior against initial estimate perturbations.

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