scholarly journals Pregnancy-Related Effects on Nelfinavir-M8 Pharmacokinetics: a Population Study with 133 Women

2006 ◽  
Vol 50 (6) ◽  
pp. 2079-2086 ◽  
Author(s):  
Déborah Hirt ◽  
Jean-Marc Treluyer ◽  
Vincent Jullien ◽  
Ghislaine Firtion ◽  
Hélène Chappuy ◽  
...  
Keyword(s):  
Population Study ◽  
Time Course ◽  
Plasma Concentrations ◽  
Elimination Rate ◽  
Concomitant Administration ◽  
Individual Characteristics ◽  
Individual Treatment ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Linear Absorption

ABSTRACT A relationship between nelfinavir antiretroviral efficacy and plasma concentrations has been previously established. As physiological changes associated with pregnancy have a large impact on the pharmacokinetics of many drugs, a nelfinavir population study with women was developed, and the large intersubject variability was analyzed in order to optimize individual treatment schedules for this drug during pregnancy. A population pharmacokinetic model was developed in order to describe the concentration time course of nelfinavir and its metabolite M8 in pregnant and nonpregnant women. Individual characteristics, such as age, body weight, and weeks of gestation or delivery, which may influence nelfinavir-M8 pharmacokinetics were investigated. Data from therapeutic drug monitoring in 133 women treated with nelfinavir were retrospectively analyzed with NONMEM. Nelfinavir pharmacokinetics was described by a one-compartment model with linear absorption and elimination and M8 produced from the nelfinavir central compartment. Mean pharmacokinetic estimates and the corresponding intersubject percent variabilities for a nonpregnant woman were the following: absorption rate, 0.83 h−1; absorption lag time, 0.85 h; apparent nelfinavir elimination clearance (CL10/F), 35.5 liters/h (50%); apparent volume of distribution (V/F), 596 liters (118%); apparent formation clearance to M8 (CL1M/F), 0.65 liters/h (69%); and M8 elimination rate constant (k M0), 3.3 h−1 (59%). During pregnancy, we observed significant increases in nelfinavir (44.4 liters/h) and M8 (5 h−1) elimination but unchanged nelfinavir transformation clearance to M8, suggesting an induction of CYP3A4 but no effect on CYP2C19. Apparent nelfinavir clearance and volume showed a twofold increase on the day of delivery, suggesting a decrease in bioavailability on this day. The M8 elimination rate was increased by concomitant administration of nonnucleoside reverse transcriptase inhibitors. A trough nelfinavir plasma concentration above 1 mg/liter was previously shown to improve the antiretroviral response. The Bayesian individual pharmacokinetic estimates suggested that the dosage should not be changed in pregnant women but may be doubled on the day of delivery.

scholarly journals Age-Related Effects on Nelfinavir and M8 Pharmacokinetics: a Population Study with 182 Children

2006 ◽  
Vol 50 (3) ◽  
pp. 910-916 ◽  
Author(s):  
Déborah Hirt ◽  
Saïk Urien ◽  
Vincent Jullien ◽  
Ghislaine Firtion ◽  
Elisabeth Rey ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Elimination Rate ◽  
Volume Of Distribution ◽  
Individual Characteristics ◽  
Individual Treatment ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Treatment Schedule ◽  
Total Clearance ◽  
Age Related

ABSTRACT As a relationship between nelfinavir antiretroviral efficacy and plasma concentrations has been previously established, nelfinavir pharmacokinetics was investigated in order to optimize the individual treatment schedule in a pediatric population. A population pharmacokinetic model was developed to describe the concentration-time course of nelfinavir and its active metabolite M8. Individual characteristics were used to explain the large interindividual variability in children. Data from therapeutic drug monitoring in 182 children treated with nelfinavir were analyzed with NONMEM. Then Food and Drug Administration (FDA) current recommendations were evaluated estimating the percentage of children who reached the target minimum plasma concentration (0.8 mg/liter) by using Bayesian estimates. Nelfinavir pharmacokinetics was described by a one- compartment model with linear absorption and elimination. Pharmacokinetic estimates and the corresponding intersubject variabilities for the model were as follows: nelfinavir total clearance, 0.93 liters/h/kg (39%); volume of distribution, 6.9 liters/kg (109%); absorption rate, 0.5 h−1; formation clearance fraction to hydroxy-tert-butylamide (M8), 0.025; M8 elimination rate, 1.88 h−1 (49%). Apparent nelfinavir total clearance and volume of distribution decreased as a function of age. M8 elimination rate was increased by concomitant administration of nevirapine or efavirenz. Our data confirm that the FDA recommendations for children from 2 to 13 years are optimal and that the dose recommended for children younger than 2 years is adequate for the children from 2 months to 2 years old. However, in children younger than 2 months, the proposed nelfinavir newborn dose of 40 mg/kg of body weight twice daily is inadequate and we suggest increasing the dose to 50 to 60 mg/kg administered thrice daily. This assumption should be further evaluated.

Estimation of Phenytoin Pharmacokinetic Parameters in Saudi Epileptic Patients

Pharmacology ◽  
2019 ◽  
Vol 104 (1-2) ◽  
pp. 60-66 ◽  
Author(s):  
Saeed Alqahtani ◽  
Thuraya Alzaidi ◽  
Mashal Alotaibi ◽  
Abdullah Alsultan
Keyword(s):  
Body Weight ◽  
Plasma Concentrations ◽  
Elimination Rate ◽  
Total Daily Dose ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Linear Absorption ◽  
Significant Covariates ◽  
Saudi Patients

Objective: This study aimed to assess the population pharmacokinetics of phenytoin in Saudi patients and identify factors affecting therapeutic parameters. Method: A retrospective chart review was performed at King Saud University Medical City on patients treated with oral phenytoin. We used Monolix 4.4. for population pharmacokinetic modeling. A base model was developed to investigate several covariates, including age, gender, weight, total daily dose (TTD), and liver function test results. Results: The analysis included a total of 81 phenytoin plasma concentrations from 43 patients (70% male). Patients’ mean (± SD) age was 41 (±18.7) years and body weight was 65.4 (±17.7) kg. The patients received a phenytoin TDD of 330.5 (±104.5) mg/day, resulting in a trough concentration of 11.2 (±10.3) mg/L. The data were sufficiently described by the one-compartment open model with linear absorption and nonlinear elimination processes. Average parameter estimates for phenytoin volume of distribution (V), maximal elimination rate (Vmax), and Michaelis-Menten constant (Km) were 0.61 L/h/kg, 6.12 mg/kg/day, and 5.33 mg/L, respectively. The most significant covariates on phenytoin Vmax and Km were the age and body weight of the patients, along with valproic acid (VPA) cotherapy. Conclusion: The population pharmacokinetic model of phenytoin in Saudi patients found significant interindividual variability between subjects, which was affected by the patients’ age, body weight, and VPA cotherapy as the most significant covariates on phenytoin Vmax and Km. To provide guidance in drug dosage decisions, further studies are required to evaluate all factors that may potentially influence the pharmacokinetics of phenytoin.

Isavuconazole: Case Report and Pharmacokinetic Considerations

Chemotherapy ◽  
2018 ◽  
Vol 63 (5) ◽  
pp. 253-256 ◽  
Author(s):  
Francesco Marchesi ◽  
Corrado Girmenia ◽  
Bianca Maria Goffredo ◽  
Emanuela Salvatorelli ◽  
Atelda Romano ◽  
...  
Keyword(s):  
Lymphoblastic Leukemia ◽  
Plasma Concentrations ◽  
Real Life ◽  
Concomitant Administration ◽  
Invasive Fungal Disease ◽  
High Plasma ◽  
Adult Patients ◽  
Therapeutic Drug ◽  
Hepatic Toxicity ◽  
Maintenance Chemotherapy

Invasive fungal disease (IFD) is one of the major causes of morbidity and mortality in immunocompromised patients. Voriconazole (VCZ) and posaconazole (PCZ) remain the most widely used antifungals for the prophylaxis and treatment of IFD. However, VCZ and PCZ are liable for drug-drug interactions and show a pharmacokinetic variability that requires therapeutic drug monitoring (TDM). Isavuconazole (IVZ) is a newest generation triazole antifungal approved for the treatment of invasive aspergillosis (IA) in adult patients and for the treatment of invasive mucormycosis in adult patients for whom treatment with amphotericin B is inappropriate. In clinical trials, IVZ showed linear pharmacokinetics and little or no evidence for interactions with other drugs. There is only modest evidence on IVZ pharmacokinetics and TDM in real-life settings. Here, we report on IVZ pharmacokinetics in a young adult with Ph chromosome-negative acute lymphoblastic leukemia (ALL) who developed a “probable” IA during induction chemotherapy. The patient was initially treated with VCZ, but she developed a severe hepatic toxicity that was associated to the high plasma levels of VCZ. Therefore, VCZ was discontinued and the patient was switched to IVZ. After a loading dose of IVZ, the patient remained on IVZ for 5 months while also receiving standard maintenance chemotherapy for ALL. At day 65 after the start of IVZ, the patient experienced a significant hepatic toxicity; however, no change in IVZ plasma concentrations was observed in the face of a concomitant administration of many other drugs (cancer drugs, antiemetics, other anti-infectives). Hepatic toxicity resolved after discontinuing maintenance chemotherapy but not IVZ. These results show that (i) IVZ plasma concentrations remained stable throughout and were not affected by concomitant ALL therapy, and (ii) there was no relation between IVZ plasma concentration and hepatic toxicity. Thus, in clinical practice IVZ may not require TDM.

scholarly journals Pharmacokinetic Modeling and Optimal Sampling Strategies for Therapeutic Drug Monitoring of Rifampin in Patients with Tuberculosis

2015 ◽  
Vol 59 (8) ◽  
pp. 4907-4913 ◽  
Author(s):  
Marieke G. G. Sturkenboom ◽  
Leonie W. Mulder ◽  
Arthur de Jager ◽  
Richard van Altena ◽  
Rob E. Aarnoutse ◽  
...  
Keyword(s):  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Mean Squared Error ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Optimal Sampling ◽  
Sampling Strategies ◽  
Wide Range

ABSTRACTRifampin, together with isoniazid, has been the backbone of the current first-line treatment of tuberculosis (TB). The ratio of the area under the concentration-time curve from 0 to 24 h (AUC0–24) to the MIC is the best predictive pharmacokinetic-pharmacodynamic parameter for determinations of efficacy. The objective of this study was to develop an optimal sampling procedure based on population pharmacokinetics to predict AUC0–24values. Patients received rifampin orally once daily as part of their anti-TB treatment. A one-compartmental pharmacokinetic population model with first-order absorption and lag time was developed using observed rifampin plasma concentrations from 55 patients. The population pharmacokinetic model was developed using an iterative two-stage Bayesian procedure and was cross-validated. Optimal sampling strategies were calculated using Monte Carlo simulation (n= 1,000). The geometric mean AUC0–24value was 41.5 (range, 13.5 to 117) mg · h/liter. The median time to maximum concentration of drug in serum (Tmax) was 2.2 h, ranging from 0.4 to 5.7 h. This wide range indicates that obtaining a concentration level at 2 h (C2) would not capture the peak concentration in a large proportion of the population. Optimal sampling using concentrations at 1, 3, and 8 h postdosing was considered clinically suitable with anr2value of 0.96, a root mean squared error value of 13.2%, and a prediction bias value of −0.4%. This study showed that the rifampin AUC0–24in TB patients can be predicted with acceptable accuracy and precision using the developed population pharmacokinetic model with optimal sampling at time points 1, 3, and 8 h.

scholarly journals Population pharmacokinetics of dolutegravir: influence of drug–drug interactions in a real-life setting

2019 ◽  
Vol 74 (9) ◽  
pp. 2690-2697 ◽  
Author(s):  
Catalina Barcelo ◽  
Manel Aouri ◽  
Perrine Courlet ◽  
Monia Guidi ◽  
Dominique L Braun ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Plasma Concentrations ◽  
Real Life ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Genetic Barrier ◽  
Good Tolerability ◽  
Standard Dosage ◽  
Real Life Setting ◽  
Trough Concentrations

Abstract Objectives Dolutegravir is widely prescribed owing to its potent antiviral activity, high genetic barrier and good tolerability. The aim of this study was to characterize dolutegravir’s pharmacokinetic profile and variability in a real-life setting and to identify individual factors and co-medications affecting dolutegravir disposition. Methods A population pharmacokinetic model was developed using NONMEM®. Relevant demographic factors, clinical factors and co-medications were tested as potential covariates. Simulations based on the final model served to compare expected dolutegravir concentrations under standard and alternative dosage regimens in the case of drug–drug interactions. Results A total of 620 dolutegravir plasma concentrations were collected from 521 HIV-infected individuals under steady-state conditions. A one-compartment model with first-order absorption and elimination best characterized dolutegravir pharmacokinetics. Typical dolutegravir apparent clearance (CL/F) was 0.93 L/h with 32% between-subject variability, the apparent volume of distribution was 20.2 L and the absorption rate constant was fixed to 2.24 h−1. Older age, higher body weight and current smoking were associated with higher CL/F. Atazanavir co-administration decreased dolutegravir CL/F by 38%, while darunavir modestly increased CL/F by 14%. Rifampicin co-administration showed the largest impact on CL/F. Simulations suggest that average dolutegravir trough concentrations are 63% lower after 50 mg/12h with rifampicin compared with a standard dosage of 50 mg/24h without rifampicin. Average trough concentrations after 100 mg/24h and 100 mg/12h with rifampicin are 92% and 25% lower than the standard dosage without rifampicin, respectively. Conclusions Patients co-treated with dolutegravir and rifampicin might benefit from therapeutic drug monitoring and individualized dosage increase, up to 100 mg/12 h in some cases.

scholarly journals Is the Recommended Dose of Efavirenz Optimal in Young West African Human Immunodeficiency Virus-Infected Children?

2009 ◽  
Vol 53 (10) ◽  
pp. 4407-4413 ◽  
Author(s):  
Déborah Hirt ◽  
Saik Urien ◽  
Mathieu Olivier ◽  
Hélène Peyrière ◽  
Boubacar Nacro ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Body Weight ◽  
Plasma Concentrations ◽  
Individual Characteristics ◽  
Population Pharmacokinetic ◽  
Ratio Test ◽  
Time Curve ◽  
Once Daily ◽  
Concentration Time ◽  
Immunodeficiency Virus

ABSTRACT We aimed in this study to describe efavirenz concentration-time courses in treatment-naïve children after once-daily administration to study the effects of age and body weight on efavirenz pharmacokinetics and to test relationships between doses, plasma concentrations, and efficacy. For this purpose, efavirenz concentrations in 48 children were measured after 2 weeks of didanosine-lamivudine-efavirenz treatment, and samples were available for 9/48 children between months 2 and 5 of treatment. Efavirenz concentrations in 200 plasma specimens were measured using a validated high-performance liquid chromatography method. A population pharmacokinetic model was developed with NONMEM. The influence of individual characteristics was tested using a likelihood ratio test. The estimated minimal and maximal concentrations of efavirenz in plasma (C min and C max, respectively) and the area under the concentration-time curve (AUC) were correlated to the decrease in human immunodeficiency virus type 1 RNA levels after 3 months of treatment. The threshold C min (and AUC) that improved efficacy was determined. The target minimal concentration of 4 mg/liter was considered for toxicity. An optimized dosing schedule that would place the highest percentage of children in the interval of effective and nontoxic concentrations was simulated. The pharmacokinetics of efavirenz was best described by a one-compartment model with first-order absorption and elimination. The mean apparent clearance and volume of distribution for efavirenz were 0.211 liter/h/kg and 4.48 liters/kg, respectively. Clearance decreased significantly with age. When the recommended doses were given to 46 of the 48 children, 19% (44% of children weighing less than 15 kg) had C mins below 1 mg/liter. A significantly higher percentage of children with C mins of >1.1 mg/liter or AUCs of >51 mg/liter·h than of children with lower values had viral load decreases greater than 2 log10 copies/ml after 3 months of treatment. Therefore, to optimize the percentage of children with C mins between 1.1 and 4 mg/liter, children should receive the following once-daily efavirenz doses: 25 mg/kg of body weight from 2 to 6 years, 15 mg/kg from 6 to 10 years, and 10 mg/kg from 10 to 15 years. These assumptions should be prospectively confirmed.

scholarly journals Plasma and Intracellular Population Pharmacokinetic Analysis of Tenofovir in HIV-1-Infected Patients

2011 ◽  
Vol 55 (11) ◽  
pp. 5294-5299 ◽  
Author(s):  
Gautam Baheti ◽  
Jennifer J. Kiser ◽  
Peter L. Havens ◽  
Courtney V. Fletcher
Keyword(s):  
Rate Constant ◽  
Sequential Analysis ◽  
Plasma Concentrations ◽  
Elimination Rate ◽  
Distribution Volume ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Response Model ◽  
Indirect Response Model ◽  
Indirect Response

ABSTRACTThe relationships among the dose of tenofovir disoproxil fumarate (TDF), tenofovir (TFV) plasma concentrations, and intracellular TFV diphosphate (TFV-DP) concentrations are poorly understood. Our objective was to characterize TFV and TFV-DP relationships. Data were pooled from two studies in HIV-infected persons (n= 55) on stable antiretroviral therapy. TFV and TFV-DP were measured with validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) methods. Nonlinear mixed effects modeling (NONMEM 7) was used to develop the population model and explore the influence of covariates on TFV. A sequential analysis approach was utilized. A two-compartment model with first-order absorption best described TFV PK (FOCEI). An indirect stimulation of response model best described TFV-DP, where formation of TFV-DP was driven by plasma TFV concentration. Final plasma population estimates were as follows: absorption rate constant, 1.03 h−1; apparent clearance (CL/F), 42 liters/h (33.5% interindividual variability [IIV]); intercompartment clearance, 181 liters/h; apparent central distribution volume (Vc/F), 273 liters (64.8% IIV); and apparent peripheral distribution volume (Vp/F), 440 liters (46.5% IIV). Creatinine clearance was the most significant covariate on CL/F and Vc/F. The correlation between CL/F and Vc/F was 0.553. The indirect response model for TFV-DP resulted in estimates of the maximal intracellular concentration (Emax), the TFV concentration producing 50% ofEmax(EC50), and the intracellular elimination rate constant (kout) of 300 fmol/106cells (82% IIV), 100 ng/ml (106% IIV), and 0.008 h−1, respectively. The estimatedkoutgave an 87-h TFV-DP half-life. A predictive check assessment indicated satisfactory model performance. This model links formation of TFV-DP with plasma TFV concentrations and should facilitate more informed investigations of TFV clinical pharmacology.

scholarly journals Estimation of Pharmacokinetic Parameters of Continuous Intravenous Flucloxacillin infusion in the Outpatient Settings (PKFLUCLOX)

2018 ◽  
Author(s):  
Nilar Lwin ◽  
Zheng Liu ◽  
Mark Loewenthal ◽  
Pauline Dobson ◽  
Ji Woong Yoo ◽  
...  
Keyword(s):  
Steady State ◽  
Continuous Infusion ◽  
Time Course ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Device Removal ◽  
Standard Dosage

Flucloxacillin, a beta-lactam antibiotic of the penicillin class, is considered first line therapy for methicillin sensitive Staphylococcus aureus (MSSA) in Australia. At our tertiary referral hospital in the home (HITH) program, it has been prescribed in a standard dosage of 8 grams per day by continuous infusion for more than 20 years. The aim of this observational study was to characterize the pharmacokinetic profile of flucloxacillin in patients who receive continuous infusion in the HITH setting, and to undertake population pharmacokinetic analysis performed with NONMEM software by comparing various structural models. This study utilised flucloxacillin concentrations from 44 separate specimens obtained from 23 patients. Twenty-five of these were collected immediately after elastomeric device removal, representing steady-state concentrations, and the remaining 19 were each collected at least 45 minutes after device removal to determine clearance of the drug. Plasma concentrations ranged from 13 to 194 mg/L with median steady-state concentration of 51.5 mg/L and inter-quartile range of 24.6 mg/L. The time-course of flucloxacillin was best described by a 1-compartment model. The best three covariates, CrCL (ΔOFV= -11.7), eGFR (ΔOFV= -5.9) and serum albumin (ΔOFV= -5.8) were found to be equivalent in terms of decreasing the OFV. CrCL was superior in explaining inter individual variability. The best model for flucloxacillin clearance was a one compartment model with CrCL as the sole covariate. The estimated population parameters were 9.5 L for volume of distribution and 8.1 L/h for flucloxacillin clearance.

scholarly journals Model Based Identification of Linezolid Exposure–toxicity Thresholds in Hospitalized Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Jie Fang ◽  
Xiao-Shan Zhang ◽  
Chun-Hong Zhang ◽  
Zi-Ye Zhou ◽  
Lu Han ◽  
...  
Keyword(s):  
Steady State ◽  
Serum Albumin ◽  
White Cell Count ◽  
Plasma Concentrations ◽  
Regression Tree ◽  
Predictive Performance ◽  
Volume Of Distribution ◽  
Classification And Regression Tree ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic

Evidence supports linezolid therapeutic drug monitoring as the exposure–response relationship has been identified for toxicity among patients receiving linezolid, but the data to establish the upper limit are limited and the published toxicity thresholds range widely. The purpose of this study was to determine the linezolid exposure–toxicity thresholds to improve the safety of linezolid. This is a multicenter retrospective study of adult patients treated with linezolid from 2018 to 2019. The population pharmacokinetic model of linezolid was established based on 270 plasma concentrations in 152 patients, which showed creatinine clearance and white cell count are covariates affecting the clearance of linezolid, and serum albumin is the covariate affecting the volume of distribution. Classification and regression tree analysis was used to determine the linezolid exposure thresholds associated with an increased probability of toxicity. Among 141 patients included for toxicity analysis, the rate of occurring toxicity was significantly higher among patients with an AUC0-24, d1 ≥163 mg h/L, AUC0-24, d2 ≥207 mg h/L, AUC0-24, ss ≥210 mg h/L, and Cmin,d2 ≥6.9 mg/L, Cmin,ss ≥6.9 mg/L, while no threshold was discovered for Cmin, d1. Those exposure thresholds and duration of linezolid treatment were independently associated with linezolid-related toxicity in the logistic regression analyses. In addition, the predictive performance of the AUC0-24 and Cmin thresholds at day 2 and steady state were close. Considering that the AUC estimation is cumbersome, Cmin threshold at 48 h and steady state with a value of ≥6.9 mg/L is recommended to improve safety, especially for patients with renal insufficiency and patients with low serum albumin.

Novel strategy to personalise use of ibuprofen for closure of patent ductus arteriosus in preterm neonates

2021 ◽  
pp. archdischild-2020-321381
Author(s):  
Samira Samiee-Zafarghandy ◽  
Tamara van Donge ◽  
Gerhard Fusch ◽  
Marc Pfister ◽  
George Jacob ◽  
...  
Keyword(s):  
Patent Ductus Arteriosus ◽  
Gestational Age ◽  
Ductus Arteriosus ◽  
Plasma Concentrations ◽  
Preterm Neonates ◽  
Pharmacokinetic Parameters ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Target Exposure ◽  
Patent Ductus

ObjectiveExploration of a novel therapeutic drug monitoring (TDM) strategy to personalise use of ibuprofen for closure of patent ductus arteriosus (PDA) in preterm neonates.DesignProspective, single-centre, open-label, pharmacokinetics study in preterm neonates.SettingNeonatal intensive care unit at McMaster Children’s Hospital.PatientsNeonates with a gestational age ≤28+6 weeks treated with oral ibuprofen for closure of a PDA.MethodsPopulation pharmacokinetic parameters, concentration-time profiles and exposure metrics were obtained using pharmacometric modelling and simulation.Main outcome measureAssociation between ibuprofen plasma concentrations measured at various sampling time points on the first day of treatment and attainment of the target exposure over the first 3 days of treatment (AUC0–72h >900 mg·hour/L).ResultsTwenty-three preterm neonates (median birth weight 780 g and gestational age 25.9 weeks) were included, yielding 155 plasma ibuprofen plasma samples. Starting from 8 hours’ postdose on the first day, a strong correlation between ibuprofen concentrations and AUC0–72h was observed. At 8 hours after the first dose, an ibuprofen concentration >20.5 mg/L was associated with a 90% probability of reaching the target exposure.ConclusionWe designed a novel and practical TDM strategy and have shown that the chance of reaching the target exposure (AUC0–72h >900 mg·hour/L) can be predicted with a single sample collection on the first day of treatment. This newly acquired knowledge can be leveraged to personalise ibuprofen dosing regimens and improve the efficacy of ibuprofen use for pharmacological closure of a PDA.

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