Population Pharmacokinetic (PK) Modeling of Hydroxyurea for Therapeutic Drug Monitoring Applications in Children and Adolescents with Sickle Cell Disease

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2136-2136
Author(s):  
Pawel Wiczling ◽  
Robert I. Liem ◽  
Julie A. Panepinto ◽  
Uttam Garg ◽  
Susan M. Abdel-Rahman ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Sickle Cell ◽  
Drug Monitoring ◽  
Drug Exposure ◽  
Oral Drug ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Average Dose ◽  
Intersubject Variability ◽  
Exposure Response

Abstract Abstract 2136 Introduction: Sickle cell anemia (SCA) is an inherited disorder of abnormal hemoglobin synthesis. Hydroxyurea (HU) is the only disease modifying agent available for use in patients with SCA. Clinically, HU has been shown to decrease pain, number of transfusions, and development of acute chest syndrome as well as improve life expectancy in adults with SCA. Although HU is increasingly utilized to treat children with SCA, drug exposure-response relationships and therapeutic drug monitoring are not well characterized in the pediatric population. The exposure-response relationships of HU are currently being evaluated as is the potential role of therapeutic drug monitoring. Objective: The objective of this study was to develop a population pharmacokinetic (PK) model sufficient to describe HU disposition in serum and urine following oral drug administration in pediatric patients. Such a model is required for exploring concentration-effect relationships in children with SCA taking HU. Methods: PK was determined in 20 subjects (mean age 10.5 yr, range 5–17 yr) with SCA either as a single dose (SD, n=6, average dose 17.4 mg/kg) or at steady state (SS, n=14, average daily dose 25.5 mg/kg). Blood and urine samples for HU assay were taken throughout the 24 hour period post HU administration. HU was quantitated by a validated gas chromatography–mass spectrometry (GC-MS) method. Population nonlinear mixed-effect modeling was done using NONMEM software. Measured HU concentrations at specific sampling time points were compared to model predicted area under the curves (AUCs) to find the most predictive relationship. Results: A one-compartment model with first-order absorption and two elimination pathways (metabolic and renal) was used. The mean absorption rate constant differed for children < 8.5 years of age (19.5 h−1) as compared to those ≥ 8.5 years of age (2.1 h−1) and demonstrated high intersubject variability (76%). The population apparent volume of distribution (V/F) was 21.3 L (for an average weight patient of 30.7 kg) with an intersubject variability of 24.7%. The apparent renal (CLu/F) and metabolic (CLm/F) clearance was 3.47 L/hr and 3.52 L/hr, respectively, with the same between subject variability of 42%. Significant relationships (p<0.005) between both CL/F and V/F and body weight were found with these parameters increasing by 2.96% and 2.49%, respectively, for every kilogram difference from the median weight. Significant linear correlations were apparent between the plasma HU concentration at 0.75, 1, 1.5, 2, 4, and 6 hours post-dose; the most significant (p<0.01, r2 =0.71) occurring at 1.5 hours. Conclusion: In children with SCA, a population PK model parameterized from a classical PK study of HU was successful in describing HU disposition in plasma and urine. Data from the model also demonstrated that HU plasma concentrations at 1.5 or 2 hours after an oral dose of the drug were especially predictive of systemic drug exposure (as reflected by AUC). Data from this study also suggest that there may be age related differences in absorption rates. Further studies are warranted to confirm this finding. Disclosures: Off Label Use: Hydroxyurea is not labeled for use in children.

scholarly journals P73 Paediatric population pharmacokinetic modeling for gentamicin – is the current dose recommendation justified?

2019 ◽  
Vol 104 (6) ◽  
pp. e47.2-e47
Author(s):  
P Paioni ◽  
C Berger ◽  
SD Krämer
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Drug Exposure ◽  
Body Height ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
List Type ◽  
Dosing Regimen ◽  
Population Pharmacokinetic Modeling ◽  
Pediatr Infect

BackgroundMonitoring of gentamicin serum trough level (Cmin) is standard practice in children to prevent toxicity by accumulation1. Cmin < 2 mg/L are recommended. Peak serum concentration (Cmax) is not routinely measured although Cmax between 10 and 12 mg/L have been recommended balancing efficacy and toxicity2,3. We aimed to develop a population pharmacokinetic (PK) model for gentamicin in children to optimise current dosing regimens.MethodsAll patients receiving once daily intravenous gentamicin (5 mg/kg in children < 7 days and 7.5 mg/kg in children >7 days of age) at the University Children’s Hospital Zurich between 10/2017 and 01/2019 were eligible for this study. Children with cystic fibrosis and renal replacement procedures were excluded. Routine Cmin were measured in all patients before administration of the second or third dose. Additional gentamicin serum levels were measured 30 min (C30) and 4 h after the second dose in patients giving written informed consent. Data were analysed by non-linear mixed-effects modeling.Results165 patients (median age 34 days; IQR 15–56 days) were included in the study. A total number of 103 C30 and 166 Cmin measurements were available, respectively. C30 (mean 19.7 mg/L, SD ±6.1 mg/L) was >12 mg/L in 94/103 (91%) and Cmin >2 mg/mL in 3/166 (1.8%) measurements. The PK model successfully predicted most C30 >12 mg/L but performed poorly at the through levels.ConclusionsOur current gentamicin dosing regimen rarely leads to accumulation but most Cmax are above optimal range. The latter was successfully modelled. Although no evidence for a Cmax upper limit exists, toxicity has been associated with high drug exposure3. This calls for an adjustment of our dosing regimen using our PK model based on body height or weight in order to lower exposure. Further studies investigating the relationship between Cmax levels and clinical outcome and additional data for PK model testing are needed for validation.ReferencesRitz N, Bielicki J, Pfister M, van den Anker J. Therapeutic Drug Monitoring for Anti-infective Agents in Pediatrics: The Way Forward. Pediatr Infect Dis J. 2016;35(5):570–572.Chattopadhyay B. Newborns and gentamicin-how much and how often? J Antimicrob Chemother. 2002;49(1):13–16.Touw DJ, Westerman EM, Sprij AJ. Therapeutic drug monitoring of aminoglycosides in neonates. Clin Pharmacokinet. 2009;48(2):71–88.Disclosure(s)Nothing to disclose

Population Pharmacokinetics of Meropenem in Preterm Infants

2021 ◽  
Vol 76 (5) ◽  
pp. 497-505
Author(s):  
Irina B. Bondareva ◽  
Sergey K. Zyryanov ◽  
Aleksandra M. Kazanova
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Pharmacokinetic Parameter ◽  
Gestational Age ◽  
Drug Monitoring ◽  
Pharmacokinetic Parameters ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Variability ◽  
Older Children ◽  
Term Neonates

Background. Meropenem, a broad spectrum carbapenem antibiotic, is often used for newborns despite of limited data available on neonatal pharmacokinetics. Due to pharmacokinetic and pharmacodynamic differences as well as to significant changes in the human body related to growth and maturation of organs and systems, direct scaling and dosing extrapolation from adults or older children with adjustment on patients weight can result in increased risk of toxicity or treatment failures. Aims to evaluate the pharmacokinetics of meropenem in premature neonates based on therapeutic drug monitoring data in real clinical settings. Materials. Of 53 pre-term neonates included in the pharmacokinetic/pharmacodynamic analysis, in 39 (73.6%) patients, gestational age ranged from 23 to 30 weeks. Population and individual pharmacokinetic parameter values were estimated by the NPAG program from the Pmetrics package based on peak-trough therapeutic drug monitoring. Samples were assayed by high-performance liquid chromatography. One-compartment pharmacokinetic model with zero-order input and first-order elimination was used to fit concentration data and to predict pharmacokinetic parameter (%T MIC of free drug) for virtual patients with simulated fast, moderate and slow meropenem elimination received different dosage by minimum inhibitory concentration (MIC) level. Univariate and multivariate regression analysis was used to evaluate the influence of patients covariates (gestational age, postnatal age, postconceptual age, body weight, creatinine clearance calculated by Schwartz formula, etc) on estimated meropenem pharmacokinetic parameters. Results. The identified population pharmacokinetic parameters of meropenem in pre-term newborns (elimination half-lives T1/2 = 1.93 0.341 h; clearance CL = 0.26 0.085 L/h/ kg; volume of distribution V = 0.71 0.22 L/h) were in good agreement with those published in the literature for adults, neonates and older children. Pharmacokinetic/pharmacodynamic modeling demonstrated that a meropenem dosage regimen of 90 mg/kg/day administered using prolonged 3-hour infusion every 8 hours should be considered as potentially effective therapy if nosocomial infections with resistant organisms (MIC 8 mg/L) are treated. Conclusions. Neonates and especially pre-term neonates have a great pharmacokinetic variability. Meropenem dosing in premature newborns derived from population pharmacokinetic/pharmacodynamic model can partly overcome the variability, but not all pharmacokinetic variability can be explained by covariates in a model. Further personalizing based on Bayesian forecasting approach and a patients therapeutic drug monitoring data can help to achieve desired pharmacodynamic target.

scholarly journals P99 Clinical validation of published vancomycin population PK models in critically ill neonates

2019 ◽  
Vol 104 (6) ◽  
pp. e58.2-e59
Author(s):  
A van der Veen ◽  
RJ Keizer ◽  
W de Boode ◽  
A Somers ◽  
R Brüggemann ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
A Priori ◽  
Predictive Performance ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Suitable Model ◽  
List Type ◽  
A Posteriori ◽  
Target Attainment

BackgroundVancomycin is commonly used for treatment of severe Gram+ neonatal infections. Currently, even with the use of optimized dosing regimens and therapeutic drug monitoring (TDM), target attainment rates are abominable, leaving patients at risk for therapeutic failure and toxicity. Model-informed precision dosing (MIPD) offers a large potential to improve therapy in the individual patient.The aim of this study was to identify a suitable model for bedside MIPD by assessing the predictive performance of published population pharmacokinetic (popPK) models.MethodsA literature search was conducted to identify parametric popPK models. PK vancomycin data were retrospectively collected from NICU patients at the Radboud University Hospital, Nijmegen, The Netherlands. The model predictive performance was assessed by comparison of predictions to observations, calculation of bias (Mean Percentage Errors, MPE) and imprecision (Normalized Root Mean Squared Errors, NRMSE). Evaluations included both a priori (model covariate input) and a posteriori (model covariate and TDM concentration input) scenarios.Results265 TDM measurements from 65 neonates (median postmenstrual age:32 weeks [range:25–45 weeks]; median weight:1281g [range:597–5360g]; median serum creatinine:0,48 mg/dL [range:0,15–1,28 mg/dL]) were used for model evaluation. Six popPK models were evaluated1–6. A posteriori predictions of all models were consistently more accurate and precise compared to the a priori (starting dose) predictions. PopPK models of Frymoyer et al. and Capparelli et al. consistently performed best through all evaluations in both the a priori and a posteriori scenario (MPE ranging from -18 to 6,4% in a priori scenario and -6,5 to -3,8% in a posteriori scenario; NRMSE ranging from 34 to 40% in a priori scenario and 23 to 24% in a posteriori scenario).ConclusionLarge differences in predictive performance of popPK models were observed. Repeated therapeutic drug monitoring remains necessary to increase target attainment rate. Best performing models for bedside MIPD were identified in our patient population.ReferencesZhao W, Lopez E, Biran V, et al. ( 2013). Vancomycin continuous infusion in neonates: Dosing optimisation and therapeutic drug monitoring. Arch Dis Child;98(6):449–453.Capparelli EV, Lane JR, Romanowski GL, et al. ( 2001). The influences of renal function and maturation on vancomycin elimination in newborns and infants. J Clin Pharmacol, 41:927–934.De Cock RFW, Allegaert K, Brussee JM, et al. ( 2014). Simultaneous pharmacokinetic modeling of gentamicin, tobramycin and vancomycin clearance from neonates to adults: towards a semi-physiological function for maturation in glomerular filtration. Pharm Res;31(10):2642–2654.Frymoyer A, Hersh AL, El-Komy MH, et al. ( 2014). Association between vancomycin trough concentration and area under the concentration-time curve in neonates. Antimicrob Agents Chemother, 58(11):6454–6461.Anderson BJ, Allegaert K, Van Den Anker JN, Cossey V, Holford NHG. ( 2006). Vancomycin pharmacokinetics in preterm neonates and the prediction of adult clearance. Br J Clin Pharmacol;63(1):75–84.Germovsek E, Osborne L, Gunaratnam F, Lounis SA, Busquets FB, Sinha AK. ( 2019). Development and external evaluation of a population pharmacokinetic model for continuous and intermittent administration of vancomycin in neonates and infants using prospectively collected data. J Antimicrob Chemother, 1–9.Disclosure(s)R. Keizer is an employee and stockholder of InsightRX.

scholarly journals P346 Single-centre experience of ustekinumab: Therapeutic drug monitoring in Crohn’s disease patients

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S331-S333
Author(s):  
C Liefferinckx ◽  
M Fassin ◽  
D Thomas ◽  
C Minsart ◽  
A Cremer ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Therapeutic Drug Monitoring ◽  
Crohn's Disease ◽  
Median Time ◽  
Real World ◽  
Drug Monitoring ◽  
Drug Exposure ◽  
Therapeutic Drug ◽  
Loss Of Response

Abstract Background Therapeutic drug monitoring (TDM) is a diagnostic tool in the monitoring of anti-TNF therapies. Yet, the benefit for TDM of new biologics such as ustekinumab (USK) is still controversial in real-world experiences. Methods This monocentric retrospective study aims to correlate USK trough levels (TLs) with clinical and endoscopic data. All patients have given written consent to the Biobank (B2011/005). Endoscopic disease was defined as quiescent in absence of endoscopic lesions, mild disease in presence of few superficial ulcerations, moderate in presence of several ulcers and severe in presence of numerous deep ulcers and/or inflammatory stenosis. 313 serum USK samples from 67 Crohn’s disease patients were used to measure USK TL (USK ELISA, apDia) while 88 samples (at week 16, and before and after optimisation) were used to measure anti-drug antibody (ADA), using a drug-tolerant affinity capture elution anti-ustekinumab assay Results Demographic and baseline data of our population are presented in Table 1. The median follow-up was 73 weeks (IQR 39–92). An optimisation due to loss of response was required in 44.8% of patients (n = 30) after a median time of 38 weeks (IQR 24–55). To evaluate the drug efficacy, an endoscopy was performed in 61% of cases at a median time of 35 weeks (IQR 27–47). TLs were 5.2 µg/ml (IQR 2.1–8.8), 1.7 µg/ml (IQR 0.3–4.3) and 2.6 µg/ml (IQR 0.6–4.1) at week 8, 16 and 24, respectively. TLs at week 8 were correlated to the induction IV dose administrated (r = 0.3, p = 0.03). At week 16, low TLs were associated with higher endoscopic activity in the follow-up (p = 0.02), although this was not the case at week 8 (p = 0.5) (Figure 1). Patients not requiring an optimisation had higher TLs in maintenance than patients requiring optimisation (2.45 µg/ml (IQR 1.3–4.4) vs. 1.15 µg/ml (IQR 0.1–2.24), p = 0.008). Obviously, optimisation significantly increased TLs (1.15 µg/ml (IQR 0.1–2.24) vs. 6.6 µg/ml (IQR 2.3–11.3), p &lt; 0.001). ADA were undetectable in all the measured samples in maintenance. Conclusion This real-world experience confirms a drug exposure-endoscopic response relationship. Week 16 seems to be an appropriate time point to monitor drug exposure. Earlier USK TLs, at week 8, appear less valuable to be monitored due to the influence of initial IV dose. The absence of immunogenicity suggests that it is not a key driver in the loss of response.

scholarly journals Multicenter Study of Posaconazole Therapeutic Drug Monitoring: Exposure-Response Relationship and Factors Affecting Concentration

2012 ◽  
Vol 56 (11) ◽  
pp. 5503-5510 ◽  
Author(s):  
Michael J. Dolton ◽  
John E. Ray ◽  
Sharon C.-A. Chen ◽  
Kingsley Ng ◽  
Lisa Pont ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Interactions ◽  
Fungal Infection ◽  
Drug Monitoring ◽  
Linear Regression Analysis ◽  
Therapeutic Drug ◽  
Cell Transplant ◽  
Clinical Factors ◽  
Hematopoietic Stem ◽  
Exposure Response

ABSTRACTPosaconazole has an important role in the prophylaxis and salvage treatment of invasive fungal infections (IFIs), although poor and variable bioavailability remains an important clinical concern. Therapeutic drug monitoring of posaconazole concentrations has remained contentious, with the use of relatively small patient cohorts in previous studies hindering the assessment of exposure-response relationships. This multicenter retrospective study aimed to investigate relationships between posaconazole concentration and clinical outcomes and adverse events and to assess clinical factors and drug interactions that may affect posaconazole concentrations. Medical records were reviewed for patients who received posaconazole and had ≥1 concentration measured at six hospitals in Australia. Data from 86 patients with 541 posaconazole concentrations were included in the study. Among 72 patients taking posaconazole for prophylaxis against IFIs, 12 patients (17%) developed a breakthrough fungal infection; median posaconazole concentrations were significantly lower than in those who did not develop fungal infection (median [range], 289 [50 to 471] ng/ml versus 485 [0 to 2,035] ng/ml;P< 0.01). The median posaconazole concentration was a significant predictor of breakthrough fungal infection via binary logistic regression (P< 0.05). A multiple linear regression analysis identified a number of significant drug interactions associated with reduced posaconazole exposure, including coadministration with proton pump inhibitors, metoclopramide, phenytoin or rifampin, and the H2antagonist ranitidine (P< 0.01). Clinical factors such as mucositis, diarrhea, and the early posttransplant period in hematopoietic stem cell transplant recipients were also associated with reduced posaconazole exposure (P< 0.01). Low posaconazole concentrations are common and are associated with breakthrough fungal infection, supporting the utility of monitoring posaconazole concentrations to ensure optimal systemic exposure.

scholarly journals Posaconazole Exposure-Response Relationship: Evaluating the Utility of Therapeutic Drug Monitoring

2012 ◽  
Vol 56 (6) ◽  
pp. 2806-2813 ◽  
Author(s):  
Michael J. Dolton ◽  
John E. Ray ◽  
Deborah Marriott ◽  
Andrew J. McLachlan
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Fungal Infections ◽  
Gastrointestinal Disease ◽  
Plasma Concentrations ◽  
Response To Therapy ◽  
Common Finding ◽  
Therapeutic Drug ◽  
Response Relationship ◽  
Exposure Response

ABSTRACTPosaconazole has become an important part of the antifungal armamentarium in the prophylaxis and salvage treatment of invasive fungal infections (IFIs). Structurally related to itraconazole, posaconazole displays low oral bioavailability due to poor solubility, with significant drug interactions and gastrointestinal disease also contributing to the generally low posaconazole plasma concentrations observed in patients. While therapeutic drug monitoring (TDM) of plasma concentrations is widely accepted for other triazole antifungal agents such as voriconazole, the utility of TDM for posaconazole is controversial due to debate over the relationship between posaconazole exposure in plasma and clinical response to therapy. This review examines the available evidence for a relationship between plasma concentration and clinical efficacy for posaconazole, as well as evaluating the utility of TDM and providing provisional target concentrations for posaconazole therapy. Increasing evidence supports an exposure-response relationship for plasma posaconazole concentrations for prophylaxis and treatment of IFIs; a clear relationship has not been identified between posaconazole concentration and toxicity. Intracellular and intrapulmonary concentrations have been studied for posaconazole but have not been correlated to clinical outcomes. In view of the high mortality and cost associated with the treatment of IFIs, increasing evidence of an exposure-response relationship for posaconazole efficacy in the prevention and treatment of IFIs, and the common finding of low posaconazole concentrations in patients, TDM for posaconazole is likely to be of significant clinical utility. In patients with subtherapeutic posaconazole concentrations, increased dose frequency, administration with high-fat meals, and withdrawal of interacting medications from therapy are useful strategies to improve systemic absorption.

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