A Population Physiologically‐Based Pharmacokinetic Model to Characterize Antibody Disposition in Pediatrics and Evaluation of the Model using Infliximab

Aims: In order to better predict the pharmacokinetics (PK) of antibodies in children, and to facilitate dose optimization of antibodies in pediatric patients, there is a need to develop systems PK models that integrate ontogeny related changes in human physiological parameters. Methods: A population-based physiological-based PK (PBPK) model to characterize antibody PK in pediatrics has been developed, by incorporating age-related changes in body weight, organ weight, organ blood flow rate, and interstitial volumes in a previously published platform model. The model was further used to perform Monte Carlo simulations to investigate clearance vs. age and dose-exposure relationship for infliximab. Results: By estimating only one parameter and associated interindividual variability, the model was able to characterize clinical PK of infliximab from two pediatric cohorts (n=141, 4-19 years) reasonably well. Model simulations demonstrated that only 50% of children reached desired trough concentrations when receiving FDA-labelled dosing regimen for infliximab, suggesting that higher doses and/or more frequent dosing are needed to achieve target trough concentrations of this antibody. Conclusion: The pediatric PBPK model presented here can serve as a framework to characterize the PK of antibodies in pediatric patients. The model can also be applied to other protein therapeutics to advance precision medicine paradigm and optimize antibody dosing regimens in children.

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Challenges of Vancomycin Dosing and Therapeutic Monitoring in Neonates

The Journal of Pediatric Pharmacology and Therapeutics ◽

10.5863/1551-6776-25.6.476 ◽

2020 ◽

Vol 25 (6) ◽

pp. 476-484

Author(s):

Jennifer T. Pham

Keyword(s):

Pediatric Patients ◽

Late Onset ◽

Therapeutic Monitoring ◽

Pharmacokinetic Parameters ◽

Coagulase Negative Staphylococci ◽

Optimal Dosing ◽

Increased Risk ◽

Dosing Regimens ◽

Vancomycin Trough ◽

Trough Concentrations

Late-onset sepsis in neonates can lead to significant morbidity and mortality, especially in preterm infants. Vancomycin is commonly prescribed for the treatment of Gram-positive organisms, particularly methicillin-resistant Staphylococcus aureus (MRSA), coagulase-negative staphylococci, and ampicillin-resistant Enterococcus species in adult and pediatric patients. Currently, there is no consensus on optimal dosing and monitoring of vancomycin in neonates. Different vancomycin dosing regimens exist for neonates, but with many of these regimens, obtaining therapeutic trough concentrations can be difficult. In 2011, the Infectious Diseases Society of America recommended vancomycin trough concentrations of 15 to 20 mg/L or an AUC/MIC ratio of ≥400 for severe invasive diseases (e.g., MRSA) in adult and pediatric patients. Owing to recent reports of increased risk of nephrotoxicity associated with vancomycin trough concentrations of 15 to 20 mg/L and AUC/MIC of ≥400, a revised consensus guideline, recently published in 2020, no longer recommends monitoring vancomycin trough concentrations in adult patients. The guideline recommends an AUC/MIC of 400 to 600, which has been found to achieve clinical efficacy while reducing nephrotoxicity. However, these recommendations were derived solely from adult literature, as there are limited clinical outcomes data in pediatric and neonatal patients. Furthermore, owing to the variation of vancomycin pharmacokinetic parameters among the neonatal population, these recommendations for achieving vancomycin AUC/MIC of 400 to 600 in neonates require further investigation. This review will discuss the challenges of achieving optimal vancomycin dosing and monitoring in neonatal patients.

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Development and Application of a Life-Stage Physiologically Based Pharmacokinetic (PBPK) Model to the Assessment of Internal Dose of Pyrethroids in Humans

Toxicological Sciences ◽

10.1093/toxsci/kfz211 ◽

2019 ◽

Vol 173 (1) ◽

pp. 86-99 ◽

Cited By ~ 9

Author(s):

Pankajini Mallick ◽

Marjory Moreau ◽

Gina Song ◽

Alina Y Efremenko ◽

Salil N Pendse ◽

...

Keyword(s):

Blood Flow ◽

Pbpk Model ◽

Life Stage ◽

Internal Exposure ◽

Target Tissue ◽

Physiologically Based Pharmacokinetic ◽

Age Related ◽

Physiologically Based

Abstract To address concerns around age-related sensitivity to pyrethroids, a life-stage physiologically based pharmacokinetic (PBPK) model, supported by in vitro to in vivo extrapolation (IVIVE) was developed. The model was used to predict age-dependent changes in target tissue exposure of 8 pyrethroids; deltamethrin (DLM), cis-permethrin (CPM), trans-permethrin, esfenvalerate, cyphenothrin, cyhalothrin, cyfluthrin, and bifenthrin. A single model structure was used based on previous work in the rat. Intrinsic clearance (CLint) of each individual cytochrome P450 or carboxylesterase (CES) enzyme that are active for a given pyrethroid were measured in vitro, then biologically scaled to obtain in vivo age-specific total hepatic CLint. These IVIVE results indicate that, except for bifenthrin, CES enzymes are largely responsible for human hepatic metabolism (>50% contribution). Given the high efficiency and rapid maturation of CESs, clearance of the pyrethroids is very efficient across ages, leading to a blood flow-limited metabolism. Together with age-specific physiological parameters, in particular liver blood flow, the efficient metabolic clearance of pyrethroids across ages results in comparable to or even lower internal exposure in the target tissue (brain) in children than that in adults in response to the same level of exposure to a given pyrethroid (Cmax ratio in brain between 1- and 25-year old = 0.69, 0.93, and 0.94 for DLM, bifenthrin, and CPM, respectively). Our study demonstrated that a life-stage PBPK modeling approach, coupled with IVIVE, provides a robust framework for evaluating age-related differences in pharmacokinetics and internal target tissue exposure in humans for the pyrethroid class of chemicals.

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Ceftolozane/tazobactam exposure in critically ill patients undergoing continuous renal replacement therapy: a PK/PD approach to tailor dosing

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkaa416 ◽

2020 ◽

Vol 76 (1) ◽

pp. 199-205 ◽

Cited By ~ 1

Author(s):

Milo Gatti ◽

Maddalena Giannella ◽

Emanuel Raschi ◽

Pierluigi Viale ◽

Fabrizio De Ponti

Keyword(s):

Renal Replacement Therapy ◽

Continuous Renal Replacement Therapy ◽

Replacement Therapy ◽

Flow Rate ◽

Case Reports ◽

Blood Flow Rate ◽

Pubmed Database ◽

Effluent Flow Rate ◽

Dosing Regimens ◽

Trough Concentrations

Abstract Objectives To investigate the influence of continuous renal replacement therapy (CRRT) intensity on the clearance of ceftolozane/tazobactam in critical care patients, and to evaluate if the reported doses would achieve an optimal pharmacokinetic/pharmacodynamic (PK/PD) target against Pseudomonas aeruginosa exhibiting different MICs. Methods The MEDLINE–PubMed database was searched from inception to January 2020 to retrieve observational studies or case reports investigating the PK behaviour of ceftolozane/tazobactam during CRRT. Relevant CRRT settings and PK variables were extracted, and the influence of CRRT intensity on ceftolozane/tazobactam total clearance (CLtot) was determined by simple linear regression. The optimal PK/PD target for the reported doses was deemed to be achieved when ceftolozane trough concentrations (Cmin) were above the MIC (less intensive target) or four times the MIC (intensive target) for P. aeruginosa. Results Data from six studies including 11 patients (mean age 56.6 years) were analysed. Mean blood flow rate and effluent flow rate were 161.8 mL/min and 2383.4 mL/h, respectively. Ceftolozane Cmin ranged from 25.8 to 79.4 mg/L. A significant correlation was found for ceftolozane CLtot and effluent flow rate (P = 0.027). The intensive PK/PD target was achieved by 100% and 50% of the reported doses for MIC, respectively, up to 4 and 8 mg/L. Conclusions A significant correlation between effluent flow rate and ceftolozane clearance during CRRT could be identified. Higher dosing regimens coupled with continuous/extended infusion may be required in the case of higher CRRT intensity, deep-seated infections or poorly susceptible isolates. Larger studies assessing ceftolozane PK in different CRRT settings are warranted.

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Use of Body Surface Area for Dosing of Vancomycin

The Journal of Pediatric Pharmacology and Therapeutics ◽

10.5863/1551-6776-24.4.296 ◽

2019 ◽

Vol 24 (4) ◽

pp. 296-303

Author(s):

Elizabeth L. Sawrey ◽

Mary W. Subramanian ◽

Kacy A. Ramirez ◽

Brandy S. Snyder ◽

Brittany B. Logston ◽

...

Keyword(s):

Serum Concentration ◽

Surface Area ◽

Body Surface ◽

Pediatric Patients ◽

Obese Patients ◽

Dosing Regimen ◽

Trough Serum ◽

Dosing Regimens ◽

Vancomycin Trough ◽

Trough Concentrations

OBJECTIVES Vancomycin weight-based dosing regimens often fail to achieve therapeutic trough serum concentration in children ≤12 years of age and rigorous studies evaluating efficacy and safety of body surface area (BSA)–based dosing regimens have not been performed. We compared vancomycin trough serum concentrations in pediatric patients receiving a weight- or BSA-based dosing regimen. METHODS This was a single-center, retrospective study evaluating pediatric patients, ages 1 to 12 years, who received vancomycin from September 2012 to October 2015. Patients received a minimum of 3 consecutive doses at the same scheduled interval within a dosing regimen prior to a measured vancomycin serum trough concentration. The primary outcome was percentage of initial vancomycin trough concentrations ≥10 mg/L. The secondary outcomes were percentage of supratherapeutic, therapeutic, and subtherapeutic vancomycin serum concentration for all patients, including a subset of overweight and obese patients, and number of nephrotoxic occurrences. RESULTS BSA-based dosing regimens resulted in 50% of the initial vancomycin trough concentrations ≥ 10 mg/L compared with 17% for the weight-based dosing regimens (p < 0.0001). No statistically significant differences were noted between the 2 dosing regimens for supratherapeutic, therapeutic, or subtherapeutic trough concentrations for all patients, and for the subset of overweight and obese patients. Nephrotoxic occurrences were noted in 7% of the weight-based dosing regimens compared with none in the BSA-based dosing regimens. CONCLUSIONS A BSA-based vancomycin dosing regimen resulted in significantly more initial vancomycin trough concentrations ≥10 mg/L and trended towards higher initial vancomycin trough concentrations without observable nephrotoxicity.

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A Physiologically Based Pharmacokinetic Model for Predicting Diazepam Pharmacokinetics after Intravenous, Oral, Intranasal, and Rectal Applications

Pharmaceutics ◽

10.3390/pharmaceutics13091480 ◽

2021 ◽

Vol 13 (9) ◽

pp. 1480

Author(s):

Sundus Khalid ◽

Muhammad Fawad Rasool ◽

Imran Imran ◽

Abdul Majeed ◽

Hamid Saeed ◽

...

Keyword(s):

Drug Response ◽

Pharmacokinetic Model ◽

Pbpk Model ◽

Adult Population ◽

Population Based ◽

Dosage Forms ◽

Whole Body ◽

Clinical Use ◽

Physiologically Based Pharmacokinetic ◽

Physiologically Based

Diazepam is one of the most prescribed anxiolytic and anticonvulsant that is administered through intravenous (IV), oral, intramuscular, intranasal, and rectal routes. To facilitate the clinical use of diazepam, there is a need to develop formulations that are convenient to administer in ambulatory settings. The present study aimed to develop and evaluate a physiologically based pharmacokinetic (PBPK) model for diazepam that is capable of predicting its pharmacokinetics (PK) after IV, oral, intranasal, and rectal applications using a whole-body population-based PBPK simulator, Simcyp®. The model evaluation was carried out using visual predictive checks, observed/predicted ratios (Robs/pred), and the average fold error (AFE) of PK parameters. The Diazepam PBPK model successfully predicted diazepam PK in an adult population after doses were administered through IV, oral, intranasal, and rectal routes, as the Robs/pred of all PK parameters were within a two-fold error range. The developed model can be used for the development and optimization of novel diazepam dosage forms, and it can be extended to simulate drug response in situations where no clinical data are available (healthy and disease).

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Evaluation of Posaconazole Dosing in Children and Young Adults: A Single-Center Review

The Journal of Pediatric Pharmacology and Therapeutics ◽

10.5863/1551-6776-26.8.834 ◽

2021 ◽

Vol 26 (8) ◽

pp. 834-840

Author(s):

Lauren M. Garner ◽

Susan Ngo ◽

Jenna Bognaski Kaplan ◽

William S. Wilson ◽

Cameron J. McKinzie

Keyword(s):

Pediatric Patients ◽

Liver Function Tests ◽

Current Data ◽

Dosing Regimen ◽

Drug Concentrations ◽

Dosing Regimens ◽

Dosing Strategies ◽

Trough Concentrations ◽

Dosing Strategy ◽

Dose Modifications

OBJECTIVE Initial posaconazole dosing regimens in children often do not achieve target concentrations, and data continue to support the need for higher initial dosing regimens. The objective of this study is to contribute to the current data regarding suboptimal posaconazole dosing in pediatric patients by retrospectively observing dosing strategies and subsequent drug concentrations. METHODS This study was conducted at a single institution in 27 patients aged 1 to 21 years. Patients who were initiated on any formulation of posaconazole for prophylaxis or treatment while admitted to the hospital were included. The primary outcome was to determine the percentage of pediatric patients who achieved the targeted trough concentration using their initial posaconazole dosing regimen. Secondary outcomes included percentage of patients who experienced a breakthrough invasive fungal infection (IFI), percentage of patients with elevated liver function tests (LFTs), and discontinuation for any reason. RESULTS There were 15 patients (55.5%) who reached desired trough serum concentration after the initial dosing regimen. The number of dose modifications to achieve the desired trough ranged from 1 to 3. Most patients received delayed-release tablets (n = 17), and the average doses for reaching prophylactic and treatment trough concentrations were 6.1 mg/kg/day and 11 mg/kg/day, respectively. There were 2 patients (7.4%) who experienced breakthrough IFI. Overall, 5 patients developed elevated LFTs and 7 patients discontinued treatment early. CONCLUSIONS The results describe a single population of pediatric patients, of whom 55% were able to achieve target trough concentrations of posaconazole with the initial dosing strategy used.

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Prediction of dolutegravir pharmacokinetics and dose optimization in neonates via physiologically based pharmacokinetic (PBPK) modelling

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkz506 ◽

2019 ◽

Vol 75 (3) ◽

pp. 640-647 ◽

Cited By ~ 2

Author(s):

Fazila Bunglawala ◽

Rajith K R Rajoli ◽

Mark Mirochnick ◽

Andrew Owen ◽

Marco Siccardi

Keyword(s):

Clinical Data ◽

Pbpk Model ◽

Simulated Data ◽

Integrase Inhibitor ◽

Antiretroviral Drugs ◽

Pbpk Modelling ◽

Physiologically Based Pharmacokinetic ◽

Age Related ◽

Optimal Dosing ◽

Physiologically Based

Abstract Background Only a few antiretroviral drugs (ARVs) are recommended for use during the neonatal period and there is a need for more to be approved to increase treatment and prophylaxis strategies. Dolutegravir, a selective integrase inhibitor, has potential for treatment of HIV infection and prophylaxis of transmission in neonates. Objectives To model the pharmacokinetics of dolutegravir in neonates and to simulate a theoretical optimal dosing regimen. Methods The physiologically based pharmacokinetic (PBPK) model was built incorporating the age-related changes observed in neonates. Virtual neonates between 0 and 28 days were simulated. The model was validated against observed clinical data for raltegravir and midazolam in neonates, prior to the prediction of dolutegravir pharmacokinetics. Results Both raltegravir and midazolam passed the criteria for model qualification, with simulated data within 1.8-fold of clinical data. The qualified model predicted the pharmacokinetics for several multidose regimens of dolutegravir. Regimen 6 involved 5 mg doses with a 48 h interval from Day 1–20, increasing to 5 mg once daily on Week 3, yielding AUC and Ctrough values of 37.2 mg·h/L and 1.3 mg/L, respectively. These exposures are consistent with those observed in paediatric patients receiving dolutegravir. Conclusions Dolutegravir pharmacokinetics were successfully simulated in the neonatal PBPK model. The predictions suggest that during the first 3 weeks of life a 5 mg dose administered every 48 h may achieve plasma exposures needed for therapy and prophylaxis.

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Physiologically-Based Pharmacokinetic (PBPK) Modeling Providing Insights into Fentanyl Pharmacokinetics in Adults and Pediatric Patients

Pharmaceutics ◽

10.3390/pharmaceutics12100908 ◽

2020 ◽

Vol 12 (10) ◽

pp. 908

Author(s):

Lukas Kovar ◽

Andreas Weber ◽

Michael Zemlin ◽

Yvonne Kohl ◽

Robert Bals ◽

...

Keyword(s):

Pbpk Model ◽

Peak Plasma ◽

Plasma Concentrations ◽

Pbpk Modeling ◽

Pharmacokinetic Studies ◽

Pbpk Models ◽

Physiologically Based Pharmacokinetic ◽

Age Related ◽

Physiologically Based ◽

Pediatric Populations

Fentanyl is widely used for analgesia, sedation, and anesthesia both in adult and pediatric populations. Yet, only few pharmacokinetic studies of fentanyl in pediatrics exist as conducting clinical trials in this population is especially challenging. Physiologically-based pharmacokinetic (PBPK) modeling is a mechanistic approach to explore drug pharmacokinetics and allows extrapolation from adult to pediatric populations based on age-related physiological differences. The aim of this study was to develop a PBPK model of fentanyl and norfentanyl for both adult and pediatric populations. The adult PBPK model was established in PK-Sim® using data from 16 clinical studies and was scaled to several pediatric subpopulations. ~93% of the predicted AUClast values in adults and ~88% in pediatrics were within 2-fold of the corresponding value observed. The adult PBPK model predicted a fraction of fentanyl dose metabolized to norfentanyl of ~33% and a fraction excreted in urine of ~7%. In addition, the pediatric PBPK model was used to simulate differences in peak plasma concentrations after bolus injections and short infusions. The novel PBPK models could be helpful to further investigate fentanyl pharmacokinetics in both adult and pediatric populations.

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Development of Physiologically Based Pharmacokinetic Model for Orally Administered Fexuprazan in Humans

Pharmaceutics ◽

10.3390/pharmaceutics13060813 ◽

2021 ◽

Vol 13 (6) ◽

pp. 813

Author(s):

Yoo-Seong Jeong ◽

Min-Soo Kim ◽

Nora Lee ◽

Areum Lee ◽

Yoon-Jee Chae ◽

...

Keyword(s):

Gastric Acid ◽

Pbpk Model ◽

Pbpk Modeling ◽

Drug Candidate ◽

Metabolite Formation ◽

Pbpk Models ◽

Physiologically Based Pharmacokinetic ◽

Physiologically Based

Fexuprazan is a new drug candidate in the potassium-competitive acid blocker (P-CAB) family. As proton pump inhibitors (PPIs), P-CABs inhibit gastric acid secretion and can be used to treat gastric acid-related disorders such as gastroesophageal reflux disease (GERD). Physiologically based pharmacokinetic (PBPK) models predict drug interactions as pharmacokinetic profiles in biological matrices can be mechanistically simulated. Here, we propose an optimized and validated PBPK model for fexuprazan by integrating in vitro, in vivo, and in silico data. The extent of fexuprazan tissue distribution in humans was predicted using tissue-to-plasma partition coefficients in rats and the allometric relationships of fexuprazan distribution volumes (VSS) among preclinical species. Urinary fexuprazan excretion was minimal (0.29–2.02%), and this drug was eliminated primarily by the liver and metabolite formation. The fraction absorbed (Fa) of 0.761, estimated from the PBPK modeling, was consistent with the physicochemical properties of fexuprazan, including its in vitro solubility and permeability. The predicted oral bioavailability of fexuprazan (38.4–38.6%) was within the range of the preclinical datasets. The Cmax, AUClast, and time-concentration profiles predicted by the PBPK model established by the learning set were accurately predicted for the validation sets.

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Incidence of diabetes mellitus among people living with and without HIV in British Columbia, Canada between 2001 and 2013: a longitudinal population-based cohort study

BMJ Open ◽

10.1136/bmjopen-2021-048744 ◽

2021 ◽

Vol 11 (5) ◽

pp. e048744

Author(s):

Andreea Bratu ◽

Taylor McLinden ◽

Katherine Kooij ◽

Monica Ye ◽

Jenny Li ◽

...

Keyword(s):

Diabetes Mellitus ◽

British Columbia ◽

Cohort Study ◽

Population Based ◽

Incidence Rates ◽

Trend Test ◽

People Living With Hiv ◽

Age Related ◽

Hiv Serostatus ◽

The Impact

IntroductionPeople living with HIV (PLHIV) are increasingly at risk of age-related comorbidities such as diabetes mellitus (DM). While DM is associated with elevated mortality and morbidity, understanding of DM among PLHIV is limited. We assessed the incidence of DM among people living with and without HIV in British Columbia (BC), Canada, during 2001–2013.MethodsWe used longitudinal data from a population-based cohort study linking clinical data and administrative health data. We included PLHIV who were antiretroviral therapy (ART) naïve at baseline, and 1:5 age-sex-matched persons without HIV. All participants had ≥5 years of historic data pre-baseline and ≥1 year(s) of follow-up. DM was identified using the BC Ministry of Health’s definitions applied to hospitalisation, physician billing and drug dispensation datasets. Incident DM was identified using a 5-year run-in period. In addition to unadjusted incidence rates (IRs), we estimated adjusted incidence rate ratios (IRR) using Poisson regression and assessed annual trends in DM IRs per 1000 person years (PYs) between 2001 and 2013.ResultsA total of 129 PLHIV and 636 individuals without HIV developed DM over 17 529 PYs and 88,672 PYs, respectively. The unadjusted IRs of DM per 1000 PYs were 7.4 (95% CI 6.2 to 8.8) among PLHIV and 7.2 (95% CI 6.6 to 7.8) for individuals without HIV. After adjustment for confounding, HIV serostatus was not associated with DM incidence (adjusted IRR: 1.03, 95% CI 0.83 to 1.27). DM incidence did not increase over time among PLHIV (Kendall trend test: p=0.9369), but it increased among persons without HIV between 2001 and 2013 (p=0.0136).ConclusionsAfter adjustment, HIV serostatus was not associated with incidence of DM, between 2001 and 2013. Future studies should investigate the impact of ART on mitigating the potential risk of DM among PLHIV.

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