P85 Prediction of raltegravir plasma concentration in HIV paediatric patients using physiologically-based pharmacokinetic model

BackgroundRaltegravir is a drug used to treat patients with HIV infection. Understanding the disposition kinetics including the ontogeny of the major metabolic enzyme (UGT1A1) is important in prediction of raltaeravir pharmacokinetics in paediatric patients.MethodsSim-Raltegravir compound file in Simcyp simulator version 18 was used to predict pharmacokinetics in paediatric subjects aged 4 weeks to 6 months, 0.5 to 2, 2 to 6 and 6 to 12 years. Details of trial design were matched as closely as possible with a clinical study.1 Rate of absorption and variability in first order absorption model within Simcyp were set to the reported values. Predicted plasma concentration time profiles with 5th and 95th percentile were compared with observations.ResultsThe predicted vs. observed geometric mean area under plasma concentration-time profile of raltegravir was 18.4 vs. 22.3 µM.h in subjects 4 weeks to 6 months and 16.5 vs. 19.8 µM.h in those 0.5 to 2 years old. In 2 to 6 and 6 to 12 year olds around 80% and 85% of observed data were within 5th and 95th percentile of the predictions.ConclusionThe results show that the UGT1A1 ontogeny profile in the Simcyp version 18 adequately addressed age-related differences in pharmacokinetics of raltegravir.ReferenceRizk, M., et al, J Clin Pharmacol 2015; 55(7):748–56Disclosure(s)Nothing to disclose

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Physiologically Based Pharmacokinetic Modeling of Cefadroxil in Mouse, Rat, and Human to Predict Concentration–Time Profile at Infected Tissue

Frontiers in Pharmacology ◽

10.3389/fphar.2021.692741 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zhongxia Tan ◽

Youxi Zhang ◽

Chao Wang ◽

Le Sun

Keyword(s):

Plasma Concentration ◽

Pbpk Model ◽

Oral Absorption ◽

Time Profile ◽

Infected Tissue ◽

Dose Selection ◽

Pbpk Models ◽

Physiologically Based Pharmacokinetic ◽

Concentration Time ◽

Physiologically Based

The aim of this study was to develop physiologically based pharmacokinetic (PBPK) models capable of simulating cefadroxil concentrations in plasma and tissues in mouse, rat, and human. PBPK models in this study consisted of 14 tissues and 2 blood compartments. They were established using measured tissue to plasma partition coefficient (Kp) in mouse and rat, absolute expression levels of hPEPT1 along the entire length of the human intestine, and the transporter kinetic parameters. The PBPK models also assumed that all the tissues were well-stirred compartments with perfusion rate limitations, and the ratio of the concentration in tissue to the unbound concentration in plasma is identical across species. These PBPK models were validated strictly by a series of observed plasma concentration–time profile data. The average fold error (AFE) and absolute average fold error (AAFE) values were all less than 2. The models’ rationality and accuracy were further demonstrated by the almost consistent Vss calculated by the PBPK model and noncompartmental method, as well as the good allometric scaling relationship of Vss and CL. The model suggests that hPEPT1 is the major transporter responsible for the oral absorption of cefadroxil in human, and the plasma concentration–time profiles of cefadroxil were not sensitive to dissolution rate faster than T85% = 2 h. The cefadroxil PBPK model in human is reliable and can be used to predict concentration–time profile at infected tissue. It may be useful for dose selection and informative decision-making during clinical trials and dosage form design of cefadroxil and provide a reference for the PBPK model establishment of hPEPT1 substrate.

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O07 Predictive performance of a physiologically based pharmacokinetic model of caffeine in the preterm population

Archives of Disease in Childhood ◽

10.1136/archdischild-2019-esdppp.7 ◽

2019 ◽

Vol 104 (6) ◽

pp. e3.2-e3

Author(s):

A Pansari ◽

K Abduljalil ◽

T Johnson

Keyword(s):

Plasma Concentration ◽

Pharmacokinetic Model ◽

Plasma Concentrations ◽

Predictive Performance ◽

Time Profile ◽

Preterm Neonates ◽

Pharmacokinetic Parameters ◽

Dose Administration ◽

Physiologically Based Pharmacokinetic ◽

Concentration Time

BackgroundCaffeine has been extensively used in the treatment of apnoea in premature infants,1 its disposition varies with postnatal age2 and can differ markedly between premature and term neonates.MethodsThe Preterm population within the Simcyp Simulator V18R1 population library was used to replicate clinical studies to predict caffeine exposure after single3 and multiple4 intravenous administration to preterm neonates of gestational weeks 28.5 and 29 (28–33) respectively, ranging in postnatal age of 3–30 days and 0–3 days respectively. Predictive performance of the Physiologically Based Pharmacokinetic Model (PBPK) was evaluated by comparing the simulated to the clinical results. A population simulation was performed for the single dose study as only pharmacokinetic parameters were available. However, for multiple doses study, where individual plasma concentration-time profile data were available, simulations were performed for each individual.ResultsPBPK model predictions for caffeine in preterm neonates were in good agreement with the clinical observations. In the case of single dose administration, the ratios of predicted vs observed mean Volume of distribution (Vss), peak plasma concentration (Cmax), Clearance (CL) and Half-life (t1/2) were 1, 1.2, 1 and 1.1, respectively. Individual predicted concentration-time profiles following multiple dose administration were in close agreement with the observed data for all 16 subjects, overall 95% of individual observed data points were within the 5th and 95th percentile of predicted plasma concentration-time profile.ConclusionsThe predictive performance of preterm PBPK models for caffeine was found to be appropriate. A similar PBPK approach can be utilized in the clinics for the accurate prediction of pharmacokinetic parameters and plasma concentrations and for dosage adjustment to attain specific plasma concentrations of drugs in premature population.ReferencesGiacoia, et al. Effects of formula feeding on oral absorption of caffeine in premature infants. Dev Pharmacol Ther 1989; 12:205–210.Johnson, et al. Prediction of the clearance of eleven drugs and associated variability in neonates, infants and children. Clin Pharmacokinet 2006; 45(9):931–56.Aranda, et al. Population Pharmacokinetic profile of caffeine in the premature newborn infant with apnea; The Journal of Pediatrics 1979; 94(4.):663–668.Lee, et al. Caffeine in apnoeic asian neonates: a sparse data analysis. Br J Clin Pharmacol 2002; 54:31–37.Disclosure(s)Nothing to disclose

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An Investigation into the Prediction of the Plasma Concentration-Time Profile and Its Interindividual Variability for a Range of Flavin-Containing Monooxygenase Substrates Using a Physiologically Based Pharmacokinetic Modeling Approach

Drug Metabolism and Disposition ◽

10.1124/dmd.118.080648 ◽

2018 ◽

Vol 46 (9) ◽

pp. 1259-1267 ◽

Cited By ~ 5

Author(s):

Venkatesh Pilla Reddy ◽

Barry C. Jones ◽

Nicola Colclough ◽

Abhishek Srivastava ◽

Joanne Wilson ◽

...

Keyword(s):

Plasma Concentration ◽

Interindividual Variability ◽

Time Profile ◽

Pharmacokinetic Modeling ◽

Physiologically Based Pharmacokinetic Modeling ◽

Modeling Approach ◽

Physiologically Based Pharmacokinetic ◽

Concentration Time ◽

Physiologically Based

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Physiologically Based Pharmacokinetic Models of Probenecid and Furosemide to Predict Transporter Mediated Drug-Drug Interactions

Pharmaceutical Research ◽

10.1007/s11095-020-02964-z ◽

2020 ◽

Vol 37 (12) ◽

Author(s):

Hannah Britz ◽

Nina Hanke ◽

Mitchell E. Taub ◽

Ting Wang ◽

Bhagwat Prasad ◽

...

Keyword(s):

Plasma Concentration ◽

Organic Anion ◽

Plasma Concentrations ◽

Whole Body ◽

Time Profiles ◽

Pbpk Models ◽

Physiologically Based Pharmacokinetic ◽

Concentration Time ◽

Anion Transporter ◽

Physiologically Based

Abstract Purpose To provide whole-body physiologically based pharmacokinetic (PBPK) models of the potent clinical organic anion transporter (OAT) inhibitor probenecid and the clinical OAT victim drug furosemide for their application in transporter-based drug-drug interaction (DDI) modeling. Methods PBPK models of probenecid and furosemide were developed in PK-Sim®. Drug-dependent parameters and plasma concentration-time profiles following intravenous and oral probenecid and furosemide administration were gathered from literature and used for model development. For model evaluation, plasma concentration-time profiles, areas under the plasma concentration–time curve (AUC) and peak plasma concentrations (Cmax) were predicted and compared to observed data. In addition, the models were applied to predict the outcome of clinical DDI studies. Results The developed models accurately describe the reported plasma concentrations of 27 clinical probenecid studies and of 42 studies using furosemide. Furthermore, application of these models to predict the probenecid-furosemide and probenecid-rifampicin DDIs demonstrates their good performance, with 6/7 of the predicted DDI AUC ratios and 4/5 of the predicted DDI Cmax ratios within 1.25-fold of the observed values, and all predicted DDI AUC and Cmax ratios within 2.0-fold. Conclusions Whole-body PBPK models of probenecid and furosemide were built and evaluated, providing useful tools to support the investigation of transporter mediated DDIs.

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Development of a Physiologically Based Pharmacokinetic Model for Prediction of Ethanol Concentration-Time Profile in Different Organs

Alcohol and Alcoholism ◽

10.1093/alcalc/agaa129 ◽

2020 ◽

Author(s):

Armin Sadighi ◽

Lorenzo Leggio ◽

Fatemeh Akhlaghi

Keyword(s):

Pbpk Model ◽

Organ Damage ◽

Time Profile ◽

Sensitivity Analyses ◽

Pbpk Modeling ◽

Time Curve ◽

Physiologically Based Pharmacokinetic ◽

Concentration Time ◽

Physiologically Based

Abstract Aims A physiologically based pharmacokinetic (PBPK) modeling approach was used to simulate the concentration-time profile of ethanol (EtOH) in stomach, duodenum, plasma and other tissues upon consumption of beer and whiskey under fasted and fed conditions. Methods A full PBPK model was developed for EtOH using the advanced dissolution, absorption and metabolism (ADAM) model fully integrated into the Simcyp Simulator® 15 (Simcyp Ltd., Sheffield, UK). The prediction performance of the developed model was verified and the EtOH concentration-time profile in different organs was predicted. Results Simcyp simulation showed ≤ 2-fold difference in values of EtOH area under the concentration-time curve (AUC) in stomach and duodenum as compared to the observed values. Moreover, the simulated EtOH maximum concentration (Cmax), time to reach Cmax (Tmax) and AUC in plasma were comparable to the observed values. We showed that liver is exposed to the highest EtOH concentration, faster than other organs (Cmax = 839.50 mg/L and Tmax = 0.53 h), while brain exposure of EtOH (AUC = 1139.43 mg·h/L) is the highest among all other organs. Sensitivity analyses (SAs) showed direct proportion of EtOH rate and extent of absorption with administered EtOH dose and inverse relationship with gastric emptying time (GE) and steady-state volume of distribution (Vss). Conclusions The current PBPK model approach might help with designing in vitro experiments in the area of alcohol organ damage or alcohol-drug interaction studies.

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Pharmacokinetics of Telbivudine in Healthy Subjects and Absence of Drug Interaction with Lamivudine or Adefovir Dipivoxil

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01313-05 ◽

2006 ◽

Vol 50 (7) ◽

pp. 2309-2315 ◽

Cited By ~ 31

Author(s):

Xiao-Jian Zhou ◽

Barbara A. Fielman ◽

Deborah M. Lloyd ◽

George C. Chao ◽

Nathaniel A. Brown

Keyword(s):

Single Dose ◽

Steady State ◽

Plasma Concentration ◽

Healthy Subjects ◽

Adefovir Dipivoxil ◽

Geometric Mean ◽

Time Curve ◽

Concentration Time ◽

Plasma Pharmacokinetics ◽

Plasma Concentration Time Curve

ABSTRACT Two phase I studies were conducted to assess the plasma pharmacokinetics of telbivudine and potential drug-drug interactions between telbivudine (200 or 600 mg/day) and lamivudine (100 mg/day) or adefovir dipivoxil (10 mg/day) in healthy subjects. Study drugs were administered orally. The pharmacokinetics of telbivudine were characterized by rapid absorption with biphasic disposition. The maximum concentrations in plasma (C max) were reached at median times ranging from 2.5 to 3.0 h after dosing. Mean single-dose C max and area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) were 1.1 and 2.9 μg/ml and 7.4 and 21.8 μg · h/ml for the 200- and 600-mg telbivudine doses, respectively. Steady state was reached after daily dosing for 5 to 7 days. The mean steady-state C max and area under the plasma concentration-time curve over the dosing interval (AUCτ) were 1.2 and 3.4 μg/ml and 8.9 and 27.5 μg · h/ml for the 200- and 600-mg telbivudine repeat doses, respectively. The steady-state AUCτ of telbivudine was 23 to 57% higher than the single-dose values. Concomitant lamivudine or adefovir dipivoxil did not appear to significantly alter the steady-state plasma pharmacokinetics of telbivudine; the geometric mean ratios and associated 90% confidence interval (CI) for the AUCτ of telbivudine alone versus in combination were 106.3% (92.0 to 122.8%) and 98.6% (86.4 to 112.5%) when coadministered with lamivudine and adefovir dipivoxil, respectively. Similarly, the steady-state plasma pharmacokinetics of lamivudine or adefovir were not markedly affected by the coadministration of telbivudine; the geometric mean ratios and associated 90% CI, alone versus in combination with telbivudine, were 99.0% (87.1 to 112.4%) and 92.2% (84.0 to 101.1%), respectively, for the lamivudine and adefovir AUCτ values. Moreover, the combination regimens studied were well tolerated in all subjects. The results from these studies provide pharmacologic support for combination therapy or therapy switching involving telbivudine, lamivudine, and adefovir dipivoxil for the treatment of chronic hepatitis B virus infection.

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Biokinetic Model for Evaluation of Effects of Breast Feeding and Consecutive Normal Food Intake on PCB Plasma Concentration-Time Profile in Infants Until 45 Months of Age

Epidemiology ◽

10.1097/01.ede.0000362469.72806.d6 ◽

2009 ◽

Vol 20 ◽

pp. S137

Author(s):

Tomas Trnovec ◽

Kinga Lancz ◽

Sona Wimmerova ◽

Lubica Palkovicova ◽

Ladislav Dedik ◽

...

Keyword(s):

Plasma Concentration ◽

Food Intake ◽

Breast Feeding ◽

Time Profile ◽

Biokinetic Model ◽

Concentration Time ◽

Normal Food

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Physiologically-Based Pharmacokinetic (PBPK) Modeling of Buprenorphine in Adults, Children and Preterm Neonates

Pharmaceutics ◽

10.3390/pharmaceutics12060578 ◽

2020 ◽

Vol 12 (6) ◽

pp. 578 ◽

Cited By ~ 1

Author(s):

Lukas Kovar ◽

Christina Schräpel ◽

Dominik Selzer ◽

Yvonne Kohl ◽

Robert Bals ◽

...

Keyword(s):

Drug Exposure ◽

Geometric Mean ◽

Pbpk Modeling ◽

Preterm Neonates ◽

Pharmacokinetic Studies ◽

Acceptance Criterion ◽

Pbpk Models ◽

Physiologically Based Pharmacokinetic ◽

Age Related ◽

Physiologically Based

Buprenorphine plays a crucial role in the therapeutic management of pain in adults, adolescents and pediatric subpopulations. However, only few pharmacokinetic studies of buprenorphine in children, particularly neonates, are available as conducting clinical trials in this population is especially challenging. Physiologically-based pharmacokinetic (PBPK) modeling allows the prediction of drug exposure in pediatrics based on age-related physiological differences. The aim of this study was to predict the pharmacokinetics of buprenorphine in pediatrics with PBPK modeling. Moreover, the drug-drug interaction (DDI) potential of buprenorphine with CYP3A4 and P-glycoprotein perpetrator drugs should be elucidated. A PBPK model of buprenorphine and norbuprenorphine in adults has been developed and scaled to children and preterm neonates, accounting for age-related changes. One-hundred-percent of the predicted AUClast values in adults (geometric mean fold error (GMFE): 1.22), 90% of individual AUClast predictions in children (GMFE: 1.54) and 75% in preterm neonates (GMFE: 1.57) met the 2-fold acceptance criterion. Moreover, the adult model was used to simulate DDI scenarios with clarithromycin, itraconazole and rifampicin. We demonstrate the applicability of scaling adult PBPK models to pediatrics for the prediction of individual plasma profiles. The novel PBPK models could be helpful to further investigate buprenorphine pharmacokinetics in various populations, particularly pediatric subgroups.

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