scholarly journals A population pharmacokinetic model is beneficial in quantifying hair concentrations of ritonavir-boosted atazanavir: A study of HIV-infected Zimbabwean adolescents.

2020 ◽  
Author(s):  
Bernard NGARA ◽  
Simbarashe Zvada ◽  
Tariro Dianah Chawana ◽  
Babill Stray-Pedersen ◽  
Charles Fungai Brian Nhachi ◽  
...  
Keyword(s):  
Drug Concentration ◽  
Pharmacokinetic Model ◽  
Plasma Concentrations ◽  
Model Development ◽  
Normal Weight ◽  
Hiv Treatment ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Modelling ◽  
Hair Samples

Abstract Background Adolescents experience higher levels of non-adherence to HIV treatment. Drug concentration in hair promises to be reliable for assessing exposure to antiretroviral (ARV) drugs. Pharmacokinetic modelling can explore utility of drug in hair. We aimed at developing and validating a pharmacokinetic model based on atazanavir/ritonavir (ATV/r) in hair and identify factors associated with variabilities in hair accumulation. Methods We based the study on secondary data analysis whereby data from a previous study on Zimbabwean adolescents which collected hair samples at enrolment and three months follow-up was used in model development. We performed model development in NONMEM (version 7.3) ADVAN 13. Results There is 16% / 18% of the respective ATV/r in hair as a ratio of steady-state trough plasma concentrations. At follow-up, we estimated an increase of 30% /42% of respective ATV/r in hair. We associated a unit increase in adherence score with 2% increase in hair concentration both ATV/r. Thinner participants had 54% higher while overweight had 21% lower atazanavir in hair compared to normal weight participants. Adolescents receiving care from fellow siblings had atazanavir in hair at least 54% less compared to other forms of care. Conclusion The determinants of increased ATV/r concentrations in hair found in our analysis are monitoring at follow up event, body mass index, and caregiver status. Measuring drug concentration in hair is feasibly accomplished and could be more accurate for monitoring ARV drugs exposure. Keywords Pharmacokinetic modelling, HIV/AIDS, Adolescents, Adherence, Hair, NONMEM

scholarly journals A population pharmacokinetic model is beneficial in quantifying hair concentrations of ritonavir-boosted atazanavir: A study of HIV-infected Zimbabwean adolescents.

2020 ◽  
Author(s):  
Bernard NGARA ◽  
Simbarashe Zvada ◽  
Tariro Dianah Chawana ◽  
Babill Stray-Pedersen ◽  
Charles Fungai Brian Nhachi ◽  
...  
Keyword(s):  
Drug Concentration ◽  
Pharmacokinetic Model ◽  
Plasma Concentrations ◽  
Model Development ◽  
Secondary Data ◽  
Normal Weight ◽  
Hiv Treatment ◽  
Population Pharmacokinetic ◽  
Hair Samples

Abstract Background Adolescents experience higher levels of non-adherence to HIV treatment. Drug concentration in hair promises to be reliable for assessing exposure to antiretroviral (ARV) drugs. Pharmacokinetic modelling can explore utility of drug in hair. We aimed at developing and validating a pharmacokinetic model based on atazanavir/ritonavir (ATV/r) in hair and identify factors associated with variabilities in hair accumulation.Methods We based the study on secondary data analysis whereby data from a previous study on Zimbabwean adolescents which collected hair samples at enrolment and three months follow-up was used in model development. We performed model development in NONMEM (version 7.3) ADVAN 13. Results There is 16% / 18% of the respective ATV/r in hair as a ratio of steady-state trough plasma concentrations. At follow-up, we estimated an increase of 30% /42% of respective ATV/r in hair. We associated a unit increase in adherence score with 2% increase in hair concentration both ATV/r. Thinner participants had 54% higher while overweight had 21% lower atazanavir in hair compared to normal weight participants. Adolescents receiving care from fellow siblings had atazanavir in hair at least 54% less compared to other forms of care. Conclusion The determinants of increased ATV/r concentrations in hair found in our analysis are monitoring at follow up event, body mass index, and caregiver status. Measuring drug concentration in hair is feasibly accomplished and could be more accurate for monitoring ARV drugs exposure.

scholarly journals A population pharmacokinetic model is beneficial in quantifying hair concentrations of ritonavir-boosted atazanavir: A study of HIV-infected Zimbabwean adolescents.

2020 ◽  
Author(s):  
Bernard Ngara ◽  
Simbarashe Zvada ◽  
Tariro Dianah Chawana ◽  
Babill Stray-Pedersen ◽  
Charles Fungai Brian Nhachi ◽  
...  
Keyword(s):  
Drug Concentration ◽  
Pharmacokinetic Model ◽  
Plasma Concentrations ◽  
Model Development ◽  
Secondary Data ◽  
Normal Weight ◽  
Hiv Treatment ◽  
Population Pharmacokinetic ◽  
Hair Samples

Abstract BackgroundAdolescents experience higher levels of non-adherence to HIV treatment. Drug concentration in hair promises to be reliable for assessing exposure to antiretroviral (ARV) drugs. Pharmacokinetic modelling can explore utility of drug in hair. We aimed at developing and validating a pharmacokinetic model based on atazanavir/ritonavir (ATV/r) in hair and identify factors associated with variabilities in hair accumulation.MethodsWe based the study on secondary data analysis whereby data from a previous study on Zimbabwean adolescents which collected hair samples at enrolment and three months follow-up was used in model development. We performed model development in NONMEM (version 7.3) ADVAN 13. ResultsThere is 16% / 18% of the respective ATV/r in hair as a ratio of steady-state trough plasma concentrations. At follow-up, we estimated an increase of 30% /42% of respective ATV/r in hair. We associated a unit increase in adherence score with 2% increase in hair concentration both ATV/r. Thinner participants had 54% higher while overweight had 21% lower atazanavir in hair compared to normal weight participants. Adolescents receiving care from fellow siblings had atazanavir in hair at least 54% less compared to other forms of care. ConclusionThe determinants of increased ATV/r concentrations in hair found in our analysis are monitoring at follow up event, body mass index, and caregiver status. Measuring drug concentration in hair is feasibly accomplished and could be more accurate for monitoring ARV drugs exposure.

scholarly journals Population Pharmacokinetics of Tenofovir in HIV-1-Uninfected Members of Serodiscordant Couples and Effect of Dose Reporting Methods

2016 ◽  
Vol 60 (9) ◽  
pp. 5379-5386 ◽  
Author(s):  
Yanhui Lu ◽  
Vineet Goti ◽  
Ayyappa Chaturvedula ◽  
Jessica E. Haberer ◽  
Michael J. Fossler ◽  
...  
Keyword(s):  
Creatinine Clearance ◽  
Drug Concentration ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Electronic Monitoring ◽  
Model Development ◽  
Population Pharmacokinetic ◽  
Main Trial ◽  
Patient Reported ◽  
Hiv 1

ABSTRACTAntiretroviral preexposure prophylaxis (PrEP) with once-daily dosing of tenofovir and tenofovir-emtricitabine was shown to be effective for preventing HIV-1 infection in individuals who had HIV-1-seropositive partners (the Partners PrEP Study). We developed a population pharmacokinetic model for tenofovir and investigated the impacts of different dose reporting methods. Dosing information was collected as patient-reported dosing information (PRDI) from 404 subjects (corresponding to 1,280 drug concentration records) from the main trial and electronic monitoring-based adherence data collected from 211 subjects (corresponding to 327 drug concentration records) in an ancillary adherence study. Model development was conducted with NONMEM (7.2), using PRDI with a steady-state assumption or using PRDI replaced with electronic monitoring records where available. A two-compartment model with first-order absorption was the best model in both modeling approaches, with the need for an absorption lag time when electronic monitoring-based dosing records were included in the analysis. Age, body weight, and creatinine clearance were significant covariates on clearance, but only creatinine clearance was retained in the final models per stepwise selection. Sex was not a significant covariate on clearance. Tenofovir population pharmacokinetic parameter estimates and the precisions of the parameters from the two final models were comparable with the point estimates of the parameters, differing from 0% to 35%, and bootstrap confidence intervals widely overlapped. These findings indicate that PRDI was sufficient for population pharmacokinetic model development in this study, with a high level of adherence per multiple measures.

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 Influence of the OATP Polymorphism on the Population Pharmacokinetics of Methotrexate in Chinese Patients

2019 ◽  
Vol 20 (7) ◽  
pp. 592-600 ◽  
Author(s):  
Zhiqi Wang ◽  
Nan Zhang ◽  
Chaoyang Chen ◽  
Shuqing Chen ◽  
Junyu Xu ◽  
...  
Keyword(s):  
Pharmacokinetic Model ◽  
Genetic Factors ◽  
Plasma Concentrations ◽  
Chinese Patients ◽  
Estimation Methods ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Mixed Effect ◽  
The Impact

Background: The Pharmacokinetics of Methotrexate (MTX) has been reported to show significant intersubject variability. MTX is metabolized by SHMT1 and transported by OATP1B1 and OATP1B3 both of which show genetic polymorphisms. The non-genetic and genetic factors may influence the pharmacokinetics of MTX. Objective: This study aimed to determine the pharmacokinetic parameters of MTX in Chinese patients and to investigate the effect of various non-genetic factors and genetic variants of OATP1B1, OATP1B3 on MTX’s pharmacokinetics. Method: MTX concentration and clinical characteristics data were collected from 71 rheumatoid arthritis patients. For each patient, SLC19A1, SHMT1, OATP1B1, and OATP1B3 genotyping were tested. Population pharmacokinetic analysis was performed by Nonlinear Mixed-Effect Modeling (NONMEM). MTX pharmacokinetic properties analysis was executed using the one-compartment pharmacokinetic model which incorporated first-order conditional estimation methods with interaction. Besides, the impact of genetic factors and demographic factors on MTX disposition were explored. Results: All the genotypes of steady-state plasma concentrations and OATP1B1 rs4149056, OATP1B1 rs2306283, and OATP1B3 rs7311358 were determined. The detected blood drug concentration reached the standard. Genotypes were all measured. At the same time, the population pharmacokinetic model of methotrexate was obtained CL(L·h-1) =8.25× e0.167× SNP (SNP: SLCO1B1 388A/A=3; SLCO1B1 388A/G=2; SLCO1B1 388G/G=1); V(L)= 32.8; Ka(h- 1)=1.69. Conclusion: : In our study, it was showed that OATP1B1-388 G>A SNP had a significant effect on CL/F. The factor should be considered when determining MTX dosing. However, prospective studies with a large number of participants are needed to validate the results of this study.

scholarly journals Modeling and Simulation Analysis of Aprepitant Pharmacokinetics in Pediatric Patients With Postoperative or Chemotherapy-Induced Nausea and Vomiting

2020 ◽  
Vol 25 (6) ◽  
pp. 528-539
Author(s):  
Anne Chain ◽  
Rebecca Wrishko ◽  
Grygoriy Vasilinin ◽  
Samer Mouksassi
Keyword(s):  
Pediatric Patients ◽  
Simulation Analysis ◽  
Pediatric Population ◽  
Plasma Concentrations ◽  
Model Development ◽  
Postoperative Nausea And Vomiting ◽  
Nausea And Vomiting ◽  
Fixed Dose ◽  
Population Pharmacokinetic ◽  
Population Pk

OBJECTIVES Aprepitant is effective for the prevention of chemotherapy-induced or postoperative nausea and vomiting (CINV/PONV). The aim of this study was to develop a population pharmacokinetic (PK) model of aprepitant in pediatric patients and to support dosing recommendations for oral aprepitant in pediatric patients at risk of CINV. METHODS A population PK model was constructed based on data from 3 clinical studies in which children (6 months to 12 years) and adolescents (12–19 years) were treated with a 3-day regimen of oral aprepitant (capsules or suspension), with or without intravenous fosaprepitant on day 1 (CINV), or a single dose of oral aprepitant (capsules or suspension; PONV). Nonlinear mixed-effects modeling was used for model development, and a stepwise covariate search determined factors influencing PK parameters. Simulations were performed to guide final dosing strategies of aprepitant in pediatric patients. RESULTS The analysis included 1326 aprepitant plasma concentrations from 147 patients. Aprepitant PK was described by a 2-compartment model with linear elimination and first-order absorption, with allometric scaling for central and peripheral clearance and volume using body weight, and a cytochrome P450 3A4 maturation component for the effect of ontogeny on systemic clearance. Simulations established that application of a weight-based (for those <12 years) and fixed-dose (for those 12–17 years) dosing regimen results in comparable exposures to those observed in adults. CONCLUSIONS The developed population PK model adequately described aprepitant PK across a broad pediatric population, justifying fixed (adult) dosing for adolescents and weight-based dosing of oral aprepitant for children.

scholarly journals Pharmacokinetics of anticoagulant edoxaban in overdose in a Japanese patient transported to hospital

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Koichiro Adachi ◽  
Jumpei Tuchiya ◽  
Satoru Beppu ◽  
Kei Nishiyama ◽  
Makiko Shimizu ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Pharmacokinetic Model ◽  
Medical Center ◽  
Plasma Concentrations ◽  
Elimination Rate ◽  
Physiologically Based Pharmacokinetic Model ◽  
Current Case ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

Abstract Background The anticoagulant edoxaban is used clinically at doses of 30–60 mg/day; however, we experienced a patient who had taken an overdose of edoxaban of 750 mg. We investigated the pharmacokinetics of edoxaban in this patient by using liquid chromatography–tandem spectrometry to estimate the follow-up period in emergency clinical practice with this medicine. Case presentation The patient was a 57-year-old woman (body weight, 69 kg) who had taken a single oral dose of 750 mg of edoxaban in a suicide attempt. She was emergently admitted to Kyoto Medical Center. The patient’s edoxaban plasma concentrations during ambulance transport (8 h after oral administration) were ~ 4900 ng/ml, and the concentration gradually decreased to ~ 10 ng/mL and to detectable but unmeasurable levels of ~ 1.0 ng/mL at 60 h and 100 h, respectively. The linear range of the relationship between the dose and plasma concentration was assumed to have been exceeded during the first 8 h; however, the measured elimination rate of edoxaban was similar to that visualized curves predicted by a simplified physiologically based pharmacokinetic model previously established. Conclusion Simplified physiologically based pharmacokinetic models for creating visualized curves have proven to be useful not only during drug discovery or chemical risk assessment but also in cases of medical poisoning. We used a physiologically based pharmacokinetic model previously established for edoxaban to predict the pharmacokinetics in the current case. It is hoped that the results of this study, which encompass drug monitoring data in the patient and visualized pharmacokinetic prediction, will serve as an index when setting the treatment and follow-up period in cases of drug overdose for medicines such as edoxaban in emergency clinical practice.

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