Pharmacokinetic/Pharmacodynamic Model of Neutropenia in Real-Life Palbociclib-Treated Patients

Palbociclib is an oral CDK4/6 inhibitor indicated in HR+/HER2- advanced or metastatic breast cancer in combination with hormonotherapy. Its main toxicity is neutropenia. The aim of our study was to describe the kinetics of circulating neutrophils from real-life palbociclib-treated patients. A population pharmacokinetic (popPK) model was first constructed to describe palbociclib pharmacokinetic (PK). Individual PK parameters obtained were then used in the pharmacokinetic/pharmacodynamic (PK/PD) model to depict the relation between palbociclib concentrations and absolute neutrophil counts (ANC). The models were built with a population of 143 patients. Palbociclib samples were routinely collected during therapeutic drug monitoring, whereas ANC were retrospectively retrieved from the patient files. The optimal popPK model was a mono-compartmental model with a first-order absorption constant of 0.187 h−1 and an apparent clearance Cl/F of 57.09 L (32.8% of inter individuality variability (IIV)). The apparent volume of distribution (1580 L) and the lag-time (Tlag: 0.658 h) were fixed to values from the literature. An increase in creatinine clearance and a decrease in alkaline phosphatase led to an increase in palbociclib Cl/F. To describe ANC kinetics during treatment, Friberg’s PK/PD model, with linear drug effect, was used. Parameters estimated were Base (2.92 G/L; 29.6% IIV), Slope (0.0011 L/µg; 28.8% IIV), Mean Transit Time (MTT; 5.29 days; 17.9% IIV) and γ (0.102). The only significant covariate was age on the initial ANC (Base), with lower ANC in younger patients. PK/PD model-based simulations show that the higher the estimated CressSS (trough concentration at steady state), the higher the risk of developing neutropenia. In order to present a risk lower than 20% to developing a grade 4 neutropenia, the patient should show an estimated CressSS lower than 100 µg/L.

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Population Pharmacokinetics of Bedaquiline (TMC207), a Novel Antituberculosis Drug

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01418-13 ◽

2014 ◽

Vol 58 (9) ◽

pp. 5315-5324 ◽

Cited By ~ 22

Author(s):

Sarah C. McLeay ◽

Peter Vis ◽

Rolf P. G. van Heeswijk ◽

Bruce Green

Keyword(s):

Apparent Volume ◽

Multidrug Resistant ◽

Volume Of Distribution ◽

Population Pharmacokinetic ◽

Time Data ◽

Content Type ◽

Mixed Effects Modeling ◽

Phase Ii Studies ◽

Apparent Clearance ◽

Residual Unexplained Variability

ABSTRACTBedaquiline is a novel agent for the treatment of pulmonary multidrug-resistantMycobacterium tuberculosisinfections, in combination with other agents. The objective of this study was to develop a population pharmacokinetic (PK) model for bedaquiline to describe the concentration-time data from phase I and II studies in healthy subjects and patients with drug-susceptible or multidrug-resistant tuberculosis (TB). A total of 5,222 PK observations from 480 subjects were used in a nonlinear mixed-effects modeling approach. The PK was described with a 4-compartment disposition model with dual zero-order input (to capture dual peaks observed during absorption) and long terminal half-life (t1/2). The model included between-subject variability on apparent clearance (CL/F), apparent central volume of distribution (Vc/F), the fraction of dose via the first input, and bioavailability (F). Bedaquiline was widely distributed, with apparent volume at steady state of >10,000 liters and low clearance. The long terminalt1/2was likely due to redistribution from the tissue compartments. The final covariate model adequately described the data and had good simulation characteristics. The CL/F was found to be 52.0% higher for subjects of black race than that for subjects of other races, andVc/F was 15.7% lower for females than that for males, although their effects on bedaquiline exposure were not considered to be clinically relevant. Small differences in F and CL/F were observed between the studies. The residual unexplained variability was 20.6% and was higher (27.7%) for long-term phase II studies.

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Tacrolimus Pharmacokinetics in Living-Donor and Deceased-Donor Liver Transplant in Saudi Patients

Journal of Pharmaceutics and Therapeutics ◽

10.18314/jpt.v5i1.1678 ◽

2019 ◽

pp. 288-294

Author(s):

Hisham S. Abou-Auda ◽

Eqbal Qaddour ◽

Hussein Alsisi ◽

Azizah Ajlan ◽

Mohammad Alsebayel

Keyword(s):

Liver Transplant ◽

Deceased Donor ◽

Apparent Volume ◽

Volume Of Distribution ◽

Transplant Recipients ◽

Donor Liver ◽

Apparent Clearance ◽

Donor Liver Transplant ◽

Liver Transplant Recipients ◽

Apparent Volume Of Distribution

Introduction: Tacrolimus is a macrolide immunosuppressant. It has a narrow therapeutic index and serious side effects which necessitate monitoring of tacrolimus blood concentration. The trough concentration of the drug may also differ based on the type of liver transplant. This study was conducted to investigate differences in pharmacokinetics between transplant types and to determine tacrolimus population pharmacokinetic in liver transplant recipients in Saudi Arabia. Method: Patients on tacrolimus, as the main immunosuppressant, who underwent liver transplant throughout2012-2014 were retrospectively studied. Demographic characteristic, tacrolimus blood trough concentrations, liver, renal, biochemistry, and hematology lab results were all collected. The pharmacokinetic parameters were estimated assuming one compartment model. Results: Tacrolimus pharmacokinetic parameters were found to be as following; elimination rate constant () 0.094 ± 0.0123, apparent volume of distribution () 112.48±63.033 L/hr, elimination half-life () 7.46± 1.01 hr and apparent total body clearance () 10.27± 5.69 L/hr (mean ± SD). Statistically significant difference was found between living-donor and deceased-donor liver transplant with respect to apparent clearance and apparent volume of distribution. Living-donor liver transplant recipients have apparent volume of distribution of 97.39±47.00 L (mean ± SD) and an apparent clearance of 8.89±4.24L/hr (mean± SD). On the other hand, deceased-donor liver transplant has an apparent clearance of 12.97±7.09L/hr (mean ± SD) and an apparent volume of distribution of 142.17± 78.65 L (mean ± SD). Conclusions: Tacrolimus pharmacokinetics parameters were accurately determined in liver transplant recipients in Saudi Arabia. The results of the present study can be clinically used in the therapeutic drug monitoring of tacrolimus in the individualization of drug dosage and taking the appropriate clinical decisions to prevent allograft rejection.

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

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkz217 ◽

2019 ◽

Vol 74 (9) ◽

pp. 2690-2697 ◽

Cited By ~ 3

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.

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A Review of Population Pharmacokinetic Studies of Levetiracetam

10.1101/2020.08.05.20167239 ◽

2020 ◽

Author(s):

Ziran Li ◽

Chenyu Wang ◽

Xiao Zhu ◽

Zheng Jiao

Keyword(s):

Renal Function ◽

Target Population ◽

Volume Of Distribution ◽

Drug Clearance ◽

The Body ◽

Population Pharmacokinetic ◽

Pharmacokinetic Studies ◽

Apparent Clearance ◽

Adults And Children ◽

Study Designs

Background: Levetiracetam has been widely used as a treatment option for different types of epilepsy in both adults and children. Because of its large between-subject variability, several population pharmacokinetic studies have been performed to identify its pharmacokinetic covariates, and thus facilitate individualised therapy. Objective: The aim of this review was to provide a synopsis for population pharmacokinetic studies of levetiracetam and explore identified influencing covariates. Methods: We systematically searched PubMed and Embase databases from inception to June 30, 2020. The information on study designs, target population, model characteristics, and identified covariates were summarised. Moreover, the pharmacokinetic profiles were compared among neonates, children, and adults. Results: A total of 14 studies were included, among which two involved neonates, four involved children, two involved both children and adults, and six involved only adults. The median value of apparent clearance for children (0.074 [range: 0.038 to 0.079] L/h/kg) was higher than that for adults (0.054 [range: 0.039 to 0.061] L/h/kg). Body weight was found to influence the apparent clearance and volume of distribution significantly, whereas renal function influenced the clearance. Likewise, co-administration with enzyme-inducing antiepileptic drugs (such as carbamazepine and phenytoin) increased the drug clearance by 9 to 22%, whereas coadministration with valproate acid decreased it by 18.8%. Conclusion: Levetiracetam dose regimen is dependent on the body size and renal function of patients. Further studies are needed to evaluate levetiracetam pharmacokinetics in neonates and pregnant women.

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

Frontiers in Pharmacology ◽

10.3389/fphar.2021.732503 ◽

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.

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Combining Therapeutic Drug Monitoring and Pharmacokinetic Modelling Deconvolutes Physiological and Environmental Sources of Variability in Clozapine Exposure

Pharmaceutics ◽

10.3390/pharmaceutics14010047 ◽

2021 ◽

Vol 14 (1) ◽

pp. 47

Author(s):

Kenneth H. Wills ◽

Stephen J. Behan ◽

Michael J. Nance ◽

Jessica L. Dawson ◽

Thomas M. Polasek ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Smoking Status ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Pharmacokinetic Modelling ◽

Environmental Covariates ◽

Poppk Model ◽

Post Hoc ◽

The Impact

Background: Clozapine is a key antipsychotic drug for treatment-resistant schizophrenia but exhibits highly variable pharmacokinetics and a propensity for serious adverse effects. Currently, these challenges are addressed using therapeutic drug monitoring (TDM). This study primarily sought to (i) verify the importance of covariates identified in a prior clozapine population pharmacokinetic (popPK) model in the absence of environmental covariates using physiologically based pharmacokinetic (PBPK) modelling, and then to (ii) evaluate the performance of the popPK model as an adjunct or alternative to TDM-guided dosing in an active TDM population. Methods: A popPK model incorporating age, metabolic activity, sex, smoking status and weight was applied to predict clozapine trough concentrations (Cmin) in a PBPK-simulated population and an active TDM population comprising 142 patients dosed to steady state at Flinders Medical Centre in Adelaide, South Australia. Post hoc analyses were performed to deconvolute the impact of physiological and environmental covariates in the TDM population. Results: Analysis of PBPK simulations confirmed age, cytochrome P450 1A2 activity, sex and weight as physiological covariates associated with variability in clozapine Cmin (R2 = 0.7698; p = 0.0002). Prediction of clozapine Cmin using a popPK model based on these covariates accounted for <5% of inter-individual variability in the TDM population. Post hoc analyses confirmed that environmental covariates accounted for a greater proportion of the variability in clozapine Cmin in the TDM population. Conclusions: Variability in clozapine exposure was primarily driven by environmental covariates in an active TDM population. Pharmacokinetic modelling can be used as an adjunct to TDM to deconvolute sources of variability in clozapine exposure.

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Disposition Kinetics of Amitraz in Lactating Does

Molecules ◽

10.3390/molecules26164769 ◽

2021 ◽

Vol 26 (16) ◽

pp. 4769

Author(s):

Sathish Nanjundappa ◽

Suresh Narayanan Nair ◽

Darsana Udayan ◽

Sreelekha Kanapadinchareveetil ◽

Mathew Jacob ◽

...

Keyword(s):

High Performance ◽

Area Under The Curve ◽

Apparent Volume ◽

Volume Of Distribution ◽

Health Concern ◽

Laboratory Animals ◽

Disposition Kinetics ◽

Kinetics Of ◽

Apparent Volume Of Distribution ◽

Dermal Application

Amitraz, a member of the formamidine pesticide family, commonly used for ectoparasite control, is applied as a dip or low-pressure hand spray to cattle and swine, and the neck collar on dogs. Data on amitraz were generated mainly on laboratory animals, hens, dogs, and baboons. The data on the toxicity and disposition of amitraz in animals and its residues in the milk are inadequate. Therefore, the present study was intended to analyze the disposition kinetics of amitraz and its pattern of elimination in the milk of lactating does after a single dermal application at a concentration of 0.25%. Blood at predetermined time intervals and milk twice daily were collected for eight days post application. The drug concentration was assayed by high-performance liquid chromatography (HPLC). Amitraz was detected in whole blood as early as 0.5 h, which attained a peak concentration at 12 ± 5 h, followed by a steady decline; however, detection persisted until 168 h. Amitraz was present in the blood at its 50% Cmax even after 48 h, and was still detectable after 7 days. The disposition after a single dermal application was best described non-compartmentally. The mean terminal half-life (t1/2), mean residence time (MRT), and area under the curve (AUC0–t) were 111 ± 31 h, 168 ± 39 h, and 539 ± 211 µg/mL/h, respectively. The apparent volume of distribution (Vdarea) was 92 ± 36 mL/g with an observed clearance (Cl) of 0.57 ± 0.33 mL/kg/h. Thus, the drug was well absorbed, widely distributed and slowly eliminated from the animal body. Amitraz achieved milk concentration approximating 0.2 per cent of the total dose after a single exposure and the steady-state elimination of amitraz in milk above the recommended maximum residue limit (MRL) of 0.01 mg/kg can act as a source of public health concern when applied on lactating animals.

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Population Pharmacokinetic and Concentration-QTc Analysis of Delamanid in Pediatric Participants with Multidrug-Resistant Tuberculosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01608-21 ◽

2021 ◽

Author(s):

Tomohiro Sasaki ◽

Elin M. Svensson ◽

Xiaofeng Wang ◽

Yanlin Wang ◽

Jeffrey Hafkin ◽

...

Keyword(s):

Plasma Concentrations ◽

Population Pharmacokinetic Analysis ◽

Apparent Volume ◽

Multidrug Resistant ◽

Volume Of Distribution ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb

A population pharmacokinetic analysis of delamanid and its major metabolite DM-6705 was conducted to characterize the pharmacokinetics of delamanid and DM-6705 in pediatric participants with multidrug-resistant tuberculosis (MDR-TB). Data from participants between the ages of 0.67 to 17 years old, enrolled in 2 clinical trials, were utilized for the analysis. The final dataset contained 634 delamanid and 706 DM-6705 valid plasma concentrations from 37 children. A transit model with three compartments best described the absorption of delamanid. Two compartment models for each component with linear elimination were selected to characterize the disposition of delamanid and DM-6705, respectively. The covariates included in the model were body weight on apparent volume of distribution and apparent clearance (for both delamanid and DM-6705); formulation (dispersible vs film coated tablet) on mean absorption time; age, formulation, and dose on bioavailability of delamanid; age on the fraction of delamanid metabolized to DM-6705. Based on the simulations, doses for participants within different age/weight groups that result in delamanid exposure comparable to that in adults following the approved adult dose were calculated. By concentration-QTc (QTcB, QT corrected by Bazett’s' formula) analysis, a significant positive correlation was detected with concentrations of DM-6705. However, the model-predicted upper bounds of the 90% confidence intervals of ΔQTc value were less than 10 ms at the simulated Cmax of DM-6705 following administration of maximum doses simulated. This suggests that the effect on the QT interval following the proposed dosing is unlikely to be clinically meaningful in children with MDR-TB who receive delamanid.

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Phase I Study To Evaluate the Pharmacokinetics, Safety, and Tolerability of Two Dosing Regimens of Oral Fosfomycin Tromethamine in Healthy Adult Participants

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00464-18 ◽

2018 ◽

Vol 62 (8) ◽

Cited By ~ 9

Author(s):

Eric Wenzler ◽

Susan C. Bleasdale ◽

Monica Sikka ◽

Kristen L. Bunnell ◽

Matthew Finnemeyer ◽

...

Keyword(s):

Phase I ◽

Healthy Adult ◽

Apparent Volume ◽

Volume Of Distribution ◽

Open Label ◽

Time Curve ◽

Elimination Half ◽

Apparent Clearance ◽

Dosing Regimens ◽

Repeated Dosing

ABSTRACTThe pharmacokinetics (PK), safety, and tolerability of two repeated dosing regimens of oral fosfomycin tromethamine were evaluated in 18 healthy adult subjects. Subjects received 3 g every other day (QOD) for 3 doses and then every day (QD) for 7 doses, or vice versa, in a phase I, randomized, open-label, two-period-crossover study. Serial blood (n= 11) and urine (n= 4 collection intervals) samples were collected before and up to 24 h after dosing on days 1 and 5, along with predose concentrations on days 3 and 7. PK parameters were similar between days 1 and 5 within and between dosing regimens. The mean (± standard deviation [SD]) PK parameters for fosfomycin in plasma on day 5 during the respective QOD and QD dosing regimens were as follows: maximum concentration of drug in serum (Cmax) = 24.4 ± 6.2 versus 23.8 ± 5.6 μg/ml, time toCmax(Tmax) = 2.2 ± 0.7 versus 2.0 ± 0.4 h, apparent volume of distribution (V/F) = 141 ± 67.9 versus 147 ± 67.6 liters, apparent clearance (CL/F) = 21.4 ± 8.0 versus 20.4 ± 5.3 liters/h, renal clearance (CLR) = 7.5 ± 4.1 versus 7.3 ± 3.5 liters/h, area under the concentration-time curve from 0 to 24 h (AUC0–24) = 151.6 ± 35.6 versus 156.6 ± 42.5 μg · h/ml, and elimination half-life (t1/2) = 4.5 ± 1.1 versus 5.0 ± 1.7 h. Urine concentrations peaked at approximately 600 μg/ml through the 0- to 8-h urine collection intervals but displayed significant interindividual variability. Roughly 35 to 40% of the 3-g dose was excreted in the urine by 24 h postdose. No new safety concerns were identified during this study. The proportion of diarrhea-free days during the study was significantly lower with the QD regimen than with the QOD regimen (61% versus 77%;P< 0.0001). Further studies to establish the clinical benefit/risk ratio for repeated dosing regimens of oral fosfomycin tromethamine are warranted. (This trial is registered at ClinicalTrials.gov under registration no. NCT02570074.)

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Population Pharmacokinetics of Tafenoquine, a Novel Antimalarial

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00711-18 ◽

2018 ◽

Vol 62 (11) ◽

Cited By ~ 5

Author(s):

Nilay Thakkar ◽

Justin A. Green ◽

Gavin C. K. W. Koh ◽

Stephan Duparc ◽

David Tenero ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Studies ◽

Apparent Volume ◽

Volume Of Distribution ◽

Population Pharmacokinetic ◽

Radical Cure ◽

Phase 3 ◽

Content Type ◽

Clinical Trial Simulations ◽

Apparent Volume Of Distribution

ABSTRACTTafenoquine is a novel 8-aminoquinoline antimalarial drug recently approved by the U.S. Food and Drug Administration (FDA) for the radical cure of acutePlasmodium vivaxmalaria, which is the first new treatment in almost 60 years. A population pharmacokinetic (POP PK) analysis was conducted with tafenoquine exposure data obtained following oral administration from 6 clinical studies in phase 1 through phase 3 with a nonlinear mixed effects modeling approach. The impacts of patient demographics, baseline characteristics, and extrinsic factors, such as formulation, were evaluated. Model performance was assessed using techniques such as bootstrapping, visual predictive checks, and external data validation from a phase 3 study not used in model fitting and parameter estimation. Based on the analysis, the systemic pharmacokinetics of tafenoquine were adequately described using a two-compartment model. The final POP PK model included body weight (allometric scaling) on apparent oral and intercompartmental clearance (CL/FandQ/F, respectively), apparent volume of distribution for central and peripheral compartments (V2/FandV3/F, respectively), formulation on systemic bioavailability (F1) and absorption rate constant (Ka), and health status on apparent volume of distribution. The key tafenoquine population parameter estimates were 2.96 liters/h for CL/Fand 915 liters forV2/FinP. vivax-infected subjects. Additionally, the analyses demonstrated no clinically relevant difference in relative bioavailability across the capsule and tablet formulations administered in these clinical studies. In conclusion, a POP PK model for tafenoquine was developed. Clinical trial simulations based on this model supported bridging the exposures across two different formulations. This POP PK model can be applied to aid and perform clinical trial simulations in other scenarios and populations, such as pediatric populations.

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