A Semi-Physiological Population Model to Quantify the Effect of Hematocrit on Everolimus Pharmacokinetics and Pharmacodynamics in Cancer Patients

Erp, Nielka P. van; Herpen, Carla M. van; Wit, Djoeke de; Willemsen, Annelieke E.C.A.B.; Burger, David M.; Huitema, Alwin D. R.; Heine, Rob ter

doi:10.1007/s40262-016-0414-3

Cited by 17 publications

(18 citation statements)

References 23 publications

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“…Albeit not significantly, DBS and DBS wb did show consistently higher everolimus concentrations compared to measuring everolimus in WB. Everolimus is strongly bound to erythrocytes (approximately 85% at the blood concentration range of 5–100 μg/L) [ 31 , 32 ], and we speculate that this fraction can have a higher concentration at the center of the punch of the sampling paper. When hematocrit levels are low (≤ 0.20 L/L), chromatographic effects can play a role, resulting in inaccurately lower everolimus concentration measurements [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

Clinical validation study of dried blood spot for determining everolimus concentration in patients with cancer

Willemsen¹,

Knapen

Beer

et al. 2017

Eur J Clin Pharmacol

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PurposeEverolimus treatment is seriously hampered by its toxicity profile. As a relationship between everolimus exposure and effectiveness and toxicity has been established, early and ongoing concentration measurement can be key to individualize the dose and optimize treatment outcomes. Dried blood spot (DBS) facilitates sampling at a patients’ home and thereby eases dose individualization. The aim of this study is to determine the agreement and predictive performance of DBS compared to whole blood (WB) to measure everolimus concentrations in cancer patients.MethodsPaired DBS and WB samples were collected in 22 cancer patients treated with everolimus and analyzed using UPLC-MS/MS. Bland-Altman and Passing-Bablok analysis were used to determine method agreement. Limits of clinical relevance were set at a difference of ± 25%, as this would lead to a different dosing advice. Using DBS concentration and Passing-Bablok regression analysis, WB concentrations were predicted.ResultsSamples of 20 patients were suitable for analysis. Bland-Altman analysis showed a mean ratio of everolimus WB to DBS concentrations of 0.90, with 95% of data points within limits of clinical relevance. Passing-Bablok regression of DBS compared to WB revealed no constant bias (intercept 0.02; 95% CI 0.93–1.35) and a small proportional bias (slope 0.89; 95% CI 0.76–0.99). Predicted concentrations showed low bias and imprecision and 90% of samples had an absolute percentage prediction error of < 20%.ConclusionsDBS is a valid method to determine everolimus concentrations in cancer patients. This can especially be of value for early recognition of over- or underexposure to enable dose adaptations.Electronic supplementary materialThe online version of this article (10.1007/s00228-017-2394-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Clinical validation study of dried blood spot for determining everolimus concentration in patients with cancer

Willemsen¹,

Knapen

Beer

et al. 2017

Eur J Clin Pharmacol

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“…As PQ is thought to be mainly metabolized by MAO and cytochrome P450s in the liver ( 12 ), a well-stirred liver model, a well-established model to describe hepatic metabolism of drugs, was implemented to describe the physiologically plausible relationship between first-pass and central metabolism ( 47 , 48 ). Apparent intrinsic hepatic clearances for MAO- and CYP2D6-mediated metabolism (CL int,MAO and CL int,CYP2D6 , respectively) were estimated.…”

Section: Methodsmentioning

confidence: 99%

Age, Weight, and CYP2D6 Genotype Are Major Determinants of Primaquine Pharmacokinetics in African Children

Gonçalves

Pett

Tiono

et al. 2017

Antimicrob Agents Chemother

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Low-dose primaquine is recommended to prevent Plasmodium falciparum malaria transmission in areas threatened by artemisinin resistance and areas aiming for malaria elimination. Community treatment campaigns with artemisinin-based combination therapy in combination with the gametocytocidal primaquine dose target all age groups, but no studies thus far have assessed the pharmacokinetics of this gametocytocidal drug in African children. We recruited 40 children participating in a primaquine efficacy trial in Burkina Faso to study primaquine pharmacokinetics. These children received artemether-lumefantrine and either a 0.25- or a 0.40-mg/kg primaquine dose. Seven blood samples were collected from each participant for primaquine and carboxy-primaquine plasma levels determinations: one sample was collected before primaquine administration and six after primaquine administration according to partially overlapping sampling schedules. Physiological population pharmacokinetic modeling was used to assess the impact of weight, age, and CYP2D6 genotype on primaquine and carboxy-primaquine pharmacokinetics. Despite linear weight normalized dosing, the areas under the plasma concentration-time curves and the peak concentrations for both primaquine and carboxy-primaquine increased with age and body weight. Children who were CYP2D6 poor metabolizers had higher levels of the parent compound, indicating a lower primaquine CYP2D6-mediated metabolism. Our data indicate that primaquine and carboxy-primaquine pharmacokinetics are influenced by age, weight, and CYP2D6 genotype and suggest that dosing strategies may have to be reconsidered to maximize the transmission-blocking properties of primaquine. (This study has been registered at ClinicalTrials.gov under registration no. NCT01935882.)

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“…Similar to descriptions by Størset et al [35] and Van Erp et al [36], the following equation was used to estimate CsA C p (Text S3) [37]:…”

Section: Strategy ⅲ: Theory-based Nonlinear Compartmental Modelmentioning

confidence: 99%

Incorporating Nonlinear Kinetics to Improve the Predictive Performance of Population Pharmacokinetic Models for Ciclosporin in Adult Renal Transplant Recipients: A Comparison of Modelling Strategies

Mao

Jiao

Qiu

et al. 2020

Preprint

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Aim: Ciclosporin (CsA) has been shown to follow nonlinear pharmacokinetics in renal transplant recipients who received Neoral-based triple immunosuppressive therapy. Some of these nonlinear properties have not been fully considered in population pharmacokinetic (popPK) analysis. Therefore, the aim of this study was to determine the potential influence of nonlinearity and the functional forms of covariates on model predictability. Methods: A total of 2969 CsA whole-blood measurements, including 1328 pre-dose and 1641 2-h post-dose concentrations, were collected from 173 patients who underwent their first renal transplantation. Four popPK models based on different modelling strategies were developed to investigate the discrepancy between empirical and theory-based, linear and nonlinear compartmental kinetic models and empirical formulae on model predictability. Prediction-based and simulation-based diagnostics (prediction- corrected visual predictive checks) were performed to determine the stability and predictive performance of these four models. Results: Model predictability improved when nonlinearity was considered. The theory-based nonlinear model which incorporated nonlinear property based on known theoretical relationships performed better than the other two compartmental models. The nonlinear Michaelis-Menten model showed a remarkable improvement in predictive performance over that of the other three compartmental models. The saturated binding of CsA to erythrocytes, and auto-inhibition that arose from the inhibitory effects of CsA on CYP3A4/P-gp and CsA-prednisolone drug interaction may have contributed to the nonlinearity. Conclusions: Incorporating nonlinear properties are likely to be a promising approach for improving CsA model predictability. However, CsA nonlinear kinetics resources need further investigation. Until then, Michaelis-Menten empirical model can be used for CsA dose adjustments.

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A Semi-Physiological Population Model to Quantify the Effect of Hematocrit on Everolimus Pharmacokinetics and Pharmacodynamics in Cancer Patients

Cited by 17 publications

References 23 publications

Clinical validation study of dried blood spot for determining everolimus concentration in patients with cancer

Clinical validation study of dried blood spot for determining everolimus concentration in patients with cancer

Age, Weight, and CYP2D6 Genotype Are Major Determinants of Primaquine Pharmacokinetics in African Children

Incorporating Nonlinear Kinetics to Improve the Predictive Performance of Population Pharmacokinetic Models for Ciclosporin in Adult Renal Transplant Recipients: A Comparison of Modelling Strategies

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