A general empirical model for renal drug handling in pharmacokinetic analyses

Wright, Daniel F. B.; Duffull, Stephen B.

doi:10.1111/bcp.13306

Cited by 7 publications

(7 citation statements)

References 10 publications

(20 reference statements)

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“…The creatinine clearance covariate value suggested by this investigation was not substantially different from that presented in this study (0.28 vs 0.224). The nonlinear covariate relationship presented in this study further supports the conclusion by Wright et al, suggesting that tubular secretion may be partly independent of impairment to glomerular filtration …”

Section: Discussionsupporting

confidence: 91%

Population pharmacokinetics of lenalidomide in patients with B‐cell malignancies

Hughes

Phelps

Upton

et al. 2019

Brit J Clinical Pharma

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Aims:Lenalidomide is an immunomodulatory imide drug used broadly in the treatment of multiple myeloma and lymphoma. It continues to be evaluated in chronic lymphocytic leukaemia (CLL) at lower doses due to dose-related toxicities including tumour flare and tumour lysis syndrome. This study aimed to develop a population pharmacokinetic model for lenalidomide in multiple cancers, including CLL, to identify any disease-related differences in disposition. Methods: Lenalidomide concentrations from 4 clinical trials were collated (1999 samples, 125 subjects), covering 4 cancers (multiple myeloma, CLL, acute myeloid leukaemia and acute lymphoblastic leukaemia) and a large dose range (2.5-75 mg).A population pharmacokinetic model was developed with NONMEM and patient demographics were tested as covariates. Results:The data were best fitted by a 1-compartment kinetic model with absorption described by 7 transit compartments. Clearance and volume of distribution were allometrically scaled for fat-free mass. The population parameter estimates for apparent clearance, apparent volume of distribution and transit rate constant were 12 L/h (10.8-13.6), 68.8 L (61.8-76.3), and 13.5 h −1 (11.9-36.8) respectively. Patients with impaired renal function (creatinine clearance <30 mL/min) exhibited a 22% reduction in lenalidomide clearance compared to patients with creatinine clearance of 90 mL/min. Cancer type had no discernible effect on lenalidomide disposition.Conclusions: This is the first report of a lenalidomide population pharmacokinetic model to evaluate lenalidomide pharmacokinetics in patients with CLL and compare its pharmacokinetics with other B-cell malignancies. As no differences in pharmacokinetics were found between the observed cancer-types, the unique toxicities observed in CLL may be due to disease-specific pharmacodynamics.

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Section: Discussionsupporting

confidence: 91%

Population pharmacokinetics of lenalidomide in patients with B‐cell malignancies

Hughes

Phelps

Upton

et al. 2019

Brit J Clinical Pharma

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“…For both M1 and M2, the linear proportional parameter θ was set to 1 and was not changed for the EMA and FDA designs regardless of whether mGFR or eGFR was used as an estimate of GFR. The EMA design recommends the use of mGFR so the value of γ for M2 was set at 0.33 based on the finding of Wright and Duffull 5 . Of note, the value of γ reported in the original study 5 was 0.28, while in this study a convenient value of 0.33 (or 1/3) was selected as a value that would be simpler to use in practice.…”

Section: Methodsmentioning

confidence: 98%

“…The EMA design recommends the use of mGFR so the value of γ for M2 was set at 0.33 based on the finding of Wright and Duffull 5 . Of note, the value of γ reported in the original study 5 was 0.28, while in this study a convenient value of 0.33 (or 1/3) was selected as a value that would be simpler to use in practice. The FDA design recommends the use of eGFR , which may give a biased estimate of the true GFR.…”

Section: Methodsmentioning

confidence: 98%

“…This model will be referred to as M2 in this paper. M2 is equivalent to the model proposed by Wright and Duffull 5 . Here, Equation 2 can be considered a general model for renal drug handling where M1 is a special case of M2 when the exponent γ = 1.…”

Section: Methodsmentioning

confidence: 99%

“…The INH is a simplification of the complex and varied pathophysiologies encountered in patients with renal impairment. The INH is also widely assumed to provide an explanation for renal drug handling 3–5 . This has been questioned by several authors 6–9 and it has been suggested that the INH may not be a suitable general model for renal drug handling 5 .…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of designs for renal drug studies based on the European Medicines Agency and Food and Drug Administration guidelines for drugs that are predominantly secreted

Pradhan

Wright

Duffull

2020

Brit J Clinical Pharma

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Aims Dose adjustment for drugs eliminated by the kidneys generally assume a linear relationship between renal drug clearance (CLR) and glomerular filtration rate (GFR). This assumption may not hold for drugs that undergo extensive tubular secretion where nonlinearity in drug handling is expected. The aim of this study is to determine if renal drug study designs recommended by the European Medicines Agency (EMA) and Food and Drug Administration (FDA) could distinguish linear from nonlinear renal drug handling. Methods In this simulation and estimation study, the study designs based on the EMA and FDA guidelines for Phase I renal drug studies were evaluated for their ability to discriminate a linear from a nonlinear relationship between CLR and GFR. The number of subjects for each simulated study ranged from 4 to 960. Power, relative standard error and bias were calculated. Results Study designs under the EMA and FDA guidelines required ≥8 and ≥48 subjects, respectively, to achieve ≥80% power to discriminate a linear from nonlinear relationship between CLR and GFR. The relative standard error of estimated parameters were 13–37 and 17–44% for the designs with 24 subjects under the EMA and FDA guidelines, respectively. The bias in parameter estimates under the EMA designs were not evident, however, they were biased (13–21%) under the FDA designs. Conclusion The EMA design was found to require fewer subjects (n = 8) compared to the FDA (n = 48) to discriminate linear from nonlinear drug renal handling at ≥80% study power while both the designs perform poorly for the parameter precision.

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A population pharmacokinetic model of intravenous telavancin in healthy individuals to assess tissue exposure

Ullah

Matzneller

Zeitlinger

et al. 2019

Naunyn-Schmiedeberg's Arch Pharmacol

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A general empirical model for renal drug handling in pharmacokinetic analyses

Cited by 7 publications

References 10 publications

Population pharmacokinetics of lenalidomide in patients with B‐cell malignancies

Population pharmacokinetics of lenalidomide in patients with B‐cell malignancies

Evaluation of designs for renal drug studies based on the European Medicines Agency and Food and Drug Administration guidelines for drugs that are predominantly secreted

A population pharmacokinetic model of intravenous telavancin in healthy individuals to assess tissue exposure

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