Population Pharmacokinetic Analysis of the Oral Absorption Process and Explaining Intra-Subject Variability in Plasma Exposures of Imatinib in Healthy Volunteers

Golabchifar, Ali-Akbar; Rezaee, Saeed; Dinan, Nahid Mobarghei; Kebriaeezadeh, Abbas; Rouini, Mohammad-Reza

doi:10.1007/s13318-015-0292-3

Cited by 7 publications

(5 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The equations describing CL/F, Vc/F, Vp/F, and Q/F parameters for the i‐th individual are listed below:

\begin{matrix} true \\ left normalCL / F_{i} = 6.27 \times {(\frac{BWT}{70})}^{0.75} \\ left \times ((), 1 - 0.173 \cdot normalCY P_{moderate}) \\ left \times ((), 1 - 0.303 \cdot normalCY P_{strong}) \\ left \times {(\frac{WNCL}{71.23})}^{0.406} \times ((), 1 - 0.004 ((), normalBPBL - 38.20)) \end{matrix}

{normalV}_{normalc} / {normalF}_{i} = 3.32 \times {((), \frac{normalBWT}{70})}^{1}

{normalV}_{normalp} / {normalF}_{i} = 279.21 \times {((), \frac{normalBWT}{70})}^{1} \times (1 - 0.825 \cdot Solid)

Q / {normalF}_{i} = 1.29 \times {((), \frac{normalBWT}{70})}^{0.75} \times (1 - 0.653 \cdot Solid)

wherein BPBL is baseline percentage bone marrow blasts, BWT is baseline body weight, and WNCL is weight‐standardized CR CL . In line with other oral oncology drugs, the residual variability for both hematologic and solid tumor patients was around 60% to 70% despite inclusion of covariates …”

Section: Resultssupporting

confidence: 58%

“…In line with other oral oncology drugs, the residual variability for both hematologic and solid tumor patients was around 60% to 70% despite inclusion of covariates. [17][18][19][20][21] Prediction-based diagnostic plots showed good agreement between model predictions and observed concentrations (Figure 2, Supplemental Figure S2). The final model described the data without any obvious bias in residual error over time and concentration (Figure 2).…”

Section: Covariate Analyses and Final Modelmentioning

confidence: 67%

See 1 more Smart Citation

Population Pharmacokinetics of Glasdegib in Patients With Advanced Hematologic Malignancies and Solid Tumors

Lin

Shaik

Martinelli

et al. 2019

The Journal of Clinical Pharma

View full text Add to dashboard Cite

Glasdegib is an inhibitor of the Hedgehog pathway recently approved in the United States for the treatment of acute myeloid leukemia. A population pharmacokinetic analysis was conducted to characterize the kinetic behavior of glasdegib and its sources of variability (covariates) by utilizing data from 269 patients with cancer treated with oral glasdegib doses ranging from 5 to 640 mg/d. Nonlinear mixed-effects modeling was conducted using NONMEM (v.7.3) and Perl-speaks NONMEM (v.4.2.0). The estimated apparent total clearance, apparent central volume of distribution, and apparent peripheral volume of distribution were 6.27 L/h, 3.32 L, and 279.2 L, respectively. Age, sex, race, and hepatic function were not significant covariates on glasdegib pharmacokinetic parameters. Baseline body weight, percentage bone marrow blasts, creatinine clearance, and use of moderate or strong cytochrome P450 3A inhibitors were statistically significant covariates on apparent total clearance; however, the magnitude of the effects was not considered clinically meaningful.

show abstract

“…The equations describing CL/F, Vc/F, Vp/F, and Q/F parameters for the i‐th individual are listed below:

\begin{matrix} true \\ left normalCL / F_{i} = 6.27 \times {(\frac{BWT}{70})}^{0.75} \\ left \times ((), 1 - 0.173 \cdot normalCY P_{moderate}) \\ left \times ((), 1 - 0.303 \cdot normalCY P_{strong}) \\ left \times {(\frac{WNCL}{71.23})}^{0.406} \times ((), 1 - 0.004 ((), normalBPBL - 38.20)) \end{matrix}

{normalV}_{normalc} / {normalF}_{i} = 3.32 \times {((), \frac{normalBWT}{70})}^{1}

{normalV}_{normalp} / {normalF}_{i} = 279.21 \times {((), \frac{normalBWT}{70})}^{1} \times (1 - 0.825 \cdot Solid)

Q / {normalF}_{i} = 1.29 \times {((), \frac{normalBWT}{70})}^{0.75} \times (1 - 0.653 \cdot Solid)

Section: Resultssupporting

confidence: 58%

Section: Covariate Analyses and Final Modelmentioning

confidence: 67%

Population Pharmacokinetics of Glasdegib in Patients With Advanced Hematologic Malignancies and Solid Tumors

Lin

Shaik

Martinelli

et al. 2019

The Journal of Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…However, challenges remain, ranging from throughput limitations of current analytic methods for the detection of imatinib, lack of specific anticancer TDM cost-effectiveness studies to support implementation, constrains of precise trough sampling, and ultimately the unwillingness of prescribers to modify established dosing approaches 3 . Furthermore, although the impact of intra-subject variability in imatinib pharmacokinetics is low (»30 % on key pharmacokinetic metrics) 100,101 virtual-TDM approaches should further consider addressing approaches to model this to fully capture the range of inter-and intra-subject variability associated with imatinib therapy.…”

Section: Discussionmentioning

confidence: 99%

The Application of Virtual Therapeutic Drug Monitoring to Assess the Pharmacokinetics of Imatinib in a Chinese Cancer Population Group

Badhan²

2023

Journal of Pharmaceutical Sciences

View full text Add to dashboard Cite

“…Therefore, the health status of the body likely affects the CL/F of imatinib. 26,30 Creatinine clearance shows an appreciable correlation with the clearance of many drugs. In this study, clearance of imatinib was not correlated with creatinine clearance, which is consistent with a previous study performed by Delbaldo et al, 24 as imatinib and its metabolites are barely excreted through the kidneys.…”

Section: Discussionmentioning

confidence: 99%

Personalized Dose of Adjuvant Imatinib in Patients with Gastrointestinal Stromal Tumors: Results from a Population Pharmacokinetic Analysis

Jiang¹,

Fu²,

Jin³

et al. 2023

DDDT

View full text Add to dashboard Cite

Imatinib is the first-line treatment for patients with gastrointestinal stromal tumors (GIST) after surgery. However, its pharmacokinetic profile varies remarkably between individuals and has not been well characterized in postoperative Chinese patients with GIST. Therefore, this study aimed to develop a population pharmacokinetic (PPK) model and recommend appropriate doses for different patients to achieve the target trough concentration in such a population. Patients and Methods: A total of 110 surgically treated GIST patients were enrolled, of which 85 were applied to conduct a PPK analysis with a nonlinear mixed-effect model and 25 for external validation of the model. Demographic and biomedical covariates, as well as six single nucleotide polymorphisms were tested to explore the sources of variation in pharmacokinetic parameters of imatinib. Monte Carlo simulations were performed to establish the initial dosing regimens. Results: A one-compartment model was established in postoperative GIST patients. The red blood cell count (RBC) and ABCG2 rs2231142 were observed to have a significant effect on the clearance of imatinib. The typical values estimated by the final model were 9.72 L/h for clearance (CL/F) and 229 L for volume of distribution (V/F). Different from the fixed dose regimen of 400 mg each day, patients carrying rs2231142 heterozygous type and with a lower level of RBC (2.9 × 10 12 /L), 300 mg imatinib daily is enough to achieve the target trough concentration. When RBC rises to 4.9 × 10 12 /L, 500 mg daily is recommended. For patients with rs2231142 GG genotype, 500 mg a day is required at RBCs of 3.9 × 10 12 /L and 4.9 × 10 12 /L. Conclusion: RBC and rs2231142 contribute to the pharmacokinetic variation of imatinib and personalized dose recommendations based on patient characteristics may be necessary.

show abstract

Population Pharmacokinetic Analysis of the Oral Absorption Process and Explaining Intra-Subject Variability in Plasma Exposures of Imatinib in Healthy Volunteers

Abstract: Analyses using NLMEM for imatinib exhibited absorption complexities such as two input rates and medium to high intra-individual variability in drug exposure.

Cited by 7 publications

References 37 publications

Population Pharmacokinetics of Glasdegib in Patients With Advanced Hematologic Malignancies and Solid Tumors

Population Pharmacokinetics of Glasdegib in Patients With Advanced Hematologic Malignancies and Solid Tumors

The Application of Virtual Therapeutic Drug Monitoring to Assess the Pharmacokinetics of Imatinib in a Chinese Cancer Population Group

Personalized Dose of Adjuvant Imatinib in Patients with Gastrointestinal Stromal Tumors: Results from a Population Pharmacokinetic Analysis

Contact Info

Product

Resources

About