DataSheet1_Exploring inter-ethnic and inter-patient variability and optimal dosing of osimertinib: a physiologically based pharmacokinetic modeling approach.docx

Purpose: This study aimed to develop and validate a physiologically based pharmacokinetic (PBPK) model for osimertinib (OSI) to predict plasma trough concentration (Ctrough) and pulmonary EGFRm+ (T790M and L858R mutants) inhibition in Caucasian, Japanese, and Chinese populations. The PBPK model was also utilized to investigate inter-ethnic and inter-patient differences in OSI pharmacokinetics (PK) and determine optimal dosing regimens.Methods: Population PBPK models of OSI for healthy and disease populations were developed using physicochemical and biochemical properties of OSI and physiological parameters of different groups. And then the PBPK models were validated using the multiple clinical PK and drug-drug interaction (DDI) study data.Results: The model demonstrated good consistency with the observed data, with most of prediction-to-observation ratios of 0.8–1.25 for AUC, Cmax, and Ctrough. The PBPK model revealed that plasma exposure of OSI was approximately 2-fold higher in patients compared to healthy individuals, and higher exposure observed in Caucasians compared to other ethnic groups. This was primarily attributed to a lower CL/F of OSI in patients and Caucasian. The PBPK model displayed that key factors influencing PK and EGFRm+ inhibition differences included genetic polymorphism of CYP3A4, CYP1A2 expression, plasma free concentration (fup), albumin level, and auto-inhibition/induction on CYP3A4. Inter-patient PK variability was most influenced by CYP3A4 variants, fup, and albumin level. The PBPK simulations indicated that the optimal dosing regimen for patients across the three populations of European, Japanese, and Chinese ancestry was OSI 80 mg once daily (OD) to achieve the desired range of plasma Ctrough (328–677 nmol/L), as well as 80 mg and 160 mg OD for desirable pulmonary EGFRm+ inhibition (>80%).Conclusion: In conclusion, this study’s PBPK simulations highlighted potential ethnic and inter-patient variability in OSI PK and EGFRm+ inhibition between Caucasian, Japanese, and Chinese populations, while also providing insights into optimal dosing regimens of OSI.</p

Table1_Exploring inter-ethnic and inter-patient variability and optimal dosing of osimertinib: a physiologically based pharmacokinetic modeling approach.DOCX

Purpose: This study aimed to develop and validate a physiologically based pharmacokinetic (PBPK) model for osimertinib (OSI) to predict plasma trough concentration (Ctrough) and pulmonary EGFRm+ (T790M and L858R mutants) inhibition in Caucasian, Japanese, and Chinese populations. The PBPK model was also utilized to investigate inter-ethnic and inter-patient differences in OSI pharmacokinetics (PK) and determine optimal dosing regimens.Methods: Population PBPK models of OSI for healthy and disease populations were developed using physicochemical and biochemical properties of OSI and physiological parameters of different groups. And then the PBPK models were validated using the multiple clinical PK and drug-drug interaction (DDI) study data.Results: The model demonstrated good consistency with the observed data, with most of prediction-to-observation ratios of 0.8–1.25 for AUC, Cmax, and Ctrough. The PBPK model revealed that plasma exposure of OSI was approximately 2-fold higher in patients compared to healthy individuals, and higher exposure observed in Caucasians compared to other ethnic groups. This was primarily attributed to a lower CL/F of OSI in patients and Caucasian. The PBPK model displayed that key factors influencing PK and EGFRm+ inhibition differences included genetic polymorphism of CYP3A4, CYP1A2 expression, plasma free concentration (fup), albumin level, and auto-inhibition/induction on CYP3A4. Inter-patient PK variability was most influenced by CYP3A4 variants, fup, and albumin level. The PBPK simulations indicated that the optimal dosing regimen for patients across the three populations of European, Japanese, and Chinese ancestry was OSI 80 mg once daily (OD) to achieve the desired range of plasma Ctrough (328–677 nmol/L), as well as 80 mg and 160 mg OD for desirable pulmonary EGFRm+ inhibition (>80%).Conclusion: In conclusion, this study’s PBPK simulations highlighted potential ethnic and inter-patient variability in OSI PK and EGFRm+ inhibition between Caucasian, Japanese, and Chinese populations, while also providing insights into optimal dosing regimens of OSI.</p

Association between 3801T>C Polymorphism of CYP1A1 and Idiopathic Male Infertility Risk: A Systematic Review and Meta-Analysis

<div><p>Background</p><p>Epidemiological studies have evaluated the association between 3801T>C polymorphism of CYP1A1 gene and the risk for idiopathic male infertility, but the results are inconclusive. We aimed to derive a more precise estimation of the relationship by conducting a meta-analysis of case-control studies.</p><p>Methods</p><p>This study conformed to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, Embase and CNKI databases were searched through November 2013 to identify relevant studies. Pooled odds ratios with 95% confidence intervals were used to assess the strength of the association between CYP1A1 3801T>C polymorphism and idiopathic male infertility risk. <i>Q</i>-test was performed to evaluate between-study heterogeneity and publication bias was appraised using funnel plots. Sensitivity analyses were conducted to evaluate the robustness of meta-analysis findings.</p><p>Results</p><p>Six studies involving 1,060 cases and 1,225 controls were included in this meta-analysis. Overall, significant associations between 3801T>C polymorphism and idiopathic male infertility risk were observed in allelic comparison (OR = 1.36, 95% CI: 1.01–1.83), homozygous model (OR = 2.18, 95% CI: 1.15–4.12), and recessive model (OR = 1.86, 95% CI: 1.09–3.20), with robust findings according to sensitivity analyses. However, subgroup analyses did not further identify the susceptibility to idiopathic male infertility in all comparisons. Funnel plot inspections did not reveal evidence of publication bias.</p><p>Conclusions</p><p>The current meta-analysis provides evidence of a significant association between CYP1A1 3801T>C polymorphism and idiopathic male infertility risk. Considering the limitation inherited from the eligible studies, further confirmation in large-scale and well-designed studies is needed.</p></div

Funnel plot for the 3801T>C polymorphism of CYP1A1 under allele comparison in idiopathic male infertility.

<p>The vertical axis represents log (OR), and the horizontal axis refers to the standard error of log (OR). The horizontal line indicates the pooled OR, and the sloping lines indicate the expected 95% CI for a given standard error. The area of each circle represents the contribution of the study to the pooled OR.</p

Flow diagram of study selection and specific reasons for exclusion in the meta-analysis.

<p>Flow diagram of study selection and specific reasons for exclusion in the meta-analysis.</p

Results of Egger's test and Begg's test.

<p>Results of Egger's test and Begg's test.</p

CAYP1A1 3801T >C genotype distribution and allele frequencies in cases and controls.

<p><i>HB</i> hospital based, <i>PCR-RFLP</i> polymerase chain reaction-restriction fragment length polymorphism, <i>MAF</i> minor allele frequency, <i>HWE</i> Hardy–Weinberg equilibrium,</p>a<p>P value for HWE in control group.</p

Effect of individual studies on the pooled OR under allele comparison for the 3801T>C polymorphism of CYP1A1 in idiopathic male infertility.

<p>The vertical axis at 1.36 indicates the overall OR, and the two vertical axes at 1.01 and 1.83 indicate the 95% CI. Every hollow round indicates the pooled OR when the left study was omitted in a meta-analysis with a random model. The two ends of every broken line represent the respective 95% CI.</p

Results of meta-analysis for 3801T>C polymorphism of CYP1A1 and idiopathic male infertility risk.

<p><i>P_h P</i> value for heterogeneity based on Q test. All pooled ORs were derived from random-effects model except for cells marked with (fixed ^F).</p

Meta-analysis of the association between the 3801T>C polymorphism of CYP1A1 and risk for idiopathic male infertility under homozygous model.

<p>The contribution of each study to the meta-analysis (its weight) is represented by the area of a box, the center of which represents the size of the OR estimated from that study. The 95% CI for the OR (extending lines) from each study is also shown. The overall OR is shown in the middle of a diamond, the left and right extremes of which represent the corresponding CI.</p