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Patients with lung cancer (n = 43), head and neck (n = 9) and ovarian cancer (n = 28) were treated with erlotinib 150 mg orally once a day. Genetic polymorphisms of four polymorphisms (-216g / T,order soma generic Chandler -191C / A, intron 1 (CA) n, and 497G / A) in the EGFR gene, the CYP3A4 * 1B, CYP3A5 * 3, and order soma generic Chandler six polymorphisms (421C / A 34G, / A,order soma generic Chandler -15994G / A 15622CT, 16702G / A and 1143C / T) in the gene was genotyped in DNA ABCG2 blood (n = 80). Methods for estimating genotype and haplotype was included in the Appendix (online).
Erlotinib pharmacokinetic analysis of order soma generic Chandler plasma samples were collected and the concentration of erlotinib was measured by high performance liquid order soma generic Chandler chromatography.
Statistics and methods of analysis of PK order soma generic Chandler data analysis are provided in the appendix. Logistic regression was used to examine the association between the pharmacokinetics and toxicity. analysis of variance t tests were performed to assess the association between polymorphisms and various pharmacokinetic parameters.
Fisher's exact test were used to analyze the association between genetic polymorphisms and toxicity. Multiple analysis order soma generic Chandler was performed to test associations in dominant genetic models, recessive and additive. Models42 multivariate logistic regression were adjusted to examine the effects of genetic polymorphisms on toxicity, while the control of the PK. Only statistically significant (P 0.05 in bold italics) or marginally significant (p ≤ 0.05 ≤ 0.10 in bold) p values are shown in the tables. More details on statistical methods is provided in the Annex to the population pharmacokinetic modeling:.
Correlation order soma generic Chandler between information and patient characteristics PK toxicity are listed in Appendix Table A1 (online). Table 1 shows the parameter estimates of the population.
Patient characteristics were not significantly associated with pharmacokinetic order soma generic Chandler parameters. Because toxic effects can be confused by order soma generic Chandler the number of treatment cycles, one cycle toxicity data were used as a phenotype in this analysis. Thirty-three patients (41%) developed grade rash and 25 patients (31%) had ≥ grade 2 rash. Thirty-one patients (39%) had a degree of diarrhea and nine patients (11%) had diarrheagrade order soma generic Chandler ≥ 2. The correlations between the toxicity and PK are listed in Table 2. The AUC of erlotinib (AUC) was slightly associated with a rash of grade ≥ 2 (p = 0.082). The high degree of probability of order soma generic Chandler toxicity increased by a factor of 1.18 with 10 mg / L increase in hours x laASC.
The residual concentrations of the steady state (Cmin, mg / L) was significantly associated with rash (p = 0.040), with the likelihood of grade ≥ 2 rash vecespor increased from 1.75 to 1 mg order soma generic Chandler / L Cmin increased. No significant association or marginally significant were observed between pharmacokinetic parameters and the occurrence of diarrhea. The correlation between genetic polymorphisms and data associations between genetic polymorphisms PK and AUC, maximum concentration (Cmax) and Cmin are listed in Table 3. CYP3A4 * 1B was associated slightly with the AUC and trough concentrations of erlotinib in a dominant allele model (possibly lower CYP3A4 expression). Patients homozygous for the CYP3A4 * 1B (A / A) had C min levels 33% higher than patients order soma generic Chandler with genotype / G and the levels of 24% for patients with G / G genotype (P = 0.066).
Homozygous for the CYP3A5 * 3 G / G (nonexpressors CYP3A5) showed a trend towards higher levels of Cmin order soma generic Chandler with respect to A / genotype or A / G (p = 0.076 [recessive model]) with similar results for the AUC .
Since the two polymorphisms are in linkage disequilibrium (r2 = 0.44), including haplotypes diplotypes were predicted and were assigned to each individual. Patients homozygous for haplotype 1 (CYP3A4 * 1B, CYP3A5 order soma generic Chandler * 3 A, G or AG, and perhaps lower nonexpressor 3A5 3A4 Expressor) was 21% higher AUC (P = 0.090) and Cmin order soma generic Chandler 26 % higher (P = 0.079) than those with other diplotypes. The ABCG2 1143 C / T or T / T (low expression) genotype was associated with increased AUC and order soma generic Chandler Cmax of erlotinib (P = 0.072 and P = 0.047, respectively). 15,622 patients with C / T or T / T (low expression) genotype has a higher Cmax than those with C / C genotype (P = 0.065).
Moderate linkage disequilibrium (r2 order soma generic Chandler = 0.56) between the two SNPs were observed, and haplotypes including predicted. The diplotypes 1 / 4 (CC / TT) or 4.4 (order soma generic Chandler TT / TT) were significantly associated with higher AUC and Cmax (p = 0.019 and P = 0.006, respectively) and slightly higher than the Cmin (P = 0.064 ).
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