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Statistics and methods of analysis of PK 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 buy soma tabs Pomona performed to assess the association between polymorphisms and various pharmacokinetic parameters. Fisher's exact test were used to analyze the association buy soma tabs Pomona between genetic polymorphisms and toxicity. Multiple analysis was performed to test associations in dominant buy soma tabs Pomona genetic models, recessive and additive. Models42 multivariate buy soma tabs Pomona logistic regression were adjusted to examine the buy soma tabs Pomona effects of genetic polymorphisms on toxicity, while buy soma tabs Pomona 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 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 parameters. Because toxic effects can be confused by 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 buy soma tabs Pomona degree of diarrhea and nine patients (11%) had diarrheagrade ≥ 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 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 / L Cmin increased. No significant association or marginally buy soma tabs Pomona 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) buy soma tabs Pomona 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 buy soma tabs Pomona min levels 33% higher than patients with genotype / G and the levels of 24% for patients with G / G buy soma tabs Pomona genotype (P = 0.066). Homozygous for the CYP3A5 * 3 G / G (nonexpressors CYP3A5) showed a trend towards higher levels of Cmin 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 buy soma tabs Pomona = 0.44), including haplotypes diplotypes were buy soma tabs Pomona predicted and were assigned to each individual. Patients homozygous for haplotype 1 (CYP3A4 * 1B, CYP3A5 * 3 A, G or AG, and perhaps lower nonexpressor 3A5 3A4 buy soma tabs Pomona Expressor) was 21% higher AUC (P = 0.090) and Cmin 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 buy soma tabs Pomona Cmax of erlotinib (P = 0.072 and P = 0.047, respectively). 15,622 patients with C / T buy soma tabs Pomona or T / T (low expression) genotype buy soma tabs Pomona has a higher Cmax than those with C / C genotype (P = 0.065). Moderate linkage disequilibrium (r2 = 0.buy soma tabs Pomona 56) between the two SNPs were observed, buy soma tabs Pomona and haplotypes including predicted. The diplotypes 1 / 4 (CC / TT) or 4.4 (TT / TT) were significantly associated with higher AUC and Cmax (p = 0.019 and P = 0.006, buy soma tabs Pomona respectively) and slightly higher than the Cmin (P = 0.064 ). Note that the number of patients with certain polymorphisms was low (for example, only four patients EGFR497 A / A, seven patients with CYP3A4 * 1B G / G, five patients with ABCG216, A 702 / A, and nine patients ABCG2 15994 A / A).