Individual estimate of Q vs. baseline total bilirubin (with full phase I dataset).

<p>Regression analysis; Q = 11.21 * Bilirubin level+0.7422 (P<0.01).</p

Demographics and baseline labs of patients included in pharmacogenetic analyses (n = 35).

<p>Demographics and baseline labs of patients included in pharmacogenetic analyses (n = 35).</p

Association of PGx, PK and bilirubin from the phase I dataset.

<p>Flavo-G PK parameter estimates from 27 patients were evaluated for relationships with PGx. Fewer TA repeats in the UGT1A1 promoter were weakly associated with lower flavo-G Cmax (Panel A) and AUC (Panel B). For SLCO1B1, the rs2306283 SNP correlated with flavo-G plasma concentrations (the total time flavo-G plasma concentrations were below 1.5 µM, p = .019; Panel C, one outlier removed). For ABCG2, the rs1564481 SNP was associated with flavo-G AUC (p = .050; Panel D) and the rs2231142 SNP was associated with flavopiridol AUC (p = 0.08, Panel E). The SLCO1B1 rs3829310 minor C allele was associated with higher baseline total bilirubin (p = .011; Panel F). For plots A and B, the x-axis indicates the number of promoter TA repeats for both gene copies (6.7 = 6 and 7 TA repeats; 7 = 7 TA repeats for each gene copy; 7.8 = 7 and 8 TA repeats; 8 = 8 TA repeats for each gene copy).</p

Significant covariate-parameter correlations after inclusion of single genetic covariates.

<p>Comparison of OFV was made between models with single genetic covariates and the base model, using the reduced dataset with deletion of subjects having missing values on each individual genetic covariate. Δ OFV, change in objective function value.</p

Uptake of flavopiridol, flavo-G, SN-38 and lenalidomide in OATP1B1 transfected cells.

<p>The bar graph indicates means + SD for triplicate determinations of 10 µM flavopiridol, flavo-G, SN-38 and lenalidomide uptake rates in cell lines (HEK-293 or MDCK-II) transfected with empty control vector or vector cloned with the OATP1B1 gene (SCLO1B1). Incubations with flavo-G were for 30 min., and all other drugs were for 10 min. Transport rates are expressed as percentages normalized to empty vector control. * p<.05, ** p<0.001,Student's t-test.</p

Uptake of flavopiridol in nonsynonymous polymorphic variants of OATP1B1.

<p>The bar graph indicates means + SD for triplicate determinations of 10 µM flavopiridol uptake rates in MDCK-II cells transfected with empty control vector or vector cloned with the reference or polymorphic SLCO1B1 genes. All incubations were for 10 min. Variants are indicated with respect to their amino acid change; T155P = rs11045819, D130N = rs2306283, V174A = rs4149056. Transport rates were normalized to empty vector control. Differences in uptake rates were compared to the reference OATP1B1 transporter. * p<.05, ** p<0.01, Student's t-test.</p

List of primers used for cloning, sequencing, and mutagenesis of SLCO1B1.

<p>List of primers used for cloning, sequencing, and mutagenesis of SLCO1B1.</p

Population estimates from final model and bootstrap analysis.

<p>Relative bias,i(%) = (Pbs,i−Pest,i)/Pest,I×100; Pbs,i: mean of parameter i estimate from bootstrap; Pest,i: final parameter i estimate.</p

Final model parameter estimates.

<p>The reduced dataset with 35 subjects and 388 plasma concentrations was used. Parameters: CL, clearance; V1, volume of central compartment; Q, intercompartmental clearance; V2, volume of peripheral compartment (units are noted in parenthesis). BSV and BOV are listed as %CV. Θ, typical value of the PK parameters; BSV, between-subject variability; BOV, between-occasion variability.</p

Six significant covariate-parameter correlations after inclusion of single demographic or lab covariates.

<p>Comparison of OFV is made between model with single covariate and the base model. Δ OFV, change in objective function value.</p