Figure S3 . Meta-analysis of studies reporting mean±SD MPA AUC0-12 at steady-state in renal transplant recipients treated with IR MMF and co-treated with CsA or macrolactams (tacrolimus or sirolimus) and genotyped for UGT1A9*3 (c.98T>C)SNP, classified as variant carriers (heterozygous, TC) vs. wild type homozygous subjects. The effect measure is ratio of means (ROM).
van Schaik 2009 [5] used reduced sampling schedule (at pre-dose, 0.5 and 2 hours post-dose) to project AUC0-12 at 3 and 10 days, and at 1, 3, 6 and 12 months postoperatively. They graphically reported geometric mean AUCs (no measures of spread or precision) at these time-points for 5 variant vs. 170 wt patients co-treated with CsA and, separately, for 5 variant vs. 158 wt patients co-treated with tacrolimus (Figure 3 in [5]). We graph-read (using digitizing software) the geometric mean values at Day 10 (considering the timing of the present measurements) and used p-values to recover common SD – this is shown in Figure S3.
The number of variant allele carriers was very low in each individual study and across studies by co-treatment and overall (Figure S3). van Schaik [5] reported that based on mixed-modelling of repeatedly assessed AUCs over time (at 6 time-points), among tacrolimus co-treated subjects, 5 TC patients vs. 158 wt subjects had by around 50% higher time-averaged AUCs (adjusted for age, sex, creatinine clearance, delayed-graft function and MPA measurement technique); and the same was reported for 5 TC subjects vs. 170 wt subjects co-treated with CsA [5]. However, considering the AUCs on postoperative day 10, the TC-wt difference in macrolactam co-treated subjects appeared even greater, but there was apparently no TC-wt difference among CsA co-treated patients (Figure S3). Kuypers [6] reported higher AUC in 3 TC vs. 92 wt subjects (Figure S3), while Picard [1] reported comparable AUCs in 10 TC vs. 105 wt subjects co-treated with CsA (Figure S3), and lower AUCs in 2 TC vs. 68 wt subjects co-treated with tacrolimus (Figure S3). When pooled, this scarce data rather consistently indicate lack of a relevant difference between TC (N=15) and wt subjects (N=275) when CsA is co-treatment (Figure S3). When marcolactams are co-treatment (Figure S3), individual study results are heterogeneous indicating also no major difference between TC (N=10) and wt subjects (N=318). In agreement, the overall pooled estimate (Figure S3) does not signal a major difference between TC (N=25) and wt subjects (N=593), but heterogeneity is huge, with 95% prediction intervals indicating from 7 times lower to 7 times higher AUCs in TC vs. wild-type subjects, i.e., approximately equal probability of TC being associated with a considerably lower or considerably higher exposure to MPA.
Based on studies including exclusively or predominantly Caucasians of European descent [1,2, 5-12] (pertinent for the present sample), prevalence of the TT/TG SLCO1B3 c.334T>G genotype is rather consistently estimated at 31.1% (95%CI 28.2-34.2; prediction interval 24.9-38.1) (Figure S4), and prevalence of variantUGT1A9*3 (c.98T>C) allele carriage is consistently estimated at 3.9% (95%CI 3.1-4.9, prediction interval 3.0-5.2) (Figure S4).