Aim. To estimate the effect of the reduced-function polymorphism SLCO1B1 c.521T>C on the renal graft function (estimated glomerular filtration rate, eGFR) over 12 months in patients treated with mycophenolic acid (MPA). Methods. Consecutive eligible adults (≥16 years of age) engrafted over a 6-year period who received MPA as a part of maintenance immunosuppression were assessed for eGFR on 9 occasions over 12 post-transplant months. The SLCO1B1 c.521C>T variant allele carriers (treated) and wild-type subjects (controls) were balanced on a range of demographic, medical, and genetic variables at baseline, and the development of eGFR (slope) was estimated with further adjustment for time-varying covariates. A subset of patients were assessed for exposure to MPA 5-7 days after the transplantation. Results. The adjusted eGFR slopes from day 1 to day 28 (peak), and from day 28 to day 365 were practically identical in treated (n=86) and control (n=168) patients (GMR=0.99, 95%CI 0.92-1.06, and GMR=0.98, 0.94-1.01, respectively). The rates of adverse renal outcomes and possible MPA-related adverse effects were low, and similar in treated and controls (adjusted RR=0.94, 0.49-1.84 and RR=1.08, 0.74-1.58, respectively). The pharmacokinetic substudy did not signal that treated and control patients differed with respect to MPA clearance, peak, trough or total exposure, overall (treated n=23, control n=45), if cotreated with cyclosporine (n=17 vs. n=26) or with tacrolimus (n=8 vs. n=17). Discussion. In patients treated with MPA, variant allele SLCO1B1 c.521T>C has no effect on the 12-month renal graft function. It does not seem to affect exposure to- and safety of MPA.
Aim. Cancer patients with reduced dihydropyrimidine dehydrogenase (DPD) activity are at increased risk of severe fluoropyrimidine (FP)-related adverse events (AE). Guidelines recommend FP dosing adjusted to genotype-predicted DPD activity based on four DPYD variants (rs3918290, rs55886062, rs67376798, rs56038477). We evaluated relationship between three further DPYD polymorphisms [c.496A>G (rs2297595), *6 c.2194G>A (rs1801160) and *9A c.85T>C (rs1801265)] and the risk of severe AEs. Methods. Consecutive FP-treated adult patients were genotyped for “standard” and tested DPYD variants, and for UGT1A1*28 if irinotecan was included, and were monitored for the occurrence of grade ≥3 (National Cancer Institute Common Terminology Criteria) vs. grade 0-2 AEs. For each of the tested polymorphisms, variant allele carriers were matched to respective wild type controls (optimal full matching combined with exact matching, in respect to: age, sex, type of cancer, type of FP, DPYD activity score, use of irinotecan/UGT1A1, adjuvant therapy, radiotherapy, biological therapy and genotype on the remaining three tested polymorphisms). Results. Of the 503 included patients (82.3% colorectal cancer), 283 (56.3%) developed grade ≥3 AEs, mostly diarrhea and neutropenia. Odds of grade ≥3 AEs were higher in c.496A>G variant carriers (n=127) than in controls (n=376) [OR=5.20 (95%CI 1.88-14.3), Bayesian OR=5.24 (95% CrI 3.06-9.12)]. Odds tended to be higher in *6 c.2194G>A variant carries (n=58) than in controls (n=432) [OR=1.88 (0.95-3.73), Bayesian OR=1.90 (1.03-3.56)]. *9A c.85T>G did not appear associated with grade ≥3 AEs (206 variant carriers vs. 284 controls). Conclusion. DPYD c.496A>G variant might need to be considered for inclusion in the DPYD genotyping panel.