MO920TRANSITION FROM GENERIC TO BRAND TACROLIMUS IN TUNISIAN RENAL TRANSPLANT RECIPIENTS

Background and Aims Due to unavailability of the generic tacrolimus, commonly used in renal transplant patients in Tunisia, all renal transplant switched to the Brand. No previous studies have assessed the pharmacokinetic differences of this generic tacrolimus compared to the brand. The aim of the present study was to evaluate the effect of this switch on the tacrolimus dose (D) and on the dose-adjusted tacrolimus trough blood concentrations (C0/D) in Tunisian renal transplant recipients. Method For the 255 renal transplant monitored in biochemestry department of Sahloul University hospital, 808tacrolimus trough concentration (C0) were collected from october 2018 to February 2020 and were divided to 406 C0 determination before switch and 402 after switch. The dose and the post-transplantation period was recorded for each C0. Results The generic tacrolimus doses used were significantly higher compared to the brand: 0,12 mg/kg [0,02-0,6] vs 0,11 mg/kg [0,02-0,22] p<0,001 and this was reported in different post graft periods: 0,17 [0,03-0,22] vs 0,13 [0,06-0,22] p<0,001in the 3 first months after the transplantation and 0,11 [0,02-0,48] vs 0,08 [0,02-0,22] p<0,001 above.The C0/D were significantly lowe runder the the generic tacrolimus compared to the brand 48,34ng/ml per mg/kg/day [11,58-210,00] vs77,35ng/ml per mg/kg/day[19,38-221,67]; p<0,001 and this was reported in different post graft periods: 71,12ng/ml per mg/kg/day [6,80, 451,56] vs80,9750ng/ml per mg/kg/day [17,33-458,80] p=0,017 in the 3 first months after the transplantation and 71,12ng/ml per mg/kg/day [6,80, 451,56] vs80,9750ng/ml per mg/kg/day [17,33-458,80] p=0,017 above. Dose needed to reach target tacrolimus C0 seems to be higher with the generic tacrolimus compared to the brand. Conclusion Approval of a generic is dependent on bioequivalence testing in healthy adult volunteers after a single dose, however studies on renal graft recipient populations after chronic use are needed to assed bioequivalence in this special population.

Cetuximab (Cet) clearance and survival in patients (pts) with metastatic colorectal cancer (mCRC).

699 Background: Cet, a monoclonal antibody against EGFR, is a standard therapy for pts with RAS wild-type (WT) mCRC. Limited previous data suggest that Cet clearance correlates with progression-free survival (PFS). We performed a population pharmacokinetic (pop-pK) analysis of Cet in pts who participated in the randomized phase III NCIC CO.20 trial in KRAS WT mCRC patients. Methods: Standard Cet doses ± brivanib were administered. Using intermittent trough blood samples, pop-pK analysis was conducted to evaluate different models. Pts were divided into quartiles according to clearance parameters to assess the exposure-response relationship to response rate (RR), PFS and overall survival (OS). Clinical variables including demographic, laboratory, disease characteristics and co-administration of brivanib were evaluated as co-variates on Cet clearance. Results: In 701 pts, Cet elimination was best described as a one-compartment model with a non-linear saturable elimination process (defined by Vmax and Km). Mean values (± standard deviation) for pop-pk parameters were 2.7 ± 0.5 L/m2 for V, 2.5 ± 0.3 mg/h/m2 for Vmax, and 101.0 ± 0.05 mg/L/m2 for Km. Grouped into quartiles, Vmax and Km were significantly associated with OS, but not RR or PFS. The median OS for pts in the lowest quartile of Vmax was 12.0 ms versus (vs.) 6.9 ms for pts in the highest quartile ( p< 0.001), while the median OS was 11.6 ms in the highest Km quartile vs. 6.9 ms in the lowest Km quartile ( p< 0.001). When compared to the quartile with the combination of highest Vmax and lowest Km, pts in the quartile with the lowest Vmax and highest Km had longer PFS (5.0 vs. 3.7 ms, HR 0.75 (95% confidence interval (CI) 0.58-0.98, p= 0.032) and OS (11.7 vs. 6.6 ms, HR 0.59 (95% CI, 0.45-0.77, p< 0.001). Pts in the lower Vmax and higher Km quartiles also experienced less grade 3 toxicity. Neither clinical variables nor brivanib administration were associated with Cet clearance parameters. Conclusions: For KRAS WT mCRC, standard Cet dosing is not optimal for all pts. Pts with slower Cet clearance have significantly improved PFS and OS. Further studies are needed to optimize Cet doses based on individual pK assessments, and to identify novel factors associated with clearance.

Switching Stable Kidney Transplant Recipients to a Generic Tacrolimus Is Feasible and Safe, but It Must Be Monitored

Background. Tacrolimus is the primary immunosuppressive drug used in kidney transplant patients. Replacing brand name products with generics is a controversial issue that we studied after a Chilean Ministry of Health mandate to implement such a switch.Methods. Forty-one stable Prograf (Astellas) receiving kidney transplant patients were switched to a generic tacrolimus (Sandoz) in a 1 : 1 dose ratio and were followed up for up to 8 months. All other drugs were maintained as per normal practice.Results. Neither tacrolimus doses nor their trough blood levels changed significantly after the switch, but serum creatinine did:1.62±0.90versus1.75±0.92 mg/dL (p<0.001). At the same time, five graft biopsies were performed, and two of them showed cellular acute rejection. There were nine infectious episodes treated satisfactorily with proper therapies. No patient or graft was lost during the follow-up time period.Conclusion. Switching from brand name tacrolimus to a generic tacrolimus (Sandoz) is feasible and appears to be safe, but it must be monitored carefully by treating physicians.