Performance of Multiple-Batch Approaches to Pharmacokinetic Bioequivalence Testing for Orally Inhaled Drug Products with Batch-to-Batch Variability

Batch-to-batch pharmacokinetic (PK) variability of orally inhaled drug products has been documented and can render single-batch PK bioequivalence (BE) studies unreliable; results from one batch may not be consistent with a repeated study using a different batch, yet the goal of PK BE is to deliver a product comparison that is interpretable beyond the specific batches used in the study. We characterized four multiple-batch PK BE approaches to improve outcome reliability without increasing the number of clinical study participants. Three approaches include multiple batches directly in the PK BE study with batch identity either excluded from the statistical model (“Superbatch”) or included as a fixed or random effect (“Fixed Batch Effect,” “Random Batch Effect”). A fourth approach uses a bio-predictive in vitro test to screen candidate batches, bringing the median batch of each product into the PK BE study (“Targeted Batch”). Three of these approaches (Fixed Batch Effect, Superbatch, Targeted Batch) continue the single-batch PK BE convention in which uncertainty in the Test/Reference ratio estimate due to batch sampling is omitted from the Test/Reference confidence interval. All three of these approaches provided higher power to correctly identify true bioequivalence than the standard single-batch approach with no increase in clinical burden. False equivalence (type I) error was inflated above the expected 5% level, but multiple batches controlled type I error better than a single batch. The Random Batch Effect approach restored 5% type I error, but had low power for small (e.g., <8) batch sample sizes using standard [0.8000, 1.2500] bioequivalence limits.

Development and Validation of UPLC-MS/MS Method for the determination of Rivaroxaban in human plasma using Liquid-liquid extraction

A simple, sensitive, and selective ultra-performance liquid chromatographic (UPLC) method with mass spectrometric (UPLC-MS/MS) detection was developed for the determination of Rivaroxaban in human plasma sample. After a simple protein-precipitation by acetonitrile, the post-treatment samples were separated on a UPLC Bridged Ethyl Hybrid (BEH) C-18 column with 0.2% (v/v) formic acid in water: acetonitrile (60:40, v/v) as a mobile phase and analyzed in positive ion mode. The method developed was validated in human plasma with a daily working range of 2.02–997.72ng/mL with correlation coefficient, r2=0.999936. The method proved to be accurate (recovery, 97.0–107.95%), precise (2.21-7.21%), rapid (run time 2.5 min) and specific. In conclusion, the present validated method could be applied for pharmacokinetic study and bioequivalence testing of Rivaroxaban products.

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&lt;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&lt;0,001in the 3 first months after the transplantation and 0,11 [0,02-0,48] vs 0,08 [0,02-0,22] p&lt;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&lt;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.

Efficient model-based bioequivalence testing

Summary The classical approach to analyze pharmacokinetic (PK) data in bioequivalence studies aiming to compare two different formulations is to perform noncompartmental analysis (NCA) followed by two one-sided tests (TOST). In this regard, the PK parameters area under the curve (AUC) and $C_{\max}$ are obtained for both treatment groups and their geometric mean ratios are considered. According to current guidelines by the U.S. Food and Drug Administration and the European Medicines Agency, the formulations are declared to be sufficiently similar if the $90\%$ confidence interval for these ratios falls between $0.8$ and $1.25 $. As NCA is not a reliable approach in case of sparse designs, a model-based alternative has already been proposed for the estimation of $\rm AUC$ and $C_{\max}$ using nonlinear mixed effects models. Here we propose another, more powerful test than the TOST and demonstrate its superiority through a simulation study both for NCA and model-based approaches. For products with high variability on PK parameters, this method appears to have closer type I errors to the conventionally accepted significance level of $0.05$, suggesting its potential use in situations where conventional bioequivalence analysis is not applicable.

Use of Bioequivalence Tests and Its Properties under Different Sampling Techniques

Bioequivalence testing is the initial approach for the analysis of quantitative determination of drugs and their metabolism in biological samples. In this research work its applications was tested and reviewed under different sampling techniques. The basic concept of bioequivalence testing crossover design was used to make assessment of medicine for breast cancer methotrexate and tamoxifen. Effectiveness of methotrexate at initial stage was 2.38 and at advance stage it was 1.85 which means it was 43% effective at initial stage while 38% effective in advance stage. Effectiveness of tamoxifen at initial stage 3.19 at advance stage 3.68 which means it was 52% effective at initial stage while 57% effective in advance stage. The relation of bioequivalence testing and distance base inference was highlighted. An attempt was made to analyze the efficiency of both medicines at initial and advance stage of diagnostic of breast cancer.