Comparative Pharmacokinetics of Generics vs. Brand Anticancer Drugs Across Ethnic Populations

Thesis Abstract

The rising use of generic anticancer medications across diverse ethnic populations raises concerns about comparable pharmacokinetic (PK) profiles relative to branded formulations, with potential implications for efficacy, safety, and dosing strategies in precision oncology. This study addresses the problem of limited cross-ethnic PK data for generics versus brand-name anticancer drugs, which may conceal clinically relevant differences in absorption, distribution, metabolism, and excretion that influence therapeutic outcomes. The aim is to compare PK parameters of selected anticancer generics and their brand-name counterparts across major ethnic groups to determine equivalence or clinically significant deviations that warrant dosing considerations. Specific objectives are to (1) quantify key PK metrics (Cmax, AUC0-?, t1/2, clearance, and volume of distribution) for generics and brands in European, East Asian, South Asian, and African-origin populations; (2) assess intra- and inter-ethnic variability using population PK modeling; (3) evaluate the impact of body weight, hepatic function, concomitant medications, and pharmacogenetic markers (CYP450 and transporter gene polymorphisms) on PK parameters; (4) test for equivalence within predefined bioequivalence margins (80–125%) and identify any clinically meaningful divergences; (5) synthesize findings to propose dosing or monitoring considerations for multi-ethnic patient cohorts. The study adopts a multi-center, prospective, cross-sectional design using opportunistic sampling of adult cancer patients undergoing intravenous or oral anticancer therapy with four commonly used agents that have both branded and generic versions paclitaxel, imatinib, capecitabine, and sorafenib. A total of 320 evaluable patients (40 per drug per ethnic stratum) will be enrolled, ensuring balanced representation across European, East Asian, South Asian, and African-origin populations. Data collection will involve serial PK sampling timed around dose administration, with plasma concentrations measured by validated high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) methods. Genotyping for select pharmacogenetic variants (CYP3A4, CYP2D6, ABCB1/MDR1, ABCC2, and SLCO1B1) will accompany phenotypic data. Population PK analyses will be conducted using nonlinear mixed-effects modeling (NONMEM) to estimate typical parameter values and interindividual as well as inter-ethnic variabilities, supplemented by Bayesian forecasting to optimize individual dosing simulations. Equivalence testing will apply standard bioequivalence criteria (geometric mean ratios and 90% confidence intervals) for PK parameters, with sensitivity analyses incorporating body weight, organ function indices, and genetic modifiers. The theoretical framework will integrate the Theory of Pharmacokinetic Variability and the Ethnopharmacology paradigm, complemented by the Biopharmaceutical Classification System to contextualize formulation differences. The study anticipates that generics and brand-name formulations will show overall PK similarity within predefined margins for most populations, but may reveal statistically and clinically significant differences in specific ethnic groups with distinct allele frequencies affecting metabolism or transporter activity. Expected findings include (i) comparable AUC and Cmax for most drugs in European and East Asian cohorts, with potential modest reductions in AUC for generics in certain African-origin subgroups due to transporter polymorphisms; (ii) slower clearance and longer half-life in individuals carrying decreased-function CYP3A4 or ABCB1 variants, leading to adjusted dosing considerations; (iii) identification of rare but impactful pharmacogenetic interactions that disproportionately affect generics versus brands in South Asian populations. The study contributes to knowledge by providing robust cross-ethnic PK evidence to guide formulation decisions, regulatory assessments, and personalized dosing in multi-ethnic oncology care. It is anticipated that results will inform pharmacovigilance plans, encourage harmonized bioequivalence testing that accounts for genetic diversity, and support clinicians in selecting and monitoring anticancer therapies across diverse patient populations. Recommendations include integrating pharmacogenetic screening into routine oncologic PK assessments, adopting population-specific dosing guidelines for generics where warranted, and expanding similar cross-ethnic PK comparisons to other therapeutic classes to strengthen equitable cancer care.