Association of Variability and Pharmacogenomics With Bioequivalence of Gefitinib in Healthy Male Subjects

Abstract

Objective: The aim of the study was to explore the association of pharmacokinetic variability and pharmacogenomics with the bioequivalence of orally administered gefitinib (Iressa®, AstraZeneca) provided by three sponsors in healthy subjects.Methods: The study designs were randomized, open-label, and two-period crossover studies in both fasting and fed healthy subjects. In one fasting study, the sample size was enlarged from 30 to 60 for the failing study. Each study subject received a 250-mg gefitinib tablet with a 21-day washout. The plasma concentrations were measured using LC-MS/MS, and pharmacokinetic parameters were determined by noncompartmental methods. Genetic analyses of CYP3A4, CYP3A5, and CYP2D6 alleles were carried out by the polymerase chain reaction (PCR).Results: Two hundred and sixty healthy male subjects were enrolled. The median maximum plasma concentration (Tmax) was 4–5 h, and the mean elimination half-life (t1/2) was 18–26 h. The maximum plasma concentration (Cmax) and area under the curve (AUC) increased but Tmax and t1/2 were unaffected by the intake of high-fat food. Three fed and two fasting studies achieved a plausible bioequivalence. The intake of high-fat food decreased the intra-subject variability significantly. In addition, CYP2D6 was associated with gefitinib exposure and may contribute to the high inter-subject variability, but it did not influence the bioequivalence result.Conclusions: Gefitinib is well tolerated, and the bioequivalence is easier to achieve under fed conditions compared to fasting conditions. The 90% confidence interval (CI) of geometric mean ratio (GMR) can be narrowed when the sample size is enlarged without changing the formulation-related technology.

Pharmacokinetics and pharmacodynamics of rongliflozin, a novel selective inhibitor of sodium‐glucose co‐transporter‐2, in people with type 2 diabetes mellitus

“…The major routes of rongliflozin elimination are renal (32%) and faecal (17%). Administration of the drug in combination with food did not influence the exposure (AUC) or concentration at 24 hours after dosing, suggesting that those taking the drug do not need to worry about the effects of food ingested within several hours of drug administration …”

“…Administration of the drug in combination with food did not influence the exposure (AUC) or concentration at 24 hours after dosing, suggesting that those taking the drug do not need to worry about the effects of food ingested within several hours of drug administration. 20 The kidneys contribute to maintaining normal blood glucose levels by reabsorbing~180 g of glucose each day. 21,22 At serum glucose levels greater than the renal threshold for glucose, the renal capacity for glucose reabsorption is saturated and the amount of glucose in urine increases in proportion to serum glucose concentrations.…”

“…In all cases, the drug was administered with 240 mL water. Participants were randomized to receive one of three doses of rongliflozin (10,20 or 50 mg). Study participants did not receive rongliflozin on days 2 to 3, when samples were collected to study the PK and pharmacodynamic (PD) characteristics.…”

Tolerance, Variability and Pharmacokinetics of Albumin-Bound Paclitaxel in Chinese Breast Cancer Patients

“…We re-estimated the sample size for the three studies based on their BE analysis results (α = 0.05, power = 0.8, GMR, and intra-cv) and the original hypothesis. The re-estimated sample size was 6–20, which is less than our enrollment size (Table 4 ) (Zhang et al, 2018a , b ).…”

“…According to the initial estimation by R software, sample size should be of 21 patients. Based on the above sample size estimation result and considering a loss to follow-up of 10% and the opinion of sponsor and investigator, the final needed sample size was considered to be 24 (Table 1 ) (Zhang et al, 2018a , b ).…”