TY - JOUR AU - Hammami, Muhammad M; Alvi, Syed N TI - Large Intra-subject Variability in Caffeine Pharmacokinetics: Randomized Cross-over Study of Single Caffeine Product SN - 2194-9379 SN - 2194-9387 PY - 2017 JO - Drug Res (Stuttg) JF - Drug Research LA - EN VL - 67 IS - 09 SP - 539 EP - 546 ET - 2017/05/23 DA - 2017/09/04 AB - Background Average bioequivalence has been criticized for not adequately addressing individual variations. Importance of subjects’ blinding in bioequivalence studies has not been well studied. We explored the extent of intra-subject pharmacokinetic variability and effect of drug-ingestion unawareness in subjects taking single caffeine product.Methods A single-dose randomized cross-over design was used to compare pharmacokinetics of 200 mg caffeine, described as caffeine (overt) or as placebo (covert). Maximum concentration (Cmax), Cmax first time (Tmax), area-under-the-concentration-time-curve, to last measured concentration (AUCT), extrapolated to infinity (AUCI), or to Tmax of overt caffeine (AUCOverttmax), and Cmax/AUCI were calculated blindly using standard non-compartmental method. Percentages of individual covert/overt ratios that are outside the ±25% range were determined. Covert-vs-overt effect on caffeine pharmacokinetics was evaluated by 90% confidence interval (CI) and 80.00–125.00% bioequivalence range.Results 32 healthy subjects (6% females, mean (SD) age 33.3 (7.2) year) participated in the study (28 analysed). Out of the 28 individual covert/overt ratios, 23% were outside the ±25% range for AUCT, 30% for AUCI, 20% for AUCOverttmax, 30% for Cmax, and 43% for Tmax. There was no significant covert-vs-overt difference in any of the pharmacokinetic parameters studied. Further, the 90% CIs for AUCT, AUCI, Cmax, AUCOverttmax, and Cmax/AUCI were all within the 80.00–125.00% bioequivalence range with mean absolute deviation of covert/overt ratios of 3.31%, 6.29%, 1.43%, 1.87%, and 5.19%, respectively.Conclusions Large intra-subject variability in main caffeine pharmacokinetic parameters was noted when comparing an oral caffeine product to itself. Subjects’ blinding may not be important in average bioequivalence studies. PB - © Georg Thieme Verlag KG DO - 10.1055/s-0043-110144 UR - http://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0043-110144 ER -