The relative bioavailabilities of digoxin, furosemide, metformin, and rosuvastatin in the probe cocktails (test T1, T2, and T3) compared to the single substances (reference) were estimated from the ratios of the geometric means (test/reference) and their two‐sided 90% CIs for the primary (AUC0‐tz, Cmax) and secondary (AUC0‐∞) endpoints. The statistical model used was an analysis of variance (ANOVA) on log‐transformed endpoints including effects for sequence, subjects within sequences, period, and treatment. The effect “subjects within sequences” was considered random, whereas the other effects were considered fixed. CIs were determined from the ANOVA residual error. No adjustment for a first‐order carryover effect was included in the statistical analyses, as the occurrence of such an effect was highly unlikely due to the chosen study design and procedures. The statistical analyses were performed on the pooled pharmacokinetic set (all subjects from the treated set who provided at least one primary or secondary endpoint value in any period) using SAS (v. 9.2, by SAS Institute, Cary, NC).
The sample size calculation for this exploratory trial was not based on a power calculation but on the expected precision, defined as the ratio of upper to lower confidence limits of the 90% CI around the geometric mean ratio. For N = 24 evaluable subjects, the precision ranges for geometric coefficients of variation of 25% to 40% were from 1.35 to 1.61. The calculation was performed as described by Kupper and Hafner33 using R version 2.14.2.
The sample size calculation for this exploratory trial was not based on a power calculation but on the expected precision, defined as the ratio of upper to lower confidence limits of the 90% CI around the geometric mean ratio. For N = 24 evaluable subjects, the precision ranges for geometric coefficients of variation of 25% to 40% were from 1.35 to 1.61. The calculation was performed as described by Kupper and Hafner
