A randomized, cross‐over trial of metoprolol succinate formulations to evaluate PK and PD end points for therapeutic equivalence

Figures

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  FIGURE 1. Study design. The brand name drug was administered for 7 to 28 days (phase 1) and overnight visits were conducted for pharmacokinetc and pharmacodynamic (PK/PD) studies. This was followed by 7‐day treatment with either generic drug 1 (a) or generic drug 2 (b) (phase 2) and the second overnight PK/PD study. The brand name drug was resumed for 7–28 days (phase 3), followed by 7 days of drug 2 (a) or drug 1 (b) (phase 4) and a final overnight PK/PD study.

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  FIGURE 2. Total metoprolol ER concentrations versus time profiles for 30 participants who completed studies with the 50 mg dose of the brand name drug and at least one of the generic formulations. Solid line with triangles, dashed line with squares, and dashed/dotted line with circles, represent the mean concentrations of the brand name drug (brand), generic drug 1, and generic drug 2, respectively. The error bars represent the standard error of the mean. For statistical comparison of metoprolol ER generic formulations to the brand name drug, p values were obtained by a mixed effect model for repeated measures to compare the time course of the concentration means within each subject by formulation. ER, extended‐release.

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  FIGURE 3. BE test results based on total (R + S) metoprolol ER concentrations for participants who completed studies with the 50 mg dose of the brand name drug and at least one of the generic formulations. The shaded area designates the 0.8 to 1.25 BE limits. The point estimates of the ratio of the geometric means and its confidence intervals are represented with the red (drug 1 vs. brand) and orange (drug 2 vs. brand) dots and error bars. AUC0‐Tlast, area under the curve from dosing time to T last; AUC0‐24, area under the curve from dosing time to 24 h after dose, which was calculated by interpolation; BE, bioequivalence; C max, maximum concentration; ER, extended‐release; N = number of the participants included in each bioequivalence test; T last, time at which the last observation occurs.

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  FIGURE 4. Low‐to‐high frequency ratio for HRV for 36 participants who completed studies with the brand name drug and at least one of the generic metoprolol ER formulations. Comparison shown of low‐to‐high frequency HRV ratios (index of sympathetic to parasympathetic balance), divided into quartiles beginning with the time the dose was administered: quartile 1 (9 a.m. to 3 p.m.), quartile 2 (3 p.m. to 9 p.m.), quartile 3 (9 p.m. to 3 a.m.), and quartile 4 (3 a.m. to –9 a.m.). Triangles, squares, and circles represent the mean values for the brand name drug, generic drug 1, and generic drug 2, respectively. Error bars represent standard error of the mean. The p values for the drug × quartile interaction terms for HRV were tested to evaluate the difference in HRV across the quartiles between formulations. ER, extended‐release; HRV, heart rate variability.

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  FIGURE 5. The 24‐h ambulatory systolic blood pressure (SBP, left panel), diastolic blood pressure (DBP, middle panel), and heart rate (HR, right panel) profiles for the 36 participants who completed studies with any dose of the brand name drug and at least one of the generic formulations. Triangles, squares, and circles represent the mean values for the brand name drug, generic drug 1, and generic drug 2, respectively. Error bars represent standard error of the mean. Timepoint zero represents time of metoprolol ER administration. The p values were obtained by a mixed effect model for repeated measures. bpm, beats per minute.

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  FIGURE 6. Total metoprolol ER plasma concentration profiles and low‐to‐high frequency ratio of HRV for 30 participants who completed studies with the 50 mg dose of the brand name drug and at least one of the generic formulations. Circles represent the mean profiles of drug concentration and triangles represent the low‐to‐high frequency ratio of HRV. The error bars represent the standard error of the mean. ER, extended‐release; HRV, heart rate variability.