A quantitative approach for cardiovascular safety evaluation of a generic drug

Mijeong Son; Yukyung Kim; Dong Woo Chae; Kyungsoo Park

doi:10.12793/tcp.2015.23.2.54

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Son, Kim, Chae, and Park: A quantitative approach for cardiovascular safety evaluation of a generic drug

Original Article

Translational and Clinical Pharmacology 2015;23(2):54-58.

Published online: 15 December 2015

DOI: https://doi.org/10.12793/tcp.2015.23.2.54

A quantitative approach for cardiovascular safety evaluation of a generic drug

Mijeong Son^1,², Yukyung Kim^1,², Dong Woo Chae^1,², Kyungsoo Park^1,^∗

¹Department of Pharmacology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea

²Brain Korea 21 Plus Project for Medical Science, Yonsei University, Seoul 03722, Republic of Korea

^∗Correspondence: K. S. Park; Tel: +82-2-2228-1735, Fax: +82-2-313-1894, E-mail: kspark@yuhs.ac

Received 14 May 20151 October 2015 Accepted 4 October 2015

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

In generic drug development, comparative pharmacokinetic (PK) studies are conducted to assess equivalence in pharmacokinetics and safety profiles between test and reference formulations. However, there is no established quantitative approach available for safety assessment. This study aimed to propose a method for drug safety evaluation in generic drug development, as assessed by drug influence on blood pressure and heart rate change. Data were taken from a randomized, open label, 2-way cross-over comparative PK study for megestrol conducted in 39 healthy male volunteers. Vital signs of systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) were measured at 0 (pre-dose), 4, 8, 12, 24, 48, 72, 96 and 120 hours after the dose. Safety parameters used in the analysis were area under vital sign change versus time curve to the last measured time (AUVlast) and maximum vital sign change (Vmax). Considering highly variable nature of vital signs, the scaled bioequivalence approach developed by US FDA was adopted as a decision rule for safety evaluation between formulations. With the FDA scaled approach, 90% confidence intervals of geometric mean ratio for DBP, 0.7969∼1.0377 for Vmax and 0.7304∼1.0660 for AUVlast, were both included in the equivalence ranges of 0.7694∼1.2997 and 0.6815∼1.4674, respectively, and similarly, those for HR were included in their respective scaled equivalence limits, while SBP satisfied the conventional equivalence criterion of 0.8–1.25. These results illustrate the feasibility of applying the suggested approach in cardiovascular safety evaluation in a generic drug.

Keywords: vital signs, safety evaluation, quantitative approach, scaled bioequivalence

References

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Figure 1.

Mean (SD) vital sign change versus time profiles of (A) systolic blood pressure, (B) diastolic blood pressure and (C) heart rate for reference (R) and test formulation (T).

Table 1.

Demographic characteristics of the subjects

Characteristics	Group 1 (n = 20)	Group 2 (n = 20)
Age, yr
Mean (SD)	25.1 (1.9)	27.1 (3.9)
Range	23–31	23–40
Weight, kg
Mean (SD)	71.6 (7.9)	67.3 (8.5)
Range	60.9–90.7	55.7–83.7
Height, cm
Mean (SD)	176.4 (5.8)	175.0 (4.4)
Range	164.8–186.4	165.8–181.5
Smoking, no. (%)
Smoker	6 (30)	9 (45)
Nonsmoker	14 (70)	11 (55)
Alcohol drinking, no. (%)
Drinker	14 (70)	13 (65)
Nondrinker	6 (30)	7 (35)

Table 2.

Scaled bioequivalence limits for highly variable drugs imposed by the FDA approach

Within-subject CV (%)	Lower limit∗	Upper limit∗
30	0.7694	1.2997
35	0.7382	1.3547
40	0.7089	1.4106
45	0.6815	1.4674
50	0.6558	1.5248

^∗ These limits were obtained from the relationship that upper/lower limits = exp (±In (1.25) · ) where S_WR is standard deviation corresponding to within-subject variability of the reference product and S_W0 is set at 0.25. See text for details.

Table 3.

Comparison of safety parameters (AUV_last and V_max) in reference and test formulations

Parameter∗	Geometric Mean		Geometric Mean Ratio Test/Reference		P-value⁺	Residual variance	CV_wR (%)	Scaled bioequivalence limit
Parameter∗	Test (n= 39)	Reference (n= 39)	Ratio	90% CI	P-value⁺	Residual variance	CV_wR (%)	Scaled bioequivalence limit
SBP
^V_max	19.65	19.78	0.9930	0.8804∼1.1200	0.9218	0.0992	31.49	0.7694∼1.2997
AUV_last	1201.1	1204.8	0.9978	0.8551∼1.1643	0.9809	0.1631	40.39	0.7089∼1.4106
DBP
V_max	15.32	16.85	0.9094	0.7969∼1.0377	0.2323	0.1193	34.53	0.7694∼1.2997
^AUV_last	784.8	889.4	0.8824	0.7304∼1.0660	0.2714	0.2446	49.46	0.6815∼1.4674
HR
^V_max	18.77	17.34	1.0923	0.9274∼1.2632	0.2833	0.1634	40.43	0.7089∼1.4106
AUV_last	1098.6	968.4	1.1335	0.9335∼1.3763	0.3932	0.2580	50.79	0.6558∼1.5248

^∗ Parameter units are ΔmmHg for V_max and ΔmmHg∗h for AUV_last for SBP and DBP, and ΔBeats/min for V_max and ΔBeats/min∗h for AUV_last for HR.

⁺ P-values were obtained using WinNonlin bioequivalence test with significance level of 0.05. AUV_last: area under vital sign change versus time curve to the last measured time. V_max: maximum vital sign change. CV_wR (%): coefficient of variation for within subject variability of the reference product, which was approximated as (%), in this work.

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