| Research Article |
Open Access |
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| Effect of Replicate Design on Drug
Variability and Bioequivalence in Humans |
| Naji M. Najib1, Isam Salem1, Nasir M. Idkaidek2* |
| 1International Pharmaceutical Research Center (IPRC), Amman, JORDAN |
| 2College of Pharmacy, Petra University, Amman, JORDAN |
| *Corresponding author: |
Dr. Nasir M. Idkaidek
College of Pharmacy,
Petra
University, Amman, JORDAN,
E-mail : medney@synchrophar.com |
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| Received November 08, 2009; Accepted December 13, 2009; Published December 13, 2009 |
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| Citation: Najib NM, Salem I, Idkaidek NM (2009) Effect of Replicate
Design on Drug Variability and Bioequivalence in Humans. J Bioanal
Biomed 1: 014-016. doi:10.4172/1948-593X.1000003 |
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| Copyright: © 2009 Najib NM, et al. This is an open-access article distributed under the terms of the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author
and source are credited. |
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| Abstract |
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| The purpose of this study is to investigate the effect of
using replicate design on the intra/inter subject variability
and bioequivalence of drugs in healthy volunteers. Model
drugs used for analysis were amoxicillin/clavulanic acid
combination. 24 healthy subjects participated in this study
using 4-phase replicate cross over design. Individual disposition
kinetic parameters of areas under plasma concentrations
(AUC0-t) and maximum concentration (Cmax)
were calculated by non-compartmental analysis using
Kinetica program V 4.2 using all phases. The 90 % confidence
intervals for log-transformed AUC0-t and Cmax were
calculated for phases I & II; then for phases I, II and III;
and for phases I, II, III and IV respectively. The intra and
inter-subject variability values did not show a trend to
decrease by the increase in phases included in analysis in
both drugs and for both parameters. In addition, the 90 %
confidence intervals for log-transformed AUC0-t and Cmax passed the 80-125 % limit range in both drugs for all phase
combinations, even though Cmax variability was shown high
for clavulanic acid. However, individual bioequivalence
was shown for AUC and not shown for Cmax of both drugs.
These results suggest not using replicate design as an approach
to show the high inter/intra subject variability of
highly variable drugs and hence justify wider acceptance
limits of 75-133 % as recommended by the draft EMEA
guideline. Literature information about drug high variability
should be adequate to justify using wider acceptance
limits of 75-133%. |
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| Keywords |
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| Replicate design; Acceptance limits;
Bioequivalence; EMEA |
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| Introduction |
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| Studies to measure bioavailability and/or establ ish
bioequivalence of a product are important elements in support
of the different drug applications and their supplements (Draft
Guideline on the Investigation of Bioequivalence, 2008). Of
special interest are bioequivalence studies of highly variable
drugs. Hence, it was recommended by the new draft EMEA guideline
that 90% confidence intervals for log-transformed areas
under curve for the maximum plasma concentration (Cmax), to
also fall between 80-125%. Wider acceptance limits of 75-133
can be justified by using replicate design to prove that drug is
highly variable (Draft Guideline on the Investigation of
Bioequivalence, 2008). |
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| Statistical analysis for pharmacokinetic measures, such as area under the curve, using the standard average bioequivalence involves
the calculation of a 90% confidence interval for the ratio
of the averages (population geometric means) of the measures
for the test and reference products. However, the average
bioequivalence method does not assess a subject-by-formulation
interaction variance, that is, the variation in the average test
and reference difference among individuals. In contrast, the individual
bioequivalence (IBE) approach assesses within-subject
variability for the test and reference products, as well as the subject-
by-formulation interaction (Guidance for Industry, 2001). |
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| The purpose of this study is to investigate the effect of using
replicate design on the bioequivalence of high (variability > 30%)
and low (variability < 30%) variable drugs. Model drugs used
amoxicillin/clavulanic acid combination. |
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| Materials and Methods |
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| Drugs |
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| Drug formulations were amoxicillin/clavulanic acid combination. |
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| Subjects and study design |
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| 24 healthy adult male volunteers participated in the two formulations,
two sequence (TRTR, RTRT), four period cross-over
single oral dose study. Sample size for each study was calculated
based on reported intra-subject variability of pharmacokinetics
primary parameters, considering α = 0.05, the
bioequivalence range (0.8-1.25) and to obtain a statistical power
greater than 80%. All subjects had mean age, mean body weight
and mean height. The volunteers were instructed to abstain from
taking any drug including over-the counter (OTC) for 2 weeks
prior to and during the study period. Studies were performed
according to the revised Declaration of Helsinki for bio-medical
research involving human subjects and the rules of Good Clinical
Practices. Also, study protocols were approved by Institutional
Review Board (IRB) of IPRC (Idkaidek, 2004). |
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| Experimental and assay procedure |
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| In each study, following a ten-hour overnight fast, single oral
dose of each drug was administered followed by 240-ml water in each study. Blood samples were collected up to 10 hour after
dosing. Samples were stored at –20 0C until parent drugs are
analyzed by validated and sensitive hplc method (Idkaidek,
2004). |
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| Data analysis |
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| Areas under plasma concentrations (AUC0-t), maximum concentration
(Cmax), time to reach maximum were calculated by
non-compartmental analysis for all subjects. Confidence intervals,
point estimates and parameter variability analysis for logtransformed
AUC0-t and Cmax were also calculated for phases I &
II; then for phases I, II and III; and for phases I, II, III and IV
using Excel and Kinetica® software (Kinetica V 4.2, 2007). |
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| Results and Discussion |
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| Average bioequivalence analysis and IBE results were summarized
in Table 1. As shown in table 1, the 90 % confidence
intervals for log-transformed AUC0-t and Cmax were calculated
for phases I & II; then for phases I, II and III; and then phases I,
II, III and IV respectively. The intra and inter-subject variability
values did not show a trend to decrease by the increase in phases
included in analysis in both drugs and for both parameters. In
addition, the 90 % confidence intervals for log-transformed
AUC0-t and Cmax passed the 80-125 % limit range in both drugs
for all phase combinations, even though Cmax variability was
shown high for clavulanic acid. Thus use of replicate design did
not add advantages in terms of decreasing inter/intra subject
variability and also for bioequivalence limits. |
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Table 1: Average Bioequivalence Analysis Results for Test / Reference Ratios after Log Transformation for AUC0-t and Cmax Parameters.
*IBE: Individual Bioequivalence analysis results, from reference 2. |
|
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| However, individual bioequivalence was shown for AUC and
not shown for Cmax of both high and low variable drugs (Idkaidek,
2004). This rendered the IBE approach and the replicate design
unsuitable for showing formulation differences. Instead, scaled
average bioequivalence of 2X2 cross over design would be more
appropriate (WHO Guideline, 2005; Midha, 2005). Actually, US
FDA guideline recommends using average cross over design, as
a default design for bioequivalence studies (Guidance for Industry,
2003). |
|
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| Conclusion |
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These results suggest not using replicate design as an approach
to show the high inter/intra subject variability of highly variable
drugs and hence justify wider acceptance limits of 75-133 % as
recommended by the draft EMEA guideline. Literature information
about drug high variability should be adequate to justify
using wider acceptance limits of 75-133%. |
| |
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| References |
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- Draft Guideline on the Investigation of Bioequivalence (2008) Doc. Ref.
CPMP/EWP/QWP/1401/98 Rev. 1. London.
- Guidance for Industry (2001) Statistical Approaches to Establishing
Bioequivalence. Population and Individual Bioequivalence Working Group
of the Biopharmaceutics Coordinating Committee in the Office of Pharmaceutical
Science, Center for Drug Evaluation and Research (CDER) at the
Food and Drug Administration (FDA).
- Guidance for Industry (2003) BA and BE Studies for orally administered
drug products – General Considerations. Center for Drug Evaluation and
Research (CDER), Food and Drug Administration (US FDA).
- Idkaidek N, Alghazawi A, Najib N (2004) Bioequivalence assessment of
Amoxicillin/Clavulanic acid 250/125 mg combination tabs in Healthy Human
Volunteers: Use of replicate design. Biopharmaceutics and Drug Disposition
25: 367-372.
- Kinetica V 4.2, (2007) Innaphase Corp., France.
- Midha K, Rawson M, Hubbard J (2005) The bioequivalence of highly variable drugs and drug products. Int J Clin Pharmacol Ther 43: 485-498. » CrossRef » PubMed » Google Scholar
- WHO Guideline (2005) Multisource (GENERIC) Pharmaceutical Products:
Guidelines on Registration Requirements to Establish Interchangeability.
Quality Assurance & Safety: Medicines (QSM), Department of Medicines
Policy and Standards (PSM), World Health Organization.
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