The Use of Truncated Area under the Curves in the Bioequivalence Evaluation of Long Half-Life Drugs

Erkent, Ulkem; Koytchev, Rossen

doi:10.1055/s-0031-1296502

Cited by 11 publications

(9 citation statements)

References 2 publications

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“…In addition, the pharmacodynamic half-life of drugs that change receptor activation levels is much longer than the tens of seconds the network activity is sustained. For instance the half-life of donepezil is well over 48 hr [38]. Therefore as a first approximation, the neuromodulatory effect is averaged over the full time range of the simulation.…”

Section: Methodsmentioning

confidence: 99%

Simulations of symptomatic treatments for Alzheimer's disease: computational analysis of pathology and mechanisms of drug action

2012

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IntroductionA substantial number of therapeutic drugs for Alzheimer's disease (AD) have failed in late-stage trials, highlighting the translational disconnect with pathology-based animal models.MethodsTo bridge the gap between preclinical animal models and clinical outcomes, we implemented a conductance-based computational model of cortical circuitry to simulate working memory as a measure for cognitive function. The model was initially calibrated using preclinical data on receptor pharmacology of catecholamine and cholinergic neurotransmitters. The pathology of AD was subsequently implemented as synaptic and neuronal loss and a decrease in cholinergic tone. The model was further calibrated with clinical Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) results on acetylcholinesterase inhibitors and 5-HT6 antagonists to improve the model's prediction of clinical outcomes.ResultsAs an independent validation, we reproduced clinical data for apolipoprotein E (APOE) genotypes showing that the ApoE4 genotype reduces the network performance much more in mild cognitive impairment conditions than at later stages of AD pathology. We then demonstrated the differential effect of memantine, an N-Methyl-D-aspartic acid (NMDA) subunit selective weak inhibitor, in early and late AD pathology, and show that inhibition of the NMDA receptor NR2C/NR2D subunits located on inhibitory interneurons compensates for the greater excitatory decline observed with pathology.ConclusionsThis quantitative systems pharmacology approach is shown to be complementary to traditional animal models, with the potential to assess potential off-target effects, the consequences of pharmacologically active human metabolites, the effect of comedications, and the impact of a small number of well described genotypes.

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Section: Methodsmentioning

confidence: 99%

Simulations of symptomatic treatments for Alzheimer's disease: computational analysis of pathology and mechanisms of drug action

2012

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“…Some authors have demonstrated bioequivalence with truncation at 24 and/or 48 hr using studies similar to those used here . Marzo et al .…”

Section: Discussionmentioning

confidence: 56%

Effect of Truncating AUC at 12, 24 and 48 hr When Evaluating the Bioequivalence of Drugs with a Long Half‐Life

Moreno

Ochoa

Román

et al. 2015

Basic Clin Pharma Tox

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Bioequivalence studies of drugs with a long half-life require long periods of time for pharmacokinetic sampling. The latest update of the European guideline allows the area under the curve (AUC) truncated at 72 hr to be used as an alternative to AUC 0-t as the primary parameter. The objective of this study was to evaluate the effect of truncating the AUC at 48, 24 and 12 hr on the acceptance of the bioequivalence criterion as compared with truncation at 72 hr in bioequivalence trials. The effect of truncated AUC on the within-individual coefficient of variation (CV w ) and on the ratio of the formulations was also analysed. Twenty-eight drugs were selected from bioequivalence trials. Pharmacokinetic data were analysed using WinNonLin 2.0 based on the trapezoidal method. Analysis of variance (ANOVA) was performed to obtain the ratios and 90% confidence intervals for AUC at different time-points. The degree of agreement of AUC 0-72 in relation to AUC 0-48 and AUC 0-24 , according to the Landis and Koch classification, was 'almost perfect'. Statistically significant differences were observed when the CV w of AUC truncated at 72, 48 and 24 hr was compared with the CV w of AUC 0-12 . There were no statistically significant differences in the AUC ratio at any time-point. Compared to AUC 0-72 , Pearson's correlation coefficient for mean AUC, AUC ratio and AUC CV w was worse for AUC 0-12 than AUC 0-24 or AUC 0-48 . These preliminary results could suggest that AUC truncation at 24 or 48 hr is adequate to determine whether two formulations are bioequivalent.The European guidelines for conducting bioequivalence studies of immediate-release formulations state that two formulations are bioequivalent if the 90% confidence interval (CI) of the ratio of the means for the pharmacokinetic parameters (area under the plasma concentration curve from administration to the last observed concentration at time t [AUC 0-t ] and maximum plasma concentration [C max ]) of the test and reference formulations is within the acceptance interval of 80.00-125.00% [1,2]. In the case of drugs with a long half-life, the latest update of these guidelines proposes truncating the AUC at 72 hr (AUC 0-72 ) as an alternative to calculating the AUC 0-t for comparison of the extent of exposure, as the absorption phase is completed during the first 72 hr [1]. Furthermore, the absorption phase of a drug in its plasma concentration versus time is more sensitive and decisive and enables better detection of the differences between formulations before the drug is completely eliminated [3]. Therefore, a sampling period longer than 72 hr is not necessary for immediate-release formulations, irrespective of half-life [1].Complete absorption of the drug formulation occurs mostly within the first 24 hr; therefore, truncation of the AUC at 24 or 48 hr as the primary parameter should be enough. Moreover, as absorption is the most relevant parameter in shorter AUCs, these intervals could be more sensitive for calculating differences between formulations.An AUC t...

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“…A crossover design was planned as per the USFDA requirements. For comparative bioavailability studies, this is considered as the preferred design in order to minimize subject-by-subject variations and to minimize variability between drug treatments [13]. …”

Section: Discussionmentioning

confidence: 99%

A Randomized, Crossover, Single-Dose Bioequivalence Study of Two Extended Release Tablets of Donepezil 23 mg in Healthy Human Volunteers under Fasting and Fed State

Gadiko

Tippabhotla²,

Thota³

et al. 2013

Sci. Pharm.

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To assess the bioequivalence of two extended-release tablets of donepezil 23 mg, open label, randomized, single-dose, two-sequence, two-period crossover studies under fasting (n=74) and fed (n=94) conditions in healthy adult human volunteers were conducted. Subjects were randomized to either of the two treatment arms (test or reference) separated by a washout period of 28 days. Blood samples were collected up to 72 h post-dose and plasma samples were analyzed for donepezil using a validated LC-MS/MS method. Pharmacokinetic parameters were derived using a non-compartmental approach. Bioequivalence was evaluated in 69 subjects in the fasting study, and 71 subjects in the fed study. In the fasting study, the 90% CI of Cmax and AUC0-72 were 82.50–90.10 and 92.38–98.60, respectively. Corresponding values in the fed study were 91.82–98.05 and 97.27–100.27. Based on the results, the test product (donepezil) met the US regulatory criteria of bioequivalence relative to the reference product (Aricept®) under both fasting and fed conditions.

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The Use of Truncated Area under the Curves in the Bioequivalence Evaluation of Long Half-Life Drugs

Cited by 11 publications

References 2 publications

Simulations of symptomatic treatments for Alzheimer's disease: computational analysis of pathology and mechanisms of drug action

Simulations of symptomatic treatments for Alzheimer's disease: computational analysis of pathology and mechanisms of drug action

Effect of Truncating AUC at 12, 24 and 48 hr When Evaluating the Bioequivalence of Drugs with a Long Half‐Life

A Randomized, Crossover, Single-Dose Bioequivalence Study of Two Extended Release Tablets of Donepezil 23 mg in Healthy Human Volunteers under Fasting and Fed State

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