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Exploration of suitable pharmacodynamic parameters for acarbose bioequivalence evaluation: A series of clinical trials with branded acarbose.

ABSTRACT: AIMS:To determine deficiencies in the Food and Drug Administration (FDA)'s guidance for assessing acarbose bioequivalence (BE) and to explore optimal pharmacodynamic (PD) metrics for better evaluation of acarbose BE. METHODS:Three clinical trials with branded acarbose were conducted in healthy subjects, including a pilot study (Study I, n = 11, 50 and 100 mg), a 2×2 crossover BE study (Study II, n = 36, 100 mg) and a 4×4 Williams study (Study III, n = 16, 50/100/150 mg). Serum glucose concentrations were measured by the glucose oxidase method. RESULTS:In Study I, compared with 50 mg acarbose, only 100 mg acarbose had a significantly lower Cmax0-4h than that of sucrose administration alone (7.96 ± 0.83 mmol/L vs 6.78 ± 1.02 mmol/L, P < .05). In Study II, the geometric mean ratios of the test formulation to the reference formulation (both formulations were the branded drug) for FDA PD metrics, ?Cmax0-4h and ?AUC0-4h , were 0.903 and 0.776, respectively, and the 90% confidence intervals were 67.44-120.90 and 53.65-112.13, respectively. The geometric mean ratios (confidence interval) for possible optimal evaluation PD metrics (Cmax0-2h and AUC0-2h ) were 1.035 (94.23-112.68) and 0.982 (89.28-107.17), respectively. Further, Cmax0-2h and AUC0-2h also met the sensitivity requirements for BE evaluation in Study III. CONCLUSION:Considering the mechanisms of action of acarbose, the PD effect was shown to be dose independent during the 2-4 hours postadministration of acarbose. Hence PD metrics based on the serum glucose concentration from 0 to 2 hours (Cmax0-2h and AUC0-2h ) are more sensitive than the FDA-recommended PD metrics for acarbose BE evaluation from 0-4 hours (?Cmax0-4h and ?AUC0-4h ). The trial has been registered at the Chinese Clinical Trial Registry (http://www.chictr.org.cn, ChiCTR1800015795, ChiCTR-IIR-17013918, ChiCTR-IIR-17011903). All subjects provided written informed consent before screening.

SUBMITTER: Huang J

PROVIDER: S-EPMC7576622 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Exploration of suitable pharmacodynamic parameters for acarbose bioequivalence evaluation: A series of clinical trials with branded acarbose.

Huang Jie J Liu Wen-Yu WY Yu Jing-Jing JJ Yang Jin-Bo JB Li Min M Zou Chan C Guo Cheng-Xian CX Yang Xiao-Yan XY Yang Shuang S Xie Jin-Lian JL Huang Zhi-Jun ZJ Chen Hui H Pei Qi Q Yang Guo-Ping GP

British journal of clinical pharmacology 20200526 11

<h4>Aims</h4>To determine deficiencies in the Food and Drug Administration (FDA)'s guidance for assessing acarbose bioequivalence (BE) and to explore optimal pharmacodynamic (PD) metrics for better evaluation of acarbose BE.<h4>Methods</h4>Three clinical trials with branded acarbose were conducted in healthy subjects, including a pilot study (Study I, n = 11, 50 and 100 mg), a 2×2 crossover BE study (Study II, n = 36, 100 mg) and a 4×4 Williams study (Study III, n = 16, 50/100/150 mg). Serum glu ...[more]

PMID: 32333407

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Project description:ImportanceSwitching between generic antiepileptic drugs is a highly debated issue that affects both clinical care and overall health care costs.ObjectiveTo evaluate the single-dose pharmacokinetic bioequivalence of 3 (1 branded and 2 generic drugs) on-market, immediate-release lamotrigine drug products.Design, setting, and participantsThe Equivalence Among Antiepileptic Drug Generic and Brand Products in People With Epilepsy (EQUIGEN) single-dose study is a crossover, prospective, sequence-randomized, replicate pharmacokinetic study conducted at 5 US academic epilepsy centers. Fifty adults (≥18 years) with epilepsy who were taking concomitant antiepileptic drugs and not currently receiving lamotrigine were enrolled between July 18, 2013, and January 19, 2015. Every participant was randomly assigned to 1 of 3 equivalent sequences, each comprising 6 study periods, during which they had blood draws before and after medication administration. Forty-nine participants were included in intention-to-treat analyses.InterventionsParticipants received a single 25-mg dose of immediate-release lamotrigine at the start of each period, with the branded and the 2 most disparate generic products each studied twice. Lamotrigine was selected as the antiepileptic drug of interest because of its wide use, publications indicating problems with generic switches, and complaints to the US Food and Drug Administration regarding generic products. Both participants and study personnel were blinded to the specific generic products selected.Main outcomes and measuresThe primary outcome was bioequivalence between products. Maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) were compared, and average bioequivalence (ABE) was established if the 90% CIs of the ratios of the 2 products were within equivalence limits (80%-125%).ResultsOf the 50 randomized participants, 49 (98%) received all 3 lamotrigine products and completed at least 3 pharmacokinetic assessments and 46 (92%) completed all 6 pharmacokinetic assessments. Among the 49 participants, 28 (57%) were men and 21 (43%) were women, 42 (86%) self-identified as white, and 46 (16) years was the mean (SD) age. The 3 drug products were considered bioequivalent because the 90% CIs were within equivalence limits (lowest and highest CI limits for Cmax, 92.6% and 110.4%; for AUC0-96, 96.9% and 101.9%). Replicate testing demonstrated no significant differences in within-subject variability across the 3 products (likelihood ratios, χ22 for log-transformed variables: AUC0-96, 2.58; Cmax, 0.64; and AUC0-∞, 4.05; P ≥ .13) and that the 3 products were also bioequivalent according to scaled ABE and individual bioequivalence criteria with no subject × formulation interaction (Cmax, 0.00; AUC0-96, 0.54; and AUC0-∞, 0.36; P ≥ .76).Conclusions and relevanceThis study provides evidence that the disparate lamotrigine products studied are bioequivalent when tested in people with epilepsy taking concomitant antiepileptic drugs.Trial registrationclinicaltrials.gov Identifier: NCT01733394.

Project description:BackgroundCiclosporin is used as an immunosuppressant in current clinical practice but recent research implies novel indications for the drug, such as neuro- and cardioprotection. The intravenous formulation currently on the market, Sandimmune(®) Injection (Sandimmune(®)), uses Cremophor(®) EL as emulsifying excipient. Cremophor(®) EL is known to cause hypersensitivity reactions in some patients, ranging from skin reactions to potentially fatal anaphylactic shock.ObjectivesThe primary objective was to assess if CicloMulsion(®), a Cremophor(®) EL-free lipid emulsion of ciclosporin for intravenous administration, is bioequivalent to Sandimmune(®), and the secondary objective was to compare the tolerability profiles of the two preparations.MethodsThis was a single-centre, open-label, subject-blind, laboratory-blind, single-dose, randomized, two-treatment, two-period, two-sequence crossover study of the pharmacokinetics of two formulations of intravenous ciclosporin. Fifty-two healthy volunteer subjects were administered 5 mg/kg of each of the two formulations of ciclosporin as a 4-h intravenous infusion. The last blood sample was acquired 48 h after the end of the infusion. Bioequivalence assessments according to current guidelines were performed.ResultsThe geometric mean ratios for CicloMulsion(®)/Sandimmune(®) (90 % confidence interval [CI]) were 0.90 (0.88, 0.92) for AUC(0-last) (area under the blood concentration-time curve from time zero to time of last measurable concentration) and 0.95 (0.92, 0.97) for C(max) (maximum blood concentration). For all additional variables analysed, the 90 % CIs were also within the accepted bioequivalence range of 0.80-1.25. One anaphylactoid and one anaphylactic reaction, both classified as serious adverse events, were reported after treatment with Sandimmune(®). No serious adverse events were recorded after treatment with CicloMulsion(®).ConclusionWe have assessed the pharmacokinetics and tolerability of a new Cremophor(®) EL-free lipid emulsion of ciclosporin, CicloMulsion(®), compared to Sandimmune(®). The proportion of adverse events was significantly higher for the Cremophor(®) EL-based product Sandimmune(®). We conclude that CicloMulsion(®) is bioequivalent to Sandimmune(®) and exhibits fewer adverse reactions.

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Exploration of suitable pharmacodynamic parameters for acarbose bioequivalence evaluation: A series of clinical trials with branded acarbose.

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Exploration of suitable pharmacodynamic parameters for acarbose bioequivalence evaluation: A series of clinical trials with branded acarbose.

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