Generic-reference and generic-generic bioequivalence of forty-two, randomly-selected, on-market generic products of fourteen immediate-release oral drugs

Hammami, Muhammad M.; Padua, Sophia J. S. De; Hussein, Rajaa Farhan; Gaai, Eman Al; Khodr, Nesrine A.; Al-Swayeh, Reem; Alvi, Syed N.; Binhashim, Nada

doi:10.1186/s40360-017-0182-1

Cited by 23 publications

(30 citation statements)

References 45 publications

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“…The PK and PD similarities between the licensed Xgeva ® products and those of the biosimilar substantiate the use of the biosimilars in phase III clinical studies ( Davit et al, 2008 ; Karalis et al, 2012 ). The inter-CV value of denosumab among Chinese subjects is high, and it is recommended that in future studies, the sample size of 152 to 180 subjects is sufficient to study the bioequivalence of denosumab biosimilar in each group, considering inter-CV (28.8–39.5%) ( Liu et al, 2012 ; Al-Sabbagh et al, 2016 ; Hammami et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

A Phase I, Randomized, Single-Dose Study to Evaluate the Biosimilarity of QL1206 to Denosumab Among Chinese Healthy Subjects

Zhang

Zhu

et al. 2020

Front. Pharmacol.

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Objective This study was conducted to explore the tolerance, variability, pharmacokinetics (PK), and pharmacodynamics (PD) of denosumab biosimilar (QL1206) in healthy Chinese subjects. Methods This is a randomized, double-blind, two-arm, parallel study performed to examine the bioequivalence of denosumab biosimilar, QL1206, with that of Xgeva ® (Denosumab) as a reference drug. A single dose of 120 mg/kg of the denosumab biosimilar or Xgeva ® was administered to the subjects, who were followed up for 134 days. Results Similar PK properties as those of Xgeva ® were exhibited by QL1206. When compared to QL1206 with Xgeva ® , the 90% confidence intervals of the ratios for C max , AUC 0-t , and AUC 0-∞ were observed to be within 80–125%. The inter-subject variability (inter-CV) ranged from 29% to 39.5%. Six and three subjects in the QL1206 and Xgeva ® groups were found to be positive for the ADA and negative for the NAb, respectively. The CTX1 concentration-time profiles appeared similar (about 80% decrease from 48 hours to134 days) between the QL1206 and Xgeva ® groups. Adverse events (AEs) were observed in 92.6% and 93.4% of subjects in the QL1206 and Xgeva ® groups, respectively. Reduction in blood calcium level was found to be the most common AE recorded, with an incidence of 72.8% versus 72.4% in the QL1206 and Xgeva ® groups, respectively. Conclusion Similar PK and PD characteristics were exhibited by QL1206 as compared to those of Xgeva ® . The inter-CV was slightly large. The safety profiles of denosumab biosimilars and Xgeva ® were found to be similar.

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Section: Discussionmentioning

confidence: 99%

A Phase I, Randomized, Single-Dose Study to Evaluate the Biosimilarity of QL1206 to Denosumab Among Chinese Healthy Subjects

Zhang

Zhu

et al. 2020

Front. Pharmacol.

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“…Using simulations, it was shown, in a cross-over trial conducted in 24 subjects, that as many as 60% of the individuals can, on average, be outside the range of BE (0.7-1.3 for this simulation) and yet still satisfy the regulatory criteria for ABE [9]. That this is not merely a speculative academic exercise has been demonstrated recently by the results of 14 four-sequence cross-over studies for a range of drugs [11]. In this large set of trials, involving 700 subjects, it was reported that the percentage of individual area under the curve (AUC) values outside the 0.8-1.25 a priori BE range was 16% on average and ranged from 2% for cephalexin to 35% for atenolol and clarithromycin.…”

mentioning

confidence: 59%

“…In this large set of trials, involving 700 subjects, it was reported that the percentage of individual area under the curve (AUC) values outside the 0.8-1.25 a priori BE range was 16% on average and ranged from 2% for cephalexin to 35% for atenolol and clarithromycin. For maximum plasma concentration, the average was 32%, with values ranging from 8% for metronidazole up to 57% for diclofenac [11]. This structurally and experimentally proven weakness of the ABE design becomes, in our opinion, a medical issue for drugs such as levothyroxine, classified as narrow therapeutic index drugs.…”

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confidence: 95%

Authors’ Reply to Krebs-Brown et al. Comment on: “Why Were More Than 200 Subjects Required to Demonstrate the Bioequivalence of a New Formulation of Levothyroxine with an Old One?”

et al. 2019

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As a preliminary response to , we remind readers that Clinical Pharmacokinetics does not publish 'opinions'. Rather, in a section of the journal entitled "Current Opinion", it publishes regular articles and these are subjected, like all articles accepted by the journal, to a peer-review evaluation. We also remind readers that the bioequivalence (BE) trial that we have commented on has itself been published in a journal entitled Current Medical Research and Opinion (Gottwald-Hostalek, Uhl, Wolna, & Kahaly, 2017). As a first comment, we ask readers to note that we have not downgraded this BE trial to the status of a Merck-Serono opinion, despite the title of this journal.However, the Letter to the Editor from Krebs-Brown et al. does offer an opinion, under the guise of seeking "further clarification". The five co-authors of the Krebs-Brown et al. "comment" are employees of the company that developed and successively marketed the old and new formulations of levothyroxine, on which we have commented in our two previous articles in Clinical Pharmacokinetics. We take it that the opinions expressed by Krebs-Brown et al. are those also of their employer, or at least sanctioned by the company. We are pleased now to answer the Merck Serono employees' opinions. In seeking to denigrate our balanced conclusions with their opinions, they fail to answer both the arguments we have put forward and conclusions reached. Inappropriate and confrontational as they may be, we choose to pass over the comments of Krebs-Brown et al. "Without wanting to appear petty, we should point out that the paper contains several inaccuracies and misrepresentations … we would like to distance ourselves from …. This implies that sponsors and planners of ABE trials inherently display a callous attitude to participants in such a trial, an accusation we must strongly protest". We choose rather to focus on the underlying science on which our conclusions are based.We re-affirm our previous comments on the question of switchability. This was the key issue to stimulate debate, when replacement of the old formulation (OF) by a new formulation (NF) of Levothyrox ® was imposed on millions of patients. Now, we are pleased to note that Merck Serono acknowledges that "it is unclear how to interpret the percentage of observed individual exposure ratio (IER) outside of this range" (i.e. the a priori BE range). Krebs-Brown et al. do not deny, in their response, that there was in their trial a large number of subjects outside the a priori BE range. Of significance is their acknowledgement that they are unable to interpret their own average BE (ABE) results on the question of switchability. Whilst there is indeed no regulatory recommendation on this point, this is not sufficient reason to simply ignore it.This question of the number of individual exposure ratios outside the a priori BE range, as a possible weakness of an ABE study, has been addressed both very early and subsequently in the long history of BE. Using simulations, it was shown, in a cross-over trial condu...

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“…Moreover, we are not mistaken, as Nicolas alleges, when considering that this point has been properly documented by others, demonstrating that, in as many as 60% of individuals in a crossover trial conducted in 24 subjects, the difference between parameters for the two formulations could, on average, be outside the range of BE (0.7-1.3 for this simulation) and yet still satisfy the regulatory criterion of ABE [10]. That this is not merely an academic exercise was shown recently by the results of 14 four-sequence cross-over studies in volunteers receiving a range of drugs [11]. In this large set of trials, involving 700 subjects, it was reported that the percentage of individual AUCs outside the 0.8-1.25 a priori BE range was 16% on average and ranged from 2% for cephalexin to 35% for atenolol and clarithromycin.…”

mentioning

confidence: 74%

“…In this large set of trials, involving 700 subjects, it was reported that the percentage of individual AUCs outside the 0.8-1.25 a priori BE range was 16% on average and ranged from 2% for cephalexin to 35% for atenolol and clarithromycin. For maximal plasma concentration, the average was 32%, with values ranging from 8% for metronidazole up to 57% for diclofenac [11].…”

mentioning

confidence: 98%

Authors’ Reply to Nicolas: “Why Were More than 200 Subjects Required to Demonstrate the Bioequivalence of a New Formulation of Levothyroxine with an Old One?”

et al. 2019

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Generic-reference and generic-generic bioequivalence of forty-two, randomly-selected, on-market generic products of fourteen immediate-release oral drugs

Cited by 23 publications

References 45 publications

A Phase I, Randomized, Single-Dose Study to Evaluate the Biosimilarity of QL1206 to Denosumab Among Chinese Healthy Subjects

A Phase I, Randomized, Single-Dose Study to Evaluate the Biosimilarity of QL1206 to Denosumab Among Chinese Healthy Subjects

Authors’ Reply to Krebs-Brown et al. Comment on: “Why Were More Than 200 Subjects Required to Demonstrate the Bioequivalence of a New Formulation of Levothyroxine with an Old One?”

Authors’ Reply to Nicolas: “Why Were More than 200 Subjects Required to Demonstrate the Bioequivalence of a New Formulation of Levothyroxine with an Old One?”

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