Toward Optimum Benefit‐Risk and Reduced Access Lag For Cancer Drugs in Asia: A Global Development Framework Guided by Clinical Pharmacology Principles

Venkatakrishnan, Karthik; Burgess, Carl; Gupta, Neeraj; Suri, Ajit; Takubo, T; Zhou, Xiaofei; DeMuria, D; Lehnert, Manfred; Takamatsu, Kiyoshi; Singhvi, Sanjay; Milton, Ashley

doi:10.1111/cts.12386

Cited by 23 publications

(37 citation statements)

References 66 publications

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“…This makes characterization of the effects of race/region on PK/PD and safety crucial ahead of clinical trial globalization . This is especially important for anticancer agents associated with a narrow therapeutic range as modest differences in systemic exposures between Asian and Western patient populations can translate to meaningful differences in the safety profile in the setting of a steep exposure–toxicity relationship . The sources of potential differences in drug exposure between Asian and Western patient populations can be multi‐factorial, including intrinsic (e.g.…”

Section: Discussionmentioning

confidence: 99%

Global population pharmacokinetics of the investigational Aurora A kinase inhibitor alisertib in cancer patients: rationale for lower dosage in Asia

Zhou

Mould

Takubo

et al. 2017

Brit J Clinical Pharma

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AimsThis population pharmacokinetic analysis was conducted to describe quantitatively the regional differences and sources of interpatient variability on the apparent oral clearance of alisertib.MethodsA population pharmacokinetic analysis was performed on data from 671 cancer patients in Western countries and in Japan/East Asia to whom alisertib 5–150 mg once or twice daily (b.i.d.) was administered in multiple dosing schedules. The final model was used to simulate alisertib pharmacokinetics in patients in the West and East Asian regions in the single‐agent schedule of 7 days of dosing in a 21‐day cycle. Exposure–safety relationships for mechanism‐related antiproliferative toxicities (neutropenia, mucositis and diarrhoea) were estimated by logistic regression.ResultsAlisertib pharmacokinetics were described by a two‐compartment model with four‐transit compartment absorption and linear elimination. The final model included a covariate effect of region on relative bioavailability, with patients in the East Asian region estimated to have a 52% higher bioavailability compared with Western patients. Population simulated exposure at 30 mg b.i.d. in patients in Asia was similar to that at 50 mg b.i.d. in Western patients [geometric mean (coefficient of variation) steady state area under the concentration‐time curve over the dosing interval (AUC(0–τ)): 21.4 μM.h (52.3%) and 24.1 μM.h (53.6%), respectively]. Exposure–AE relationships could be described for neutropenia, stomatitis and diarrhoea, supporting the lower dosage of alisertib in Asia for global clinical development.ConclusionsModel‐based simulations support the achievement of similar alisertib exposures in patients in Asia who are administered a 40% lower dose compared with the Western population, thereby providing a quantitative clinical pharmacology bridging and regional dosing rationale for global drug development.

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Section: Discussionmentioning

confidence: 99%

Global population pharmacokinetics of the investigational Aurora A kinase inhibitor alisertib in cancer patients: rationale for lower dosage in Asia

Zhou

Mould

Takubo

et al. 2017

Brit J Clinical Pharma

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“…This strategy is also being implemented with pembrolizumab in a phase III trial in recurrent esophageal cancer (KEYNOTE‐181) . In this approach (in which Chinese patients join global trials), the ethnic sensitivity of the drug must be considered, not only with regard to PK, but also with regard to the safety of the recommended phase I/II or phase III dose for Chinese/Asian patients, with an appropriate dose identified for Chinese/Asian patients if necessary …”

Section: Regulatory Environment In Chinamentioning

confidence: 99%

Challenges and Opportunities With Oncology Drug Development in China

Bajaj

Gupta

Wang³

et al. 2018

Clin Pharma and Therapeutics

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“…On top of this, companies may have an incentive to set the same recommended dose in all regions. Setting a different dose traditionally necessitates a separate phase III study with Japanese patients, although innovative approaches including exposure‐matched regional dosing have been proposed to provide scientifically solid rationale for choosing a bridging strategy study or a global phase III study with a different dose . This would sometimes incur additional dosage forms and marketing materials only for the Japanese market.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Global Drug Development Pathways and Postmarketing Safety in Japan: Local Studies May Reduce Drug‐Related Deaths

Okubo

Ono

2019

Clinical Translational Sci

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Recent International Conference on Harmonization (ICH) guidelines provide pharmaceutical companies with regulatory justifications to pursue various global drug‐development pathways, in some of which “local” dose‐ranging and/or pivotal phase III studies are skipped. We examined the association between the clinical development pathway and postmarketing safety in Japan for 177 new molecular entities approved between 2004 and 2013 focusing on dose setting histories for each drug. The risk of drug‐related deaths was higher when companies did not conduct local (i.e., Japanese) dose‐ranging studies and/or pivotal studies. Even when local dose‐ranging studies were conducted, the risk remained higher in some drugs for which the approved dose in Japan was set equal to that in the United States. Drugs developed under a bridging strategy tended to show lower risks. These results suggested that local clinical studies may play a substantial role in achieving optimization of postmarketing drug use in each local target population.

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Toward Optimum Benefit‐Risk and Reduced Access Lag For Cancer Drugs in Asia: A Global Development Framework Guided by Clinical Pharmacology Principles

Cited by 23 publications

References 66 publications

Global population pharmacokinetics of the investigational Aurora A kinase inhibitor alisertib in cancer patients: rationale for lower dosage in Asia

Global population pharmacokinetics of the investigational Aurora A kinase inhibitor alisertib in cancer patients: rationale for lower dosage in Asia

Challenges and Opportunities With Oncology Drug Development in China

Analysis of Global Drug Development Pathways and Postmarketing Safety in Japan: Local Studies May Reduce Drug‐Related Deaths

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