Clinical pharmacology and therapeutics
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Clin. Pharmacol. Ther. · May 2019
Randomized Controlled TrialPharmacokinetics and Pharmacodynamics of the BACE1 Inhibitor Verubecestat (MK-8931) in Healthy Japanese Adults: A Randomized, Placebo-Controlled Study.
β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is required for the production of β-amyloid (Aβ) peptides and is considered a potential treatment target for Alzheimer's disease (AD). To support Japan's participation in the global clinical development program, we characterized the safety, pharmacokinetics (PKs), and pharmacodynamics of the BACE1 inhibitor verubecestat (MK-8931) in 24 healthy Japanese adults in a two-part, single-center, randomized, placebo-controlled phase I trial (protocol MK-8931-007) and compared the results with historical data from non-Japanese subjects. ⋯ Verubecestat also reduced mean cerebrospinal fluid concentrations of the Aβ proteins Aβ40, Aβ42, and soluble β fragment of amyloid precursor protein; the level of reduction was comparable between Japanese and non-Japanese subjects. These results support the continued global development of verubecestat as a potential disease-modifying agent for Japanese and non-Japanese subjects who are at risk for developing AD.
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Clin. Pharmacol. Ther. · Apr 2019
Identifiability of Biologicals in Adverse Drug Reaction Reports Received From European Clinical Practice.
Biologicals are established treatment options that require pharmacovigilance adapted to their specific nature, including the need for products to be identifiable up to the specific manufacturer in reports of adverse drug reactions (ADRs). This study explored the identifiability of 10 classes of similar and related biologicals up to the level of the manufacturer in ADR reports received from European clinical practice between 2011 and June 2016. ⋯ The overall batch traceability was, however, only ensured for 20.5% of the suspected biologicals and needs further improvement. This study shows that the European system for identification of ADRs to the level of the manufacturer is robust, allowing for the timely detection of potential product-specific safety signals for biologicals.
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Clin. Pharmacol. Ther. · Apr 2019
EditorialRegulation and Innovation: Role of Regulatory Science in Facilitating Pharmaceutical Innovation.
Regulatory science is defined as science and research intended to inform decision making in a regulatory framework. This issue of Clinical Pharmacology & Therapeutics and the papers herein deal with the expansive topic of regulatory science and its role in fostering innovation and accelerating access to medicines. Regulatory health authorities, industry, and multiple stakeholders have a shared objective in advancing regulatory science to keep up with the ever-increasing pace of biomedical science.
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Clin. Pharmacol. Ther. · Mar 2019
ReviewClinical Development and Initial Approval of Novel Immune Checkpoint Inhibitors in Oncology: Insights From a Global Regulatory Perspective.
Immune checkpoint inhibitors (ICI) have demonstrated meaningful patterns of clinical efficacy across various cancers. During their development, novel regulatory strategies and clinical design approaches were explored. This metrics-based narrative review examines submission strategies and clinical evidence expectations of the US, European, and Japanese drug agencies, as well as their impact on approval and overall development times. Also discussed is the role of emerging clinical science and biomarker evaluation to get the first six ICI initially approved.
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Clin. Pharmacol. Ther. · Feb 2019
Meta AnalysisPharmacogenomics of Vincristine-Induced Peripheral Neuropathy Implicates Pharmacokinetic and Inherited Neuropathy Genes.
Vincristine is an effective chemotherapeutic drug for various cancers, including acute lymphoblastic leukemia (ALL). Unfortunately, clinical utility is restricted by dose-limiting vincristine-induced peripheral neuropathies (VIPN). We sought to determine the association of VIPN with a recently identified risk variant, CEP72 rs924607, and drug absorption, distribution, metabolism, and excretion (ADME) gene variants in pediatric ALL. ⋯ ADME analyses identified associations between VIPN and ABCC1 rs3784867 (P = 5.34 × 10-5 ; OR = 4.9), and SLC5A7 rs1013940 (P = 9.00 × 10-4 ; OR= 8.6); genes involved in vincristine transport and inherited neuropathies, respectively. Meta-analysis identified an association with a variant related to TTPA (rs10504361: P = 6.85 × 10-4 ; OR = 2.0), a heritable neuropathy-related gene. This study provides essential corroboratory evidence for CEP72 rs924607 and highlights the importance of drug transporter and inherited neuropathy genes in VIPN.