CPT: pharmacometrics & systems pharmacology
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CPT Pharmacometrics Syst Pharmacol · Sep 2018
A Semi-Mechanistic Population Pharmacokinetic Model of Nusinersen: An Antisense Oligonucleotide for the Treatment of Spinal Muscular Atrophy.
A pharmacokinetic (PK) model was developed for nusinersen, an antisense oligonucleotide (ASO) that is the first approved treatment for spinal muscular atrophy (SMA). The model was built with data from 92 nonhuman primates (NHPs) following intrathecal doses (0.3-7 mg) and characterized the PK in cerebrospinal fluid (CSF), plasma, total spinal cord, brain, and pons. The estimated volumes were 13.6, 937, 4.5, 53.8, and 2.11 mL, respectively. ⋯ Physiological age-based and body weight-based allometric scaling was implemented with exponent values of -0.08 and 1 for the rate constants and the volume of distribution, respectively. Simulations of the scaled model were in agreement with clinical observations from 52 pediatric phase I PK profiles. The developed model can be used to guide the design of clinical trials with ASOs.
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CPT Pharmacometrics Syst Pharmacol · Oct 2017
Randomized Controlled TrialPopulation Exposure-Response Modeling Supported Selection of Naloxegol Doses in Phase III Studies in Patients With Opioid-Induced Constipation.
Naloxegol is approved for the treatment of opioid-induced constipation (OIC) in adults with chronic noncancer pain. Population exposure-response models were developed using data from a phase II study comprising 185 adults with OIC. ⋯ The model predicted that 12.5, 25, and 37.5 mg doses would produce median response rates of 40%, 50%, and 60%, and dropout rates of 13.3%, 16.7%, and 23.3%, respectively. The large overlap of predicted difference of the response rate between placebo and the 25 or 37.5 mg doses suggested little utility of using a 37.5 mg dose in phase III studies.
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CPT Pharmacometrics Syst Pharmacol · Jul 2017
Randomized Controlled Trial Multicenter StudyPopulation Modeling of Selexipag Pharmacokinetics and Clinical Response Parameters in Patients With Pulmonary Arterial Hypertension.
Selexipag (Uptravi) is an oral selective IP prostacyclin receptor agonist approved for the treatment of pulmonary arterial hypertension (PAH). The pivotal GRIPHON study was the largest clinical study ever conducted in PAH patients, providing long-term data from 1,156 patients. ⋯ Using log-linear regression models linking model-predicted steady-state exposure to pharmacodynamics (PD), exposure to selexipag and ACT-333679 showed some statistically significant, albeit not clinically relevant, effects on exercise capacity, laboratory values, and the occurrence of prostacyclin-related adverse events, but not on vital signs or adverse events denoting hemorrhage. Using suitable modeling techniques, the GRIPHON study yielded clinically relevant data with limited burden of pharmacokinetics (PK) blood sampling, demonstrating that PK/PD modeling enables firm conclusions even with sparse PK and PD sampling.
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CPT Pharmacometrics Syst Pharmacol · Mar 2017
CATTLE (CAncer treatment treasury with linked evidence): An integrated knowledge base for personalized oncology research and practice.
Despite the existence of various databases cataloging cancer drugs, there is an emerging need to support the development and application of personalized therapies, where an integrated understanding of the clinical factors and drug mechanism of action and its gene targets is necessary. We have developed CATTLE (CAncer Treatment Treasury with Linked Evidence), a comprehensive cancer drug knowledge base providing information across the complete spectrum of the drug life cycle. ⋯ A total of 2,323 unique cancer drugs are currently linked to rich information from these databases in CATTLE. Through two use cases, we demonstrate that CATTLE can be used in supporting both research and practice in personalized oncology.