Daily Archives: April 11, 2017

Pharmacovigilance and Drug Safety In Clinical Trials

Drug options selection includes perspectives from various disciplines (drug discovery, drug safety and drug metabolism), pharmaceutics, clinical pharmacology and biostatistics).  Many organizations make use of the fail fast model by integrating development functions into discovery to minimize failures in preclinical studiesMoreoevr testing allows organizations to select better compounds and to build better, long-term development plans.

Clinical proof-of-concept is a critical milestone that needs translation from animal pharmacology models to man. Making sure drug and metabolite exposures in plasma and at site-of-action is critical to validate the model.  In the central nervous systems (CNS), measurements in cerebral spinal fluid yield penetration or effect.  For anti-infective agents, tissue penetration or intracellular studies ensure that the minimum inhibitory concentration (MIC) is covered.

Drugs that bind with high affinity, free fractions might drive penetration and effect. Building pharmacokinetic/pharmacodynamic (PK-PD) models then needs protein binding.  For others, total drug levels drive pharmacology.  When moving into the clinic, translation of the pharmacology model to clinical effect should be accomplished as quickly as possible.

The No-Adverse-Effect Level and Dose-Limiting Toxicity

Establishing a safety margin is a crucial aspect that drives candidate selection. Knowledge of the no-adverse-effect level (NOAEL) and dose-limiting toxicity in the most selective species is critical, as these determine what doses can be given in man.  If metabolism-mediated toxicity is seen, examination of inter-species differences provides insights into relevance to man.  U.S. Food & Drug Administration (FDA) Metabolites in Safety Testing (MIST) guidance requires knowing 10% metabolites at steady-state, and bioanalysis using tiered assays plays a critical role in getting these assessments done early.  Many organizations delay clinical absorption, metabolism and elimination (AME) studies, with preference to establish early metabolism coverage without the use of radiolabel studies.  Bio analysis of animal tissues for parent drug and metabolites provides great insights into whether a toxicity seen in animals may be seen in man.  Worldwide has customised many bioanalysis plans to accommodate early metabolite determinations, helping make informed decisions about drug candidates.

Building an accurate safety margin in animals is more straight than defining human safety in large populations. Apart from the numerous human variables, concomitant medications can result in drug-drug interactions (DDI) that modulate drug exposure or effect.  FDA has guidance on how to predict in vivo DDI from in vitro metabolism, and scientists must ensure that a drug is tested in cytochrome (CYP) P450s and carriers.  Knowing whether a drug or its major metabolites are substrates, inhibitors or inducers is critical before allowing drug candidates to progress into studies where the interacting drugs are onboard or into sensitive (hepatic, renal impaired) populations.  Worldwide has supported numerous DDI studies using a variety of drug assays as probe substrates.  We recently presented a comprehensive assay of all warfarin stereoisomer which was used to unravel a clinical DDI4.  Worldwide also has several hundred validated drug assays which can be used to test drug interactions of selected inhibitors or inducers. 

The Increased Use of Personalized Medicine

The use of personalized medicine has increased, not just to target individuals who respond to therapy but to ensure that the proper dose is given.

Drug liabilities might be uncovered from metabolism or DDI studies, based upon observed differences in clearance. One can also select these populations based upon their pharmacogenetics for more focused PK testing. 

New Advances Highlighted at ASCPT & CPIC Symposium

The CPIC Symposium which was recently held with the American Society for Clinical Pharmacology and Therapeutics (ASCPT). summarised the BIA 10-2474 first-in-human (FIH) trial.  The cause of the brain lesions and death which occurred in this FIH trial is still being investigated.  The steepness of the toxicity-response on a 2-fold multiple dose escalation was particularly puzzling, especially as higher single doses were given without incident.  It was a stark reminder of the importance of vigilant investigators and oversight from Institutional Review Boards (IRBs).

Contract Research Organization (CRO), regulatory, legal and pharma perspectives on ensuring subject safety in FIH human studies were covered at the meeting among several topics, including clinical designs which could lower these risks.

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