Clinical Pharmacokinetics and Pharmacodynamics of Drugs in the Central Nervous System

Abstract

Despite contributing significantly to the burden of global disease, the translation of new treatment strategies for diseases of the central nervous system (CNS) from animals to humans remains challenging, with a high attrition rate in the development of CNS drugs. The failure of clinical trials for CNS therapies can be partially explained by factors related to pharmacokinetics/pharmacodynamics (PK/PD), such as lack of efficacy or improper selection of the initial dosage. A focused assessment is needed for CNS-acting drugs in first-in-human studies to identify the differences in PK/PD from animal models, as well as to choose the appropriate dose. In this review, we summarize the available literature from human studies on the PK and PD in brain tissue, cerebrospinal fluid, and interstitial fluid for drugs used in the treatment of psychosis, Alzheimer's disease and neuro-HIV, and address critical questions in the field. We also explore newer methods to characterize PK/PD relationships that may lead to more efficient dose selection in CNS drug development.

Predicting Efavirenz Concentrations in the Brain Tissue of HIV‐Infected Individuals and Exploring their Relationship to Neurocognitive Impairment

“…Several studies have investigated neurocognitive impairment as a function of ARV cerebrospinal fluid (CSF) pharmacokinetics (PK) but have been inconclusive. 4 This may be because neurocognitive impairment was assessed as a function of CSF exposure. With the inability to obtain brain tissue in humans premortem for PK sampling, either CSF concentrations or CNS-penetration effectiveness (CPE) scores are used as surrogates.…”

“…Alternatively, for ARVs that achieve high brain tissue concentrations, potential neurotoxicity may contribute to HAND. Several studies have investigated neurocognitive impairment as a function of ARV cerebrospinal fluid (CSF) pharmacokinetics (PK) but have been inconclusive . This may be because neurocognitive impairment was assessed as a function of CSF exposure.…”

Pharmacology of HIV Cure: Site of Action

“…35 It was previously noted that lopinavir concentrations were greater in white matter vs. cortical gray matter and global pallidus regions of the brain. 36 However, this assessment was based on findings in nine PLWH diagnosed with AIDS near the time of their death and may not be reflective of persons receiving current standard of care. Srinivas et al utilized mass spectrometry imaging (described in greater detail in Future Directions) to visualize the spatial location of efavirenz within the brain of NHPs and noted no morphological differences in distribution patterns between white and gray matter within the cerebellum.…”

“…Finally, spatial location within the brain is an important consideration when exploring ART pharmacology in the CNS, especially considering that specialized immune cells (microglial cells and astrocytes) may harbor latent HIV and are typically located throughout the brain parenchyma and along the tight junctions of the BBB 35 . It was previously noted that lopinavir concentrations were greater in white matter vs. cortical gray matter and global pallidus regions of the brain 36 . However, this assessment was based on findings in nine PLWH diagnosed with AIDS near the time of their death and may not be reflective of persons receiving current standard of care.…”

Introductory Chapter: Linkages between Pharmacokinetics and Adverse Effects of Drugs

“…It should be said here that atypical or new side effects may occur even with normal doses in certain individuals because of their uniqueness with regard to the receptors, enzymes, or proteins, they may have in abundance or absence thereof as a matter of their genetic makeup or as a result of a subclinical or clinical Pharmacokinetics and Adverse Effects of Drugs -Mechanisms and Risks Factors disease state as well as their lifestyle as already explained. In case of overdose, drug metabolism is altered because enzymes responsible for metabolism become saturated; this leaves the excess drug free to force its way to nonspecific receptors by overcoming both inhibition or competition; consequently, it produces nontypical adverse effects while its clearance is decreased and its half-life is prolonged [27][28][29][30].…”