Pharmacotherapy variability and precision medicine in neurocritical care

Abstract

Pharmacotherapy variability is defined as the variability in drug response among and within individuals that is attributed to the inter and intra-individual differences in the action and disposition of drugs. Neurological and medical complications in neurocritical care contribute significantly to the overall disease prognosis. Pharmacological management plays a key role in managing many of those complications such as cerebral vasospasm, delayed cerebral ischemia, hyponatremia, infections, and seizures. However, pathophysiologic changes secondary to neurological and critical illnesses make the medical management of these patients challenging, contributing to pharmacotherapy variability. Interindividual differences in disease pathophysiology, altered organ function, systemic inflammation, hemodynamic instability, and common interventions employed in intensive care settings could alter the pharmacokinetics and pharmacodynamics of medications. The use of potentially ineffective treatments and suboptimal dosing of medications to manage patients can lead to poor outcomes as the understanding of the effect of neurological injury on the action and disposition of drugs is limited. This narrative review highlights the factors contributing to pharmacotherapy variability in neurocritical care, equipping clinicians with critical insights to refine patient management strategies. In conclusion, pharmacotherapy variability within neurocritical care introduces additional layers of complexity that may significantly contribute to therapy failure, adverse drug reactions, and setbacks in drug development. Understanding these variations is essential for identifying subpopulations that may derive the greatest benefit from specific therapies, representing a critical step toward achieving precision medicine in neurocritical care, ensuring the administration of the appropriate medication to the right patient at the correct dosage regimen.

Keywords: neurocritical care; pharmacodynamics; pharmacokinetics; pharmacotherapy; precision medicine.

Figure 1

Hanafy’s Neuro-CPK Pharmaco-variability Wheel illustrates the factors influencing the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs in neurocritical care. Pharmacogenomics contribute to inter-individual variability in drug responses, affecting PK through mechanisms such as cytochrome P450 (CYP) polymorphisms and altered transporter expression, and PD through drug tolerance and structural/functional changes at the drug-target level. Co-interventions in neurocritical care, including renal replacement therapies, therapeutic hypothermia, fluid resuscitation, and therapeutic plasma exchange, can result in pharmacotherapy variability. Comorbid conditions like systemic inflammation, ARC, and neurological injury impact the body’s drug response, leading to erratic and unpredictable drug levels. Practice variations between institutions and health care teams are critical factors often underemphasized. Different formulations and administration techniques result in variable drug plasma levels. Drug dosing practices may also vary. Concomitant medication administration is prevalent among ICU patients, resulting in drug–drug interactions, with many drugs classified as CYP inducers or inhibitors. Drug-food interactions may also occur through adsorption, chelation, or complexation. Patient characteristics, including age, sex, race and socioeconomic status are important factors affecting drug concentrations in the body. Despite efforts to identify factors causing drug variability, gaps remain that are currently unexplainable. Neuro-CPK, Neurotherapeutics and Clinical Pharmacokinetic laboratory; PK, pharmacokinetics; PD, pharmacodynamics; CYP, Cytochrome P450 enzymes. Created in BioRender. Lab, Neuro-CPK. (2025) https://biorender.com/bu0h3tj.

Figure 2

Pathophysiology of augmented renal clearance (ARC) (top) the use inotropes, autonomic dysregulation, fluid resuscitation, and systemic inflammatory response syndrome (SIRS) contribute to increasing cardiac output and hence renal blood flow. Other mechanisms (e.g., vasodilatory vasopressors, atrial natriuretic peptide (ANP) secreted secondary to hypervolemia, or SIRS directly increase renal blood flow), also contribute subsequently leading to ARC development. Independent predictors of ARC (bottom) comprise patient demographics (young age, male sex), neurological illnesses [traumatic brain injury, intracranial hemorrhage (ICH) and subarachnoid hemorrhage (SAH)], and clinical factors (e.g., lower morbidity scores, lower serum creatinine, increased protein intake, and vasopressor administration). Created in BioRender. Lab, Neuro-CPK. (2025) https://BioRender.com/0fuwuz5.

Figure 3

Checklist to determine how likely drugs are removed by therapeutic plasma exchange (TPE). Mahmoud et al. (127) reproduced with permission from Springer Nature.

Figure 4

Peak plasma nimodipine concentrations following oral administration (CmaxPO) of a single 60-mg nimodipine dose in healthy individuals and patients with liver cirrhosis and epilepsy. This figure illustrates the pharmacokinetic variability of nimodipine across studies. Mahmoud et al. (97) reproduced from Springer Nature under a creative commons attribution-non commercial 4.0 international license.