Elucidation of the pathophysiology of intradialytic muscle cramps: pharmacokinetics applied to translational research

In the conventional concept of translational research, investigations flow from the laboratory bench to the bedside. However, clinical research can also serve as the starting point for subsequent laboratory investigations that then lead back to the bedside. This article chronicles the evolution of a series of studies in which a detailed analysis of pharmacokinetics in hemodialysis patients revealed new physiological insight that, through a systems approach incorporating kinetic, physicochemical, physiologic, and clinical trial results, led to an elucidation of the pathophysiology of intradialytic skeletal muscle cramps. Based on this understanding, a therapeutic path forward is proposed.

Augmented renal clearance

Adding to the complexity of caring for critically ill patients is the fact that many of them have a creatinine clearance that exceeds 130 mL/min/1.73 m². This phenomenon, termed augmented renal clearance (ARC), has only recently been widely recognized and its pathogenesis remains incompletely understood. However, ARC has been shown to result in increased dose requirements for drugs that are primarily eliminated by renal excretion, including many antimicrobial agents and enoxaparin. Recognition of ARC is hampered by the fact that the standard creatinine-based equations used to estimate renal function are not accurate in this clinical setting and the diagnosis is best established using both serum and urine creatinine measurements to calculate clearance. So a high index of clinical suspicion and awareness is usually required before this step is taken to confirm the diagnosis of ARC.

Intracerebroventricular drug administration

Among the various routes of drug administration, perhaps the least studied is intracerebroventricular (ICV) administration. This route has been shown to be particularly useful in administering to the central nervous system (CNS) drugs that do not cross the blood-brain barrier readily. As such, the ICV route is a valuable option for providing therapeutic CNS drug concentrations to treat patients with CNS infectious and neoplastic diseases. This route of drug administration also has the advantage of minimizing systemic toxicity.

The stable isotope method for determining absolute bioavailability

The bioavailability of a drug is usually assessed in healthy subjects. However, it is reasonable to expect that significant alterations in bioavailability may occur in actual patients with different diseases or in individuals belonging to special populations. Relatively few studies have been conducted to examine this possibility. The stable isotope method is well suited to compare absolute bioavailability in patients and healthy subjects. Studies in which this method was used indicate that significant changes in the bioavailability of some drugs are particularly likely in patients with advanced liver disease and in those whose splanchnic blood flow is reduced. The expectation is that bioavailability in neonates, children, and pregnant women may also differ from that in non-pregnant adults.

Pitfalls in the calculation of hemodialysis clearance and in the assessment of dialysis efficacy

The therapeutic technique of hemodialysis and the concept of clearance have both followed a long but instructive course of development. In addition, it recently has been shown that physiological changes occurring during hemodialysis have important clinical consequences both in the treatment of drug toxicity and in the selection of appropriate replacement doses of therapeutic drugs. Two major approaches for calculating hemodialysis clearance are currently used. The first approach, termed the recovery method is the “gold standard” that is recommended for use in the current US FDA draft guidance on the conduct of pharmacokinetic studies in patients with impaired renal function. The second approach, termed the A-V difference method, is used more commonly. Unfortunately, this method results in erroneous plasma clearance estimates when improper values for dialyzer flow are chosen. This constitutes a major pitfall that should be avoided in future studies.

Physiological spaces and multicompartmental pharmacokinetic models

The idea of body compartments has its origins in physiology and antedates their use in both physiologically-based predictive pharmacokinetic models and in the simpler compartmental models used to analyze pharmacokinetic data. Whereas physiologically-based pharmacokinetics has evolved to use increasingly sophisticated organ-based models, most compartmental models for data analysis are used without regard for their underlying physiological basis. However, detailed analysis of inulin and urea kinetics has offered some understanding of the physiological basis underlying some three-compartment pharmacokinetic models. In addition, these simple models have yielded new insight into physiological phenomena.

Individualization of drug therapy: an historical perspective

No abstract available.