General Purpose Pharmacokinetic-Pharmacodynamic Models for Target-Controlled Infusion of Anaesthetic Drugs: A Narrative Review

Abstract

Target controlled infusion (TCI) is a clinically-available and widely-used computer-controlled method of drug administration, adjusting the drug titration towards user selected plasma- or effect-site concentrations, calculated according to pharmacokinetic-pharmacodynamic (PKPD) models. Although this technology is clinically available for several anaesthetic drugs, the contemporary commercialised PKPD models suffer from multiple limitations. First, PKPD models for anaesthetic drugs are developed using deliberately selected patient populations, often excluding the more challenging populations, such as children, obese or elderly patients, of whom the body composition or elimination mechanisms may be structurally different compared to the lean adult patient population. Separate PKPD models have been developed for some of these subcategories, but the availability of multiple PKPD models for a single drug increases the risk for invalid model selection by the user. Second, some models are restricted to the prediction of plasma-concentration without enabling effect-site controlled TCI or they identify the effect-site equilibration rate constant using methods other than PKPD modelling. Advances in computing and the emergence of globally collected databases has allowed the development of new “general purpose” PKPD models. These take on the challenging task of identifying the relationships between patient covariates (age, weight, sex, etc) and the volumes and clearances of multi-compartmental pharmacokinetic models applicable across broad populations from neonates to the elderly, from the underweight to the obese. These models address the issues of allometric scaling of body weight and size, body composition, sex differences, changes with advanced age, and for young children, changes with maturation and growth. General purpose models for propofol, remifentanil and dexmedetomidine have appeared and these greatly reduce the risk of invalid model selection. In this narrative review, we discuss the development, characteristics and validation of several described general purpose PKPD models for anaesthetic drugs.

A great tool that resurfaced during the pandemic: Remifentanil

“…21,22 Continuous intravenous administration of Remifentanil can be performed using conventional infusion pumps and rate-of-use techniques that allow the anesthesiologist to select and adjust a target plasma concentration to achieve the desired pharmacodynamic effect. 23 The advantages of remifentanil over other opiates are great analgesic potency, short latency, rapid dosage, and elimination. For these reasons, it is the drug indicated in neurosurgical surgery since it provides hemodynamic stability, faster awakening, and better postoperative recovery than other opioids, allowing an immediate postoperative neurological evaluation.…”

General purpose models for intravenous anesthetics, the next generation for target-controlled infusion and total intravenous anesthesia?

“…Table 1 shows some of the commercially available models with their boundaries [3][4][5][6][7][8][9][10]27]. A detailed comparison between the models was recently described by Vandemoortele et al [28]. They concluded that general-purpose models have the potential to increase the clinical acceptance of TCI, as there are less restrictions in their use compared with other models.…”

Pharmacokinetic pharmacodynamic modeling of analgesics and sedatives in children

“…Using allometric scaling and maturation function on the PK parameters is a useful way of comparing model parameter estimates across studies 50,51 . These techniques have been discussed in a number of recent PKPD modeling reviews 21,52,53 …”

“… 50 , 51 These techniques have been discussed in a number of recent PKPD modeling reviews. 21 , 52 , 53 …”