Dexmedetomidine Clearance Decreases with Increasing Drug Exposure: Implications for Current Dosing Regimens and Target-controlled Infusion Models Assuming Linear Pharmacokinetics

Background Numerous pharmacokinetic models have been published aiming at more accurate and safer dosing of dexmedetomidine. The vast majority of the developed models underpredict the measured plasma concentrations with respect to the target concentration, especially at plasma concentrations higher than those used in the original studies. The aim of this article was to develop a dexmedetomidine pharmacokinetic model in healthy adults emphasizing linear versus nonlinear kinetics. Methods The data of two previously published clinical trials with stepwise increasing dexmedetomidine target-controlled infusion were pooled to build a pharmacokinetic model using the NONMEM software package (ICON Development Solutions, USA). Data from 48 healthy subjects, included in a stratified manner, were utilized to build the model. Results A three-compartment mamillary model with nonlinear elimination from the central compartment was superior to a model assuming linear pharmacokinetics. Covariates included in the final model were age, sex, and total body weight. Cardiac output did not explain between-subject or within-subject variability in dexmedetomidine clearance. The results of a simulation study based on the final model showed that at concentrations up to 2 ng · ml–1, the predicted dexmedetomidine plasma concentrations were similar between the currently available Hannivoort model assuming linear pharmacokinetics and the nonlinear model developed in this study. At higher simulated plasma concentrations, exposure increased nonlinearly with target concentration due to the decreasing dexmedetomidine clearance with increasing plasma concentrations. Simulations also show that currently approved dosing regimens in the intensive care unit may potentially lead to higher-than-expected dexmedetomidine plasma concentrations. Conclusions This study developed a nonlinear three-compartment pharmacokinetic model that accurately described dexmedetomidine plasma concentrations. Dexmedetomidine may be safely administered up to target-controlled infusion targets under 2 ng · ml–1 using the Hannivoort model, which assumed linear pharmacokinetics. Consideration should be taken during long-term administration and during an initial loading dose when following the dosing strategies of the current guidelines. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Assessment of Pharmacokinetic Interaction Potential Between Caffeine and Methylliberine

Methylliberine and theacrine are methylurates found in the leaves of various Coffea species and Camellia assamica var. kucha, respectively. We previously demonstrated that the methylxanthine caffeine increased theacrine oral bioavailability in humans. Consequently, we conducted a double-blind, placebo-controlled study pharmacokinetic study in humans administered methylliberine, theacrine, and caffeine to determine methylliberine pharmacokinetic interaction potential with either caffeine or theacrine. Subjects (n = 12) received an oral dose of either methylliberine (25 or 100 mg), caffeine (150 mg), methylliberine (100 mg) plus caffeine (150 mg), or methylliberine (100 mg) plus theacrine (50 mg) using a randomized, double-blind, crossover design. Blood samples were collected over 24 hours and analyzed for methylliberine, theacrine, and caffeine using UPLC-MS/MS. Methylliberine exhibited linear pharmacokinetics that were unaffected by co-administration of either caffeine or theacrine. However, methylliberine co-administration resulted in decreased oral clearance (41.9 +/- 19.5 vs. 17.1 +/- 7.80 L/hr) and increased half-life (7.2 +/- 5.6 versus 15 +/- 5.8 hrs) of caffeine. Methylliberine had no impact on caffeine maximum concentration (440 +/- 140 vs. 458 +/- 93.5 ng/mL) or oral volume of distribution (351 +/- 148 vs. 316 +/- 76.4 L). We previously demonstrated theacrine bioavailability was enhanced by caffeine, however, caffeine pharmacokinetics were unaffected by theacrine. Herein, we found that methylliberine altered caffeine pharmacokinetics without a reciprocal interaction, which suggests caffeine may interact uniquely with different methylurates. Understanding the mechanism(s) of interaction between methylxanthines and methylurates is of critical importance in light of the recent advent of dietary supplements containing both purine alkaloid classes.

A review Commentary on Quinidine kinetics (PK modelling)

This article takes you through the possible pharmacokinetic models and parameters for the antiarrhythmic drug Quinidine. The shuffle between the linear and non-linear pharmacokinetics of quinidine make it a candidate for therapeutic drug monitoring. The adverse effect in the form of QT-elongation is one of the major challenges to go for estimating good kinetics of the quinidine. The current article helps in providing a wide perspective towards the available models for the quinidine's ADME and compile the information published by several authors to help you to understand the quinidine pharmacokinetic behaviour.

Linear pharmacokinetics of doxazosin in healthy subjects

Doxazosin is used for treating symptoms of benign prostatic hyperplasia (BPH). Besides, it is also prescribed for patients with mild to moderate essential hypertension. The object of the current study was to assess the linearity in the pharmacokinetics of doxazosin after administration of doxazosin as a single dose tablet containing 2, 4 and 8 mg doxazosin mesylate. Thirty Iraqi healthy male adult subjects were given 2, 4 and 8 mg doxazosin mesylate tablet in a randomized, cross-over, open-label, fasting, three-period, three-sequence design separated by one week wash out the interval between dosing. Serial blood samples were obtained from each subject before drug intake (zero time) and then at 0.33, 0.67, 1.0, 1.33, 1.67, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 12.0, 24.0, 36, 48, 60, and eventually at 72 hours after dosing. The pharmacokinetic parameters Cmax, AUC0–t, AUC0–∞, Tmax and Thalf were determined from plasma concentration-time data of the drug by non-compartmental analysis. Statistical analysis of doxazosin pharmacokinetic parameters obtained after administration of the investigated dose ranges 2-8 mg demonstrated linear pharmacokinetics.

Ácido micofenólico en trasplante renal ¿El problema es la selección de la dosis o su alta variabilidad farmacocinética?

Introduction. Mycophenolic acid, in combination with tacrolimus, is the cornerstone of the immunosuppressive therapy in transplants. Nevertheless, its use is controversial because it is associated with adverse events, high variability in plasma concentrations, and because monitoring it in plasma levels is still debatable. Case presentation. A female sixteen-year-old patient with kidney transplant and with maintenance immunosup-pressive therapy. She had been treated with mycophenolate mofetil, tacrolimus, and prednisone according to her size and weight, but she presented recurrent gastrointestinal disorders associated with the administration of mycophenolate mofetil and with overexposure to the drug. Pharmacokinetic monitoring of mycophenolate mofetil was performed and the findings showed high levels of the drug (double concentration); then the dose was reduced. Nevertheless, after two attempts to adjust the levels (and the corresponding monitoring), the goal levels were not achieved; she passed from overexposure to underexposure; there was no relationship among doses adjustments. Based on the risk of graft rejection due to plasma concentration variability, azathioprine was used as an antimetabolite drug instead of mycophenolic acid and the outcomes were good. Conclusions. The pharmacokinetic monitoring was useful to identify overexposure to mycophenolic acid, but it was not possible to properly adjust the dose regimen due to the pharmacokinetic variability, even though the literature claims that mycophenolic acid shows linear pharmacokinetics.