Three-compartment Mamillary Model Research Articles

Mechanism-Based Pharmacokinetic Modeling of Absorption and Disposition of a Deferoxamine-Based Nanochelator in Rats.

Deferoxamine (DFO) is an effective FDA-approved iron chelator. However, its use is considerably limited by off-target toxicities and an extremely cumbersome dose regimen with daily infusions. The recent development of a deferoxamine-based nanochelator (DFO-NP) with selective renal excretion has shown promise in ameliorating animal models of iron overload with a substantially improved safety profile. To further the preclinical development of this promising nanochelator and to inform on the feasibility of clinical development, it is necessary to fully characterize the dose and administration-route-dependent pharmacokinetics and to develop predictive pharmacokinetic (PK) models describing absorption and disposition. Herein, we have evaluated the absorption, distribution, and elimination of DFO-NPs after intravenous and subcutaneous (SC) injection at therapeutically relevant doses in Sprague Dawley rats. We also characterized compartment-based model structures and identified model-based parameters to quantitatively describe the PK of DFO-NPs. Our modeling efforts confirmed that disposition could be described using a three-compartment mamillary model with elimination and saturable reabsorption both occurring from the third compartment. We also determined that absorption was nonlinear and best described by parallel saturable and first-order processes. Finally, we characterized a novel pathway for saturable SC absorption of an ultrasmall organic nanoparticle directly into the systemic circulation, which offers a novel strategy for improving drug exposure for nanotherapeutics.

Comparative canine Pharmacokinetics–Pharmacodynamics of Fospropofol Disodium Injection, Propofol Eemulsion, and Cyclodextrin-Enabled Propofol Solution Following Bolus Parenteral Administration

The pharmacokinetics and pharmacodynamics of fospropofol (FP) disodium injection, propofol emulsion (PE), and cyclodextrin-enabled propofol (CDP) solution following bolus parenteral administration in dogs was evaluated. Three healthy male beagle dogs were treated in a three-way cross-over study (14 day washout period) with 6 mg/kg propofol equivalents. Blood samples were collected predose and at 16 points postdose through 1440 min and analyzed for propofol and FP, when appropriate. From 5 min predose to 30 min postdose, brain electrical activity [electroencephalography (EEG)] was recorded and analyzed by power spectrum analysis techniques. Each formulation appeared to be well tolerated with transient discomfort observed in the PE and CDP animals and minor excitability in the FP animals prior to loss of consciousness. Blood propofol followed three-compartment pharmacokinetic behavior and derived parameters were not statistically different except for elimination half-life from the CDP formulation and onset, and duration of anesthesia from the FP formulation. The effect site concentrations at 50% the maximum EEG effect for the FP and CDP formulations were approximately one-half that of the PE formulation. Onset and duration of anesthesia are correlated with modeled effect site propofol concentrations. The implications of formulation on pain on injection and propofol activity are discussed.

A Physiologically Based, Recirculatory Model of the Kinetics and Dynamics of Propofol in Man

The disposition of propofol in man is commonly described using a three-compartment mamillary model. However, these models do not incorporate blood flows as parameters. This complicates the representation of the changes in blood flows that may occur in surgical patients. In contrast, complex physiologically based models are derived from data sets (e.g., tissue:blood partition coefficients) that may not be readily collected in man. Alternatively, the authors report a recirculatory model of propofol disposition in a "standard" man that incorporates detailed descriptions of the lungs and brain, but with a lumped description of the remainder of the body. The model was parameterized from data in the literature using a "meta-modeling" approach. The first-pass passage of propofol through the venous vasculature and the lungs was a function of the injected drug mixing with cardiac output and passing through a three-"tank in series" model for the lungs. The brain was represented as a two-compartment model defined by cerebral blood flow and a permeability term. The Bispectral Index was a linear function of the mean brain concentration. The remainder of the body was represented by compartment systems for the liver, fast distribution and slow distribution. The model was a good fit of the data and was able to predict other data not used in the development of the model. The model may ultimately find a role in improving the fidelity of patient simulators currently used to train anesthetists and for clinical practice simulation to optimize dosing and management strategies.

Pharmacokinetics of eltanolone following bolus injection and constant rate infusion.

Disposition of intravenous anaesthetic eltanolone was studied when administered as a bolus injection (B) of 0.75 mg/kg and constant rate intravenous infusion at 2 mg/kg/hr (12) and 3.5 mg/ kg/hr (13.5) for 2 hr in healthy male volunteers. Venous blood samples were collected for 12 hr and 20 hr following bolus injection and intravenous infusion, respectively. Serum eltanolone concentrations were determined by a specific gas chromatographic mass spectrometric assay. Using a nonlinear regression analysis, the individual data sets were best fitted by a three-compartment mamillary model with central elimination. Derived pharmacokinetic parameters expressed as median and 95% confidence intervals indicated an initial fast distribution with a half-life of 1.80 (0.23-5.47) min (B), 1.44 (0.97-2.06) min (12) and 1.44 (0.95-2.39) min (13.5), an intermediate phase with a half-life of 35.4 (28.7-45.2) min (B), 39.6 (31.0-47.9) min (12) and 35.4 (33.3-44.9) min (13.5) and a moderately short terminal phase with a half-life of 3.8 (2.7-5.9) hr (B), 5.0 (4.2-6.1) hr (12) and 4.6.(4.0-4.8) hr (13.5). The serum clearance after bolus injection was 1.37 (1.23-1.67) L/hr/kg and after infusion was 1.36 (1.25-1.52) L/hr/kg (12) and 1.17 (1.11-1.31) L/hr/kg (13.5). The pharmacokinetics of eltanolone appear to be linear over the dosage range studied. Pharmacokinetic parameters obtained after bolus injection were very much similar to the parameters obtained after infusion with the exception of t1/2 beta which was longer after the infusion (significant) and the volume of central compartment which was lower after infusion (not significant). Context sensitive times were estimated for a 30%, 50% and 80% drop in the concentration of eltanolone after different infusion times. A 30% drop in concentration is estimated to take about 2 to 3 min. A 50% drop in concentration is estimated to take about 8 min when duration of infusion is 3 hr and reaches a value of about 10 min by a duration of infusion of 10 hr. A 80% drop in concentration is estimated to take about 55 min following an infusion of 1 hr and it reaches a value of 70-80 min following an infusion of 10 hr.

Mild Hypothermia Alters Propofol Pharmacokinetics and Increases the Duration of Action of Atracurium

Mild intraoperative hypothermia is common.We therefore studied the effects of mild hypothermia on propofol pharmacokinetics, hepatic blood flow, and atracurium duration of action in healthy volunteers. Six young volunteers were studied on two randomly assigned days, at either 34 degrees C or 37 degrees C. Anesthesia was induced with thiopental, 3 mg/kg, and maintained with 70% N2 O and 0.6% isoflurane. Core hypothermia was induced by conductive and convective cooling. On the other study day, normothermia was maintained by a Bair Hugger Registered Trademark (Augustine Medical, Inc., Eden Prairie, MN) forced-air warmer. Propofol, 1 mg/kg lean body mass (LBM), then was given, followed by a 4-h infusion at 5 mg centered dot kg-1 centered dot h-1. After 2 h, atracurium 0.5 mg/kg was administered as an intravenous bolus. Indocyanine green was administered for estimation of hepatic blood flow. Arterial blood was assayed for propofol and indocyanine green concentration. Pharmacokinetic analysis was performed using NONMEM. Results are reported as means +/- SEM. Propofol blood concentrations averaged approximate equals 28% more at 34 degrees C than at 37 degrees C (P < 0.05). Hepatic blood flow decreased 23% +/- 11% in normothermic volunteers during the propofol infusion, and 33% +/- 11% in hypothermic volunteers (P = not significant). A three-compartment mamillary model fitted the data best. Inclusion of hepatic blood flow change from the prepropofol baseline as a covariate for total body clearance significantly improved the fit. The intercompartmental clearances were decreased in the presence of hypothermia. Core hypothermia prolonged the time to recovery of the first twitch in the train-of-four to 10% of its control value (T1 = 10%) after atracurium administration by approximate equals 60% (P < 0.05), from 44 +/- 4 min to 68 +/- 7 min. In contrast, T1 = 25%-75% remained unchanged. We conclude that 3 degrees C of core hypothermia increased propofol blood concentrations and prolonged atracurium duration of action. Hepatic blood flow was decreased during propofol administration, and this change was a significant predictor of propofol clearance, indicating that the effect of propofol on hepatic blood flow impairs the clearance of propofol itself. (Anesth Analg 1995;80:1007-14)

Pharmacokinetic parameters relevant to recovery from opioids.

Several recent studies have suggested that the terminal half-lives of many drugs do not predict the rate of washout of drug after the relatively short durations of infusions used in anesthesia. Many anesthetic drugs fit a three-compartment mamillary model, with three volumes of distribution (central [V1] and peripheral [V2 and V3]) and three clearances (elimination or metabolic [Cl1] and distribution [Cl2 and Cl3]). It has been suggested that a large V3:Cl3 ratio contributes to rapid recovery after infusion. We investigated the role of each of these primary pharmacokinetic parameters to determine values of each that would contribute to rapid recovery after various dosing schemes. Three sets of computer simulations were performed based on a three-compartment mamillary model for fentanyl, alfentanil, and sufentanil. Set I predicted the change in plasma concentration of each drug after a bolus if each pharmacokinetic parameter were independently increased by 5%. Set II predicted the time for an 80%, 50%, or 20% decrease in plasma concentration after infusions of varying duration (the 80%, 50%, and 20% decrement time, respectively) if each pharmacokinetic parameter were independently increased by 5%. Set III calculated the percent change in each pharmacokinetic parameter alone that would give a 30% shorter decrement time after infusions of varying duration. Set I demonstrated that after a bolus dose to obtain identical initial plasma concentrations, the drug with a larger V1 had a higher plasma concentration than did the parent drug at all subsequent times. The drug with a larger Cl1 had a lower plasma concentration than did the parent drug at all times. A larger V2, V3, Cl2, or Cl3 led to a lower plasma concentration at times soon after the bolus and subsequently to a higher plasma concentration than did the parent drug. Set II demonstrated that after an infusion, increasing V1 led to a longer decrement time and increasing Cl1 led to a shorter decrement time for infusions of all durations. Increasing V2, V3, Cl2, or Cl3 led to a shorter decrement time when the infusion had been short and when a small decrease in plasma concentration was desired. Increasing each of these four parameters led to a longer decrement time when the infusion had been long and when a larger decrease in plasma concentration was desired. Set III demonstrated that a smaller V1 or a larger Cl1 always led to a shorter decrement time. For infusions of short duration and for a small decrease in plasma concentration, a larger V2, V3, Cl2, or Cl3 led to the desired decrease in decrement time. For infusions of longer duration and for larger decreases in plasma concentration, a smaller V2, V3, Cl2, or Cl3 was able to decrease the decrement time by 30%. This study proposes qualitative guidelines for pharmacokinetic properties desirable in anesthetic drugs. If a rapid decrease in plasma concentration is desired after an infusion, it is always beneficial to have a small V1 and a large Cl1. For infusions of short duration, after which only a small decrease in plasma concentration is required, it is beneficial to have a larger V2, V3, Cl2, and Cl3. For infusions of longer duration, after which a large decrease in plasma concentration is desired, it is beneficial to have a smaller V2, V3, Cl2, and Cl3. These proposals may be beneficial for planning clinical trials of new drugs.

The Pharmacokinetics of the New Short-acting Opioid Remifentanil (GI87084B) in Healthy Adult Male Volunteers

Remifentanil (GI87084B) is a new short-acting opioid with a unique ester structure. Metabolism of remifentanil by ester hydrolysis results in very rapid elimination. The aim of this study was to characterize in detail the pharmacokinetic profile of remifentanil in healthy male volunteers. Ten healthy adult male volunteers received a zero-order infusion of remifentanil at doses ranging from 1 to 8 micrograms.kg-1.min-1 for 20 min. Frequent arterial blood samples were drawn and analyzed by gas chromatographic mass spectroscopy to determine the remifentanil blood concentrations. The raw pharmacokinetic data were analyzed using three different parametric compartmental modeling methods (traditional two-stage, naive pooled data, and NONMEM). The raw pharmacokinetic data also were analyzed using numeric deconvolution and a nonparametric moment technique. A computer simulation using hte pharmacokinetic parameters of the NONMEM compartmental model was performed to provide a more intuitively meaningful and clinically relevant description of the pharmacokinetics. The simulation estimated the time necessary to achieve a 50% decrease in remifentanil concentration after a variable-length infusion. For each parametric method, a three-compartment mamillary model that accurately describes remifentanil's concentration decay curve was constructed. The NONMEM analysis population pharmacokinetic parameters included a central clearance of 2.8 l/min, a volume of distribution at steady state of 32.8 l, and a terminal half-life of 48 min. The mean results of the nonparametric moment analysis included a clearance of 2.9 l/min, a volume of distribution at steady state of 31.8 l, and a mean residence time of 10.9 min. The computer simulation revealed the strikingly unique pharmacokinetic profile of remifentanil compared to that of the currently available fentanyl family of opioids. Remifentanil is a new, short-acting opioid with promising clinical potential in anesthesiology.

Amphotericin B pharmacokinetics in humans.

The pharmacokinetics of amphotericin B were studied in two patients at the conclusion of long-term therapy for disseminated histoplasmosis. The distribution kinetics of this drug were adequately described by a three-compartment mamillary model with a total distribution volume averaging 4 liters/kg. The elimination phase half-life of amphotericin B was approximately 15 days, reflecting slow release of amphotericin B from a peripheral compartment. In accordance with previous reports, renal excretion accounted for only 3% of total amphotericin B elimination. The pharmacokinetic model for one of the patients also was used to compare the simulated amphotericin B serum levels that would be expected if initial therapy followed two recommended regimens.