Real-Time Analytical Solutions as Series Formulas and Heaviside off/on Switch Functions for Multiple Intermittent Intravenous Infusions in One- and Two-Compartment Models

Pharmacokinetic compartment models are the only models that can extract pharmacokinetic parameters from data collected in clinical studies but their estimates lack accuracy, explanations and physiological significance. The objective of this work was to develop particular solutions to drug concentration and AUC in the form of mathematical series and Heaviside functions for repetitive intermittent infusions in the one- and two-compartment models, as a function of dose number and total time using differential calculus. It was demonstrated that the central and peripheral compartment volumes determined from regression analysis of the aminoglycoside antibiotic Sisomicin concentration in plasma represent the actual physiological body fluid volumes accessible by the drug. The drug peak time and peak concentration in the peripheral compartment were also calculated as a function of dose number. It is also shown that the time of intercompartmental momentary distribution equilibrium can be used to determine the drug’s apparent volume of distribution within any dosing interval in multi-compartment models. These estimates were used to carry out simulations of plasma drug concentration with time in the one-compartment model. In conclusion, the two-compartment open mammillary pharmacokinetic model was fully explained for the aminoglycoside antibiotic sisomicin through the new concept of the apparent volume of distribution.

A Reevaluation of Prazosin Pharmacokinetics in a Two-Compartment Model, the Apparent Volume of Distribution and Comparative Simulations in the One-Compartment Model

Published clinical data of Prazosin were reevaluated pharmacokinetically using explicit solutions to drug concentration as a function of total time for IV bolus injection, intermittent intravenous infusion and oral routes of administration in an open two-compartment model. In a novel way, the apparent volume of distribution was estimated from a two-compartment model and found to be close to the total body water suggesting that Prazosin is distributed in all tissues both extracellularly and intracellularly. In addition, extracting the value of the apparent volume of distribution from a two-compartment model allowed comparative simulations in the one-compartment model. It is shown that dosage calculations of Prazosin intermittent infusion can be safely performed using the simpler one-compartment model equations. Lastly, several additional time-dependent pharmacokinetic parameters e.g., the peak time in the central and peripheral compartment and non-steady state and steady state peak concentration and AUC were determined using series equations for all three routes of administration, as a function of dose number and total time upon multiple drug administrations in the two-compartment model. It is also the first time that steady-state plasma drug concentration equations were derived in a two-compartment mammillary model.

Pharmacokinetic and Pharmacodynamic Efficacies of Continuous versus Intermittent Administration of Meropenem in Patients with Severe Sepsis and Septic Shock： A Prospective Randomized Pilot Study

Background： The antibiotic meropenem is commonly administered pharmacokinetic, clinical, and bacteriological efficacies of continuous patients. n patients with severe sepsis and septic shock. We compared the infusion of meropenem versus internaittent administration in such Methods： Patients admitted to the Intensive Care Unit （ICU） with severe sepsis or septic shock who received meropenem were randomly assigned to either the continuous （n = 25） or intermittent groups 01 = 25）. The continuous group received a loading dose of 0.5 g of meropenem lbllowed by a continuous infusion of 3 g/day： the intermittent group received an initial dose of 1.5 g lbllowed by 1 g lbr every 8 h. Clinical success, microbiological eradication, superinfection, ICU mortality, length of ICU stay, and duration of meropenem treatment were assessed. Serial plasma meropenem concentrations tbr the first and third dosing periods （steady state） were also measured. Results： Clinical success was similar in both the continuous （64%） and intermittent （56%） groups （P = 0.564）： the rates of microbiological eradication and superinfection （81.8% vs. 66.7% [P = 0.255] and 4% vs. 16% [P 0.157], respectively） showed improvement in the continuous group. The duration of meropenem treatment was significantly shorter in the continuous group （7.6 vs. 9.4 days; P = 0.035）, where a better steady-state concentration was also achieved. Peak and trough concentrations were significantly different between the continuous and intermittent groups both in the first （Cmax： 19.8 mg/L vs. 51.8 mg/L, P = 0.000; Cmin： 11.2 mg/L vs. 0.5 nag/L, P = 0.000） and third dosing periods （Cmax： 12.5 mg/L vs. 46.4 rag/L, P = 0.000; Cmin： 11.4 mg/L vs. 0.6 rag/L, P = 0.000）. For medium-susceptibility pathogens, continuous inthsion concentrations above the minimal inhibitory concentration were 100%, which was better than that in the intermittent group- Conclusions： Continuous infusion of meropenem provides significantly shorter treatment duration and a tendency for superior bacteriological efficacy than intermittent administration. Continuous inthsion may be more optimal against imermediate-susceptibility pathogens.