Drugs are combined to achieve a specific pharmacodynamic objective a) increase efficacy (eg cancer treatment) b) reduce development of resistance (eg infection treatment) The choice of drugs to be combined to treat a specific disorder will depend on the drug-drug interactions at the pharmacokinetic level and at the pharmacodynamic level. There are a few approaches…
Clearance (CL) relates the rate of elimination of a molecule with its concentration in vivo. Many small molecules are cleared by enzymatic (metabolism) and transporter based mechanisms. Consequently, molecules cleared by these mechanisms tend to display Michaelis-Menten (MM) or saturable (capacity dependent) kinetics. When concentrations are much below Km, CL is constant (Vmax/Km), exposures increase…
The discharge of antibiotics into the environment such as excretion of intact antibiotic drugs from humans (during treatment of infections) and animals (growth promoters in meat animals, veterinary medicine, aquatic animals) can lead to significant antibiotic levels in sewage water, discharge, and agricultural fields. This in turn leads to accumulation of the antibiotics in grazing…
There are many drugs that are extensively metabolized by the liver by drug metabolizing enzymes (DME). In many cases a single DME is responsible for the metabolic clearance of a drug. For many drugs the intrinsic metabolic clearance by the liver far exceeds the liver blood flow of an animal species. In such cases the…
Dose fractionation (DF) is an experimental method used to identify the pharmacokinetic/pharmacodynamic (PK/PD) index of an anti-bacterial molecule. Two non-compartmental PK parameters Cmax and AUC, in addition to time above a threshold concentration and in vitro potency (e.g.MIC) are the basis for determining the PK/PD index that best describes the pharmacodynamics of the molecule. PK/PD…
The shape of the pharmacokinetic curve is a function of drug dissolution, rate and extent of absorption across the gastro-intestinal tract, distribution and elimination. The PK parameters of a molecule following oral dosing can be estimated using graphical methods.
In critical care medicine, the goal is to deliver therapeutic drug concentrations rapidly in blood and then maintain therapeutic concentrations for extended durations for optimum therapeutic outcome. Oral dosing has the disadvantage of not being able to rapidly achieve therapeutic concentrations in blood due to delay in absorption and bioavailability issues. IV infusion to reach…
Ramesh Jayaraman DoseQuartics Consulting Steady state concentrations and accumulation Selection of dosing regimen is as important as dose for designing pharmacology and toxicology studies. The objectives of the pharmacology/toxicology studies could be based on answering specific questions such as Time to achieve steady state is determined by Volume of distribution and clearance. Steady state concentrations…
Ramesh Jayaraman DoseQuartics Consulting The Exposure (AUC) of a therapeutic when administered as infusions and bolus When a dose of a drug is administered as an intravenous bolus and as infusions of different durations, the exposures (AUC) will be the same in the dosing interval, under linear conditions. However, the peak concentrations achieved will decrease…
