Healthy adult volunteers are enrolled in a phase I clinical trial investigating the properties of a newly developed oral antimicrobial agent. The drug is administered in different amounts to the volunteers over the course of several weeks to determine the best dosage that minimizes toxicity while maintaining trough levels above the minimum inhibitory concentration. While reviewing the data, the researchers note that the drug's half-life seems to vary amongst the study participants. An increase in which of the following pharmacologic parameters is most likely responsible for the longer half-life seen in certain individuals?

Question

Healthy adult volunteers are enrolled in a phase I clinical trial investigating the properties of a newly developed oral antimicrobial agent.  The drug is administered in different amounts to the volunteers over the course of several weeks to determine the best dosage that minimizes toxicity while maintaining trough levels above the minimum inhibitory concentration.  While reviewing the data, the researchers note that the drug's half-life seems to vary amongst the study participants.  An increase in which of the following pharmacologic parameters is most likely responsible for the longer half-life seen in certain individuals?

Quizplus · Accepted Answer

11ec160b_3c37_be0d_9249_89ffc263fe4a_MD0001_00 The half-life (t_1/2) is the time required for the plasma concentration of a drug with first-order elimination kinetics to decrease by 50%. At time zero, 100% of the drug is present, and with the passage of each subsequent half-life, half of the remaining drug is eliminated. After 5 half-life intervals, a drug is almost completely eliminated from the body. A drug's half-life depends on 2 pharmacokinetic properties: Clearance (CL) represents the volume of plasma completely cleared of a substance per unit time (eg, mL/min). The CL rate is constant for most drugs and depends on the particular metabolic conversion (eg, glucuronidation to inactive form) and/or elimination pathways (eg, biliary or urinary excretion) used to remove the drug from the body. Increased glucuronidation or glomerular filtration would increase plasma CL of the drug, leading to decreased drug half-life (Choices A and B). Volume of distribution (V_d) refers to the extent to which a drug distributes in body tissue compared to its plasma concentration. A drug's V_d is determined by its intrinsic properties (eg, lipid solubility, protein binding), as well as patient factors such as body weight and composition (eg, increased fat vs lean mass). In general, a higher V_d means that the drug is increasingly bound to body tissues with a smaller proportion found in the plasma. Because plasma concentrations are lower for any given dose, drugs with higher V_d take longer to eliminate from the body and therefore have a longer half-life. The half-life of a drug can be calculated using these parameters, as follows: t_1/2 = (0.7 × V_d) / CL In this case, the increased drug half-life seen in certain patients is likely due to increased total body weight, resulting in a higher volume of distribution. (Choices C and D) Oral bioavailability can vary between individuals due to intrinsic differences (eg, age, sex, disease), diet, and medications (eg, proton pump inhibitors). Although increased oral bioavailability can raise peak serum drug levels, drug half-life would not be affected because the amount of drug eliminated per unit time increases as the drug's plasma concentration increases (true of drugs exhibiting first-order kinetics, which account for the vast majority of all clinically used drugs). Educational objective: Half-life (t_1/2) is a measure of how quickly a drug with first-order kinetics is eliminated from the body. A drug is almost completely eliminated after 5 half-life intervals. The half-life can be calculated from the drug's volume of distribution (V_d) and clearance rate (CL) using the following equation: t_1/2 = (0.7 × V_d) / CL.

Healthy Adult Volunteers Are Enrolled in a Phase I Clinical