Researchers are developing a new glycopeptide antibiotic similar to vancomycin. Susceptibility testing reveals that the new drug is bactericidal against gram-positive organisms at serum concentrations above 15 µg/mL. Two different dosage regimens are developed to achieve a target serum trough concentration of 15-20 µg/mL: one administered as 1 gram every 6 hours and the other as 2 grams every 12 hours. The two regimens are tested in healthy volunteers during an early-phase clinical trial, and the following pharmacokinetic profiles are obtained. Compared to the 12-hour dosing regimen, the 6-hour regimen is most likely to exhibit which of the following features?

Question

Researchers are developing a new glycopeptide antibiotic similar to vancomycin.  Susceptibility testing reveals that the new drug is bactericidal against gram-positive organisms at serum concentrations above 15 µg/mL.  Two different dosage regimens are developed to achieve a target serum trough concentration of 15-20 µg/mL: one administered as 1 gram every 6 hours and the other as 2 grams every 12 hours.  The two regimens are tested in healthy volunteers during an early-phase clinical trial, and the following pharmacokinetic profiles are obtained.  Compared to the 12-hour dosing regimen, the 6-hour regimen is most likely to exhibit which of the following features?

Quizplus · Accepted Answer

11ec160b_3c39_44b0_9249_03190bc6bc3e_MD0001_00 Drug dosing regimens are typically designed to maximize drug effectiveness and minimize toxicity. The above graph is comparing two different regimens with the same total dose (ie, 4 grams/24 hr) but with different dosing intervals (ie, 6 hr,12 hr). Both regimens have similar trough levels (ie, lowest concentration level before next dose) and maintain plasma levels above the bactericidal cutoff (eg, 15-20 µg/mL). As such, both regimens are likely to exhibit similar efficacy. However, peak and average drug levels are substantially higher with the 12-hour dosing regimen. Because drug toxicity most often correlates with peak or average plasma drug levels, the 6-hour regimen is likely to have lower toxicity. (Choice A) Clearance (hepatic or renal) of a substance depends on the intrinsic properties of the agent. It is defined as the amount of plasma that is cleared of the drug over a given period (eg, mL/min). Drug clearance is typically the same regardless of the dosing schedule. (Choice B) Average plasma drug levels are lower when a fixed amount of drug is given in more divided doses. In this example, 4 grams are administered every 24 hours, either in 2 doses (12-hr regimen) or 4 doses (6-hr regimen). Therefore, the more frequent 6-hour regimen would result in lower average plasma drug levels. (Choice C) Patient compliance is increased when the frequency of dosing is minimized. Only 2 doses per day are needed with the 12-hour regimen; however, the 6-hour regimen needs 4 doses and is likely to be more disruptive to the patient's schedule. (Choice E) The therapeutic window refers to the range of drug dosages that have an appropriate clinical effect. It begins at the lowest dose at which the drug is effective and ends at the highest dose without significant toxic effects. Drugs with a narrow therapeutic window are often dosed more frequently to prevent large swings in plasma concentration. Educational objective: Drug dosing regimens with more frequent dosing have lower peak and average drug levels, which can help reduce drug toxicity.

Researchers Are Developing a New Glycopeptide Antibiotic Similar to Vancomycin