Examples of dosage regimen design
Intravenous therapy is often required for acutely ill patients who are unable to take oral medicines and for drugs that have a low oral bioavailability. Most drugs are administered by bolus injection or short infusions but longer infusion times are sometimes necessary to reduce concentration-related adverse effects. Continuous infusions are often used to maintain therapeutic concentrations of drugs with short elimination half-lives.
Intravenous bolus administration
Mr B, a 72-year-old male patient, who weighs 80kg and has a serum creatinine concentration of 120mmol/L, is started on a gentamicin dose of 120mg three times daily to treat a severe infection caused by a gram-negative organism.“Peak” and “trough” blood samples are taken one and eight hours after the first dose and the gentamicin concentrations are found to be 5.0 and 1.8mg/L, respectively. Peak samples are important because response to gentamicin is concentration-dependent (see PJ, 31 July, p153).
Is 120mg eight-hourly an appropriate dosage regimen for Mr B?
Gentamicin is an aminoglycoside antibiotic used to treat potentially life-threatening infections. Response to therapy has been associated with achieving serum concentrations above 5mg/L, measured one hour after the dose (often called “peak” serum concentration), while 8 to 10mg/L (10 times the minimum inhibitory concentration) has been advocated for severe gram-negative infections. However, peak concentrations of only 3 to 5mg/L are recommended for streptococcal and enterococcal endocarditis. Trough concentrations greater than 2mg/L are associated with an increased risk of nephrotoxicity.
Some hospitals use “high dose, extended interval” gentamicin, where doses of 5 to 7mg/kg are given 24- to 48-hourly. Peak concentrations with such doses are expected to be well above 10mg/L and troughs are often below 0.5mg/L for at least four hours. Due to assay problems with these high and low concentrations, dose adjustment is often based on a gentamicin concentration measured between six and 14 hours after the dose.
To determine whether the dose is appropriate for Mr B, the peak (one hour post dose) and trough concentrations he would be likely to achieve at steady state need to be calculated. It takes about five half lives for steady state to be achieved (see PJ, 19 June, p769). Mr B’s gentamicin elimination rate constant and volume of distribution can be estimated from the concentrations that were measured after the first dose.
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Citation: The Pharmaceutical Journal URI: 10997178
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