Clinical Pharmacokinetics of Gentamicin

Objectives: The objectives of this study were to: (1) derive equations for estimating gentamicin clearance (Cl gent ) and volume of distribution (V d ) based on the local population attending Al-Amiri Hospital, Kuwait; (2) independently evaluate these equations by comparison with other published methods in their predictive ability to estimate Cl gent and V d . Materials and Methods: Cl gent and V d were calculated in 47 patients (group 1) using the Sawchuk-Zaske method. Regression analysis was used to derive a correlation between creatinine clearance (Cl cr ) and Cl gent , V d and actual body weight (ABW). Based on actual Cl gent and V d values, the predictive ability of the estimated parameters from the regression equations was validated and compared with 4 published methods using mean error (ME), i.e. bias, and mean squared error (MSE) and root mean squared error (RMSE), i.e. precision. All equations were also evaluated in an independent second group (group 2) of 23 patients. Results: The mean 8 SD values of Cl gent and V d were 4.0 8 1.8 l h –1 and 16.8 8 6.7 liters, respectively. The derived equations were: Cl gent = (0.760) (Cl cr ) + 1.117 (r = 0.701) and V d = (0.165) (ABW) + 5.604 (r = 0.532). In comparison to the 4 published methods, the Received: April 14, 2008 Revised: July 8, 2008 Yousef Al-Lanqawi PO Box 491 32005 Hawaly (Kuwait) Tel. +965 929 3308, ext. 5079/7016 E-Mail [email protected] © 2009 S. Karger AG, Basel 1011–7571/09/0183–0209$26.00/0 Accessible online at: www.karger.com/mpp Al-Lanqawi /Capps /Abudlmalek / Al-Anezi /Thusu /Sharma Med Princ Pract 2009;18:209–216 210 is to compute the best dose for the patient according to the site and severity of the infection and any concurrent conditions which may influence gentamicin pharmacokinetics. Several kinetics equations are available for initial gentamicin dosing in patients to attain desired peak (5–10 mg l –1 ) and trough ( ! 2 mg l –1 ) serum concentrations [4–7] . Such methods use defined population-based parameters, from which the gentamicin clearance (Cl gent ) and volume of distribution (V d ) are calculated prior to initial gentamicin dosing. There have been 2 main approaches to aminoglycoside dosing in adults, the traditional multiple daily dosing and extended interval dosing (once daily). The rationale of once daily dosing is to achieve a high peak concentration which increases the postantibiotic effect and may also help minimize toxicity [8–10] . In Kuwait, gentamicin treatment in hospitalized patients is based on traditional multiple daily dosing (often 80 mg every 8 or 12 h). Substantial interpatient variability exists in Cl gent and V d [11– 13] , and there is a need for dosing methods based on local (Kuwaiti) population data [13] . Therefore, the objectives of this study were to: (1) calculate gentamicin pharmacokinetic parameters for the local inpatient population; (2) develop dosing equations based on these parameters; (3) independently compare these equations with 4 published methods for their predictive ability in estimating Cl gent and V d . Materials and Methods The study population comprised adult inpatients (medical/ surgical) at Al-Amiri Hospital who were initiated on a gentamicin regimen, as decided by the responsible physician. The study did not alter clinically indicated therapy with gentamicin. Hospital inpatients who received intravenous gentamicin as part of their routine therapy were considered eligible for the study if: (1) they had gentamicin levels drawn at steady state (after 24–48 h of starting therapy); (2) levels were drawn appropriately, defined as a peak being drawn 1 h after a bolus injection and a trough immediately (or within 30 min) before the next dose; (3) blood sample times were correctly documented; (4) serum creatinine concentrations were determined 24 h before gentamicin dosing. Patients were excluded from the study if: (1) demographic data, such as age, weight and height were not available; (2) they had experienced unstable renal function (defined as 6 0.3 mg  dl –1 change in serum creatinine concentration); (3) received dialysis treatment; (4) previous gentamicin doses had not been given; (5) serum gentamicin concentration had been reported as below the sensitivity of assay (i.e. ! 0.1 mg l –1 ). The study comprised 2 groups; group 1: 47 patients who were randomly selected based on the chronological order of patients’ admissions to the medical/surgical wards between March 2003 and October 2005. This group was used to establish the relationship of creatinine clearance (Cl cr ), age and body weight to individual gentamicin kinetic parameters (Cl gent and V d ), so that subsequently initial dosing equations could be developed to estimate the Cl gent and V d . Group 2: 23 patients admitted to the medical/ surgical wards between December 2005 and February 2007. The patient selection criteria were the same as those in group 1. In this group, the derived equations were assessed and compared independently with 4 other published methods ( table 1 ) for ability to predict Cl gent and V d . Gentamicin Dosage and Concentration All doses of gentamicin were determined by the patient’s attending physician and ranged from 2.5 to 3.5 mg kg –1 total body weight. All doses were diluted in 20 ml of 5% dextrose in water and administered by bolus intravenous injection over 1–3 min (with an average value of 1.5 min). Peak blood samples were obtained 1 h after the injection was completed, and trough samples within 30 min before the end of the dosing interval. The samples were assayed for gentamicin using the Cobas Integra System (Roche Diagnostics, Mannheim, Germany), utilizing fluorescence polarization. Precision for the assay (% coefficient of variation) was ! 5% for the concentration range 0.1–9.8 mg l –1 . Gentamicin Kinetics Gentamicin kinetic parameters were calculated from the measured serum gentamicin concentrations, using a modified twopoint Sawchuk-Zaske method [14] . Although gentamicin is more accurately described by a multi-compartment model, a one-compartment model was used, as is frequently done in clinical practice [15] . The DataKinetics program (MDK), which is based on a Table 1. Equations used by different methods to estimate gentamicin pharmacokinetic parameters