Pharmacokinetics Of Gentamicin Research Articles

Single UK centre experience on the treatment of PD peritonitis--antibiotic levels and outcomes

There are few studies of the pharmacokinetics of vancomycin and gentamicin in peritoneal dialysis (PD) patients and the influence of antibiotic concentrations on treatment outcome. Concerns about resistance to ceftazidime and potential of aminoglycoside toxicity make the choice of empiric antibiotic difficult. We retrospectively collected data from 613 patients on PD between 1 June 2002 and 31 December 2005. During this time, we adopted a protocol that minimized aminoglycoside exposure to patients with residual renal function and carefully monitored serum antibiotic concentrations. There were no statistical differences in mean day-5 vancomycin concentrations for continuous ambulatory peritoneal dialysis (CAPD) vs automated peritoneal dialysis (APD) and for anuric vs not-anuric patients. However, low levels (<12 mg/l) were recorded for 12.8% CAPD and 15% APD patients. These remained low at day 10 in 16% patients (25% if not anuric) despite incremental dosing. Vancomycin concentration did not predict cure or relapse of Gram-positive or culture-negative peritonitis. Gentamicin concentration (>2 mg/l in >50% patients) did not predict outcome of Gram-negative and culture-negative peritonitis. Moreover, cure rates were the same irrespective of whether gentamicin was continued for 14 days or was switched to ceftazidime after 5 days. We have confirmed that the International Society for Peritoneal Dialysis (ISPD) dosing guideline for vancomycin in CAPD and APD patients produces adequate serum concentrations of the antibiotics in the vast majority. However, large incremental dosing of vancomycin is needed if day-5 levels are low; especially for not-anuric patients. Whilst evidence of gentamicin toxicity in PD remains controversial, ISPD dosing regimen resulted in high levels for >50% patients. High gentamicin concentrations did not correlate with treatment success, but switching gentamicin to ceftazidime at day 5 appeared safe and limited aminoglycoside exposure. Increasing vancomycin and gentamicin concentrations do not appear to improve cure rates and alternative strategies (such as combination treatment) should be considered for future research.

Population pharmacokinetics of a single daily intramuscular dose of gentamicin in children with severe malnutrition

The World Health Organization recommends that all children admitted with severe malnutrition should routinely receive parenteral ampicillin and gentamicin; despite this, mortality remains high. Since this population group is at risk of altered volume of distribution, we aimed to study the population pharmacokinetics of once daily gentamicin (7.5 mg/kg) in children with severe malnutrition and to evaluate clinical factors affecting pharmacokinetic parameters. Thirty-four children aged 0.5-10 years were studied. One hundred and thirty-two gentamicin concentrations (median of four per patient), drawn 0.4-24.6 h after administration of the intramuscular dose, were analysed. The data were fitted by a two-compartment model using the population package NONMEM. Gentamicin was rapidly absorbed and all concentrations measured within the first 2 h after administration were > 8 mg/L (indicating that satisfactory peak concentrations were achieved). Ninety-eight percent of samples measured more than 20 h after the dose were < 1 mg/L. The best model included weight, and it was found that high base deficit, high creatinine concentration and low temperature (all markers of hypovolaemic shock) reduced clearance (CL/F). Weight influenced volume of the central (V1/F) and peripheral (V2/F) compartments, and high base deficit reduced V2/F and intercompartmental CL (Q/F). Interindividual variability in CL was 26%, in V1/F 33% and in V2/F and Q/F was 52%. Individual estimates of CL/F ranged from 0.02 to 0.16 (median 0.10) L/h/kg and those of Vss/F from 0.26 to 1.31 (median 0.67) L/kg. Initial half-lives had a median of 1.4 h and elimination half-lives and a median of 14.9 h. Excessive concentrations were observed in one patient who had signs of renal impairment and shock. Although a daily dose of 7.5 mg/kg achieves satisfactory gentamicin concentrations in the majority of patients, patients with renal impairment and shock may be at risk of accumulation with 24 hourly dosing. Further studies of gentamicin pharmacokinetics in this group are now needed to inform future international guideline recommendations.

Comparative Pharmacokinetics of Gentamicin after Intravenous, Intramuscular, Subcutaneous and Oral Administration in Broiler Chickens

The pharmacokinetics and bioavailability of gentamicin sulphate (5 mg/kg body weight) were studied in 50 female broiler chickens after single intravenous (i.v.), intramuscular (i.m.), subcutaneous (s.c.) and oral administration. Blood samples were collected at time 0 (pretreatment), and at 5, 15 and 30 min and 1, 2, 4, 6, 8, 12, 24 and 48 h after drug administration. Gentamicin concentrations were determined using a microbiological assay and Bacillus subtillis ATCC 6633 as a test organism. The limit of quantification was 0.2 microg/ml. The plasma concentration-time curves were analysed using non-compartmental methods based on statistical moment theory. Following i.v. administration, the elimination half-life (t (1/2beta)), the mean residence time (MRT), the volume of distribution at steady state (V (ss)), the volume of distribution (V (d,area)) and the total body clearance (Cl(B)) were 2.93 +/- 0.15 h, 2.08 +/- 0.12 h, 0.77 +/- 0.05 L/kg, 1.68 +/- 0.39 L/kg and 5.06 +/- 0.21 ml/min per kg, respectively. After i.m. and s.c. dosing, the mean peak plasma concentrations (C (max)) were 11.37 +/- 0.73 and 16.65 +/- 1.36 microg/ml, achieved at a post-injection times (t (max)) of 0.55 +/- 0.05 and 0.75 +/- 0.08 h, respectively. The t (1/2beta) was 2.87 +/- 0.44 and 3.48 +/- 0.37 h, respectively after i.m. and s.c. administration. The V (d,area) and Cl(B) were 1.49 +/- 0.21 L/kg and 6.18 +/- 0.31 ml/min per kg, respectively, after i.m. administration and were 1.43 +/- 0.19 L/kg and 4.7 +/- 0.33 ml/min per kg, respectively, after s.c. administration. The absolute bioavailability (F) of gentamicin after i.m. administration was lower (79%) than that after s.c. administration (100%). Substantial differences in the resultant kinetics data were obtained between i.m. and s.c. administration. The in vitro protein binding of gentamicin in chicken plasma was 6.46%.

Development of a Semimechanistic Model to Describe the Pharmacokinetics of Gentamicin in Patients Receiving Hemodialysis

The aim of this study was to ascertain the most suitable dosing schedule for gentamicin in patients receiving hemodialysis. We developed a model to describe the concentration-time course of gentamicin in patients receiving hemodialysis. Using the model, an optimal dosing schedule was evaluated. Various dosing regimens were compared in their ability to achieve maximum concentration (C(max), > or = 8 mg/L) and area under the concentration time-curve (AUC > or = 70 mg x h/L and < or = 120 mg x h/L per 24 hours). The model was evaluated by comparing model predictions against real data collected retrospectively. Simulations from the model confirmed the benefits of predialysis dosing. The mean optimal dose was 230 mg administered immediately before dialysis. The model was found to have good predictive performance when simulated data were compared to data observed in real patients. In summary, a model was developed that describes gentamicin pharmacokinetics in patients receiving hemodialysis. Predialysis dosing provided a superior pharmacokinetic profile than did postdialysis dosing.

Population pharmacokinetics of gentamicin in premature newborns

To determine the pharmacokinetic parameters of gentamicin in a population of 200 premature newborns and to investigate the influence of several clinical and physiopathological covariates on the pharmacokinetics of the drug. To validate the pharmacokinetic analysis performed in another population of 50 premature newborns. A total of 200 premature newborns were evaluated at the neonatal intensive care unit of Severo Ochoa Hospital (Madrid, Spain). Four hundred and seventeen serum drug concentrations were included. Mean gestational age (GA) was 32.19+/-2.97 weeks, mean postnatal age (PNA) was 5.49+/-5.41 days and mean body weight (BW) was 1.68+/-0.63 kg. Fifty additional newborns were studied for validation (mean GA 32.62+/-3.07 weeks, mean PNA 5.17+/-3.77 days and mean BW 1.80+/-0.67 kg). Dosing, serum gentamicin concentrations and 15 covariates were collected. Data analysis was performed with NONMEM. One- and two-compartment open models were evaluated. Four parameters were analysed with the two-compartment open model: clearance (CL), central volume (Vc), peripheral volume (Vp) and intercompartmental clearance (Q). The two-compartment open model was found to significantly better describe gentamicin pharmacokinetics in the neonate. More than PNA or GA, creatinine clearance (CLCR) plays an important role in the elimination of gentamicin in premature newborns. Creatinine clearance is also related to GA. The appropriate dosing regimens given in accordance with the characteristics of the patients are 5 mg/kg/48 h and 4 mg/kg/24 or 36 h for neonates<32 weeks and >or=32 weeks of GA, respectively.

Population pharmacokinetic modelling of gentamicin and vancomycin in patients with unstable renal function following cardiothoracic surgery

To describe the population pharmacokinetics of gentamicin and vancomycin in cardiothoracic surgery patients with unstable renal function. Data collected during routine care were analyzed using NONMEM. Linear relationships between creatinine clearance (CL(Cr)) and drug clearance (CL) were identified, and two approaches to modelling changing CL(Cr) were examined. The first included baseline (BCOV) and difference from baseline (DCOV) effects and the second allowed the influence of CL(Cr) to vary between individuals. Final model predictive performance was evaluated using independent data. The data sets were then combined and parameters re-estimated. Model building was performed using data from 96 (gentamicin) and 102 (vancomycin) patients, aged 17-87 years. CL(Cr) ranged from 9 to 172 ml min(-1) and changes varied from -76 to 58 ml min(-1) (gentamicin) and -86 to 93 ml min(-1) (vancomycin). Inclusion of BCOV and DCOV improved the fit of the gentamicin data but had little effect on that for vancomycin. Inclusion of interindividual variability (IIV) in the influence of CL(cr) resulted in a poorly characterized model for gentamicin and had no effect on vancomycin modelling. No bias was seen in population compared with individual CL estimates in independent data from 39 (gentamicin) and 37 (vancomycin) patients. Mean (95% CI) differences were 4% (-3, 11%) and 2% (-2, 6%), respectively. Final estimates were: CL(Gent) (l h(-1)) = 2.81 x (1 + 0.015 x (BCOV(CLCr)-BCOV(CLCr Median)) + 0.0174 x DCOV(CLCr)); CL(Vanc) (l h(-1)) = 2.97 x (1 + 0.0205 x (CL(Cr)-CL(Cr Median))). IIV in CL was 27% for both drugs. A parameter describing individual changes in CL(cr) with time improves population pharmacokinetic modelling of gentamicin but not vancomycin in clinically unstable patients.

Extended-Interval Gentamicin Administration in Malnourished Children

Malnourished children have several physiologic abnormalities that can affect drug distribution and elimination. The aim of this study was to determine the efficacy, safety and pharmacokinetics of a once-daily dose of gentamicin compared with conventional thrice-daily dosing in malnourished children. To our knowledge, it has not been investigated in this population so far. A total of 310 malnourished children of either gender aged 6 months to 5 years with diarrhea and pneumonia were randomized to receive intramuscular gentamicin 5 mg/kg/day once-daily (OD) (n=148) or the same total daily amount given in three divided doses (TD) (n=162) in addition to ceftriaxone 75 mg/kg/day. After 48 h at steady state, gentamicin pharmacokinetics was assessed by fluorescence polarization immunoassay in a subgroup of 59 children and 43 children in the OD and TD groups, respectively. The groups were equivalent in baseline demographic, clinical and laboratory characteristics. Good and partial clinical responses occurred in 64 per cent vs. 54 per cent and 25 per cent vs. 27 per cent in the OD and the TD children, respectively (p=NS for both comparisons). Five patients in each treatment group died. Renal toxicity defined by change in serum creatinine was not observed in any patient from either group. In the OD group, mean+/-SD serum gentamicin concentrations at 1 (peak), 3, 5, 8, 23, and 24 (trough value) hours after the dose were 11.7+/-4.1, 4.4+/-1.2, 2.08+/-0.9, 1.01+/-0.6, 0.31+/-0.09 and 0.29+/-0.07 mg/l respectively. In the TD group, mean +/-SD serum gentamicin concentration at 1 hour (peak) was 4.7+/-1.8 mg/l and the trough concentration was 0.48+/-0.21 mg/l. In OD group, the gentamicin trough concentration was significantly lower (p<0.001) and the peak concentration was significantly higher (p<0.001) compared to TD group. The results of this study indicate that once-daily gentamicin is effective and safe in malnourished children. Widespread implementation of once-daily dosing in malnourished children is appropriate and will reduce number of intramuscular injections and hospital costs.

The influence of weight with assay error on gentamicin pharmacokinetics using the Bayesian and nonlinear least square regression analysis in appendicitis patients

The purpose of this study was to determine the influence of weight with gentamicin assay error on the Bayesian and nonlinear least squares regression analysis in 12 Korean appendicitis patients. Gentamicin was administered intravenously over 0.5 h every 8 h. Three specimens were collected 48 h after the first dose from all patients at the following times, just before the regularly scheduled infusion, at 0.5 h and 2 h after the end of the 0.5 h infusion. Serum gentamicin levels were analysed by fluorescence polarization immunoassay technique with TDxFLx. The standard deviation (SD) of the assay over its working range had been determined at the serum gentamicin concentrations of 0, 2, 4, 8, 12 and 16 microg/ml in quadruplicate. The polynominal equation of gentamicin assay error was found to be SD (microg/ml) = 0.0246-(0.0495C) + (0.00203C(2)). There were differences in the influence of weight with gentamicin assay error on pharmacokinetic parameters of gentamicin using the nonlinear least squares regression analysis but there were no differences on the Bayesian analysis. This polynominal equation can be used to improve the precision of fitting of pharmacokinetic models to optimize the process of model simulation both for population and for individualized pharmacokinetic models. The result would be improved dosage regimens and the better, safer care of patients receiving gentamicin.

The influence of assay error weight on gentamicin pharmacokinetics using the bayesian and nonlinear least square regression analysis in appendicitis patients

The purpose of this study was to determine the influence of weight with gentamicin assay error on the Bayesian and nonlinear least squares regression analysis in 12 Korean appendicitis patients. Gentamicin was administered intravenously over 0.5 h every 8 h. Three specimens were collected at 48 h after the first dose from all patients at the following times, just before regularly scheduled infusion, at 0.5 h and 2 h after the end of 0.5 h infusion. Serum gentamicin levels were analyzed by fluorescence polarization immunoassay technique with TDxFLx. The standard deviation (SD) of the assay over its working range had been determined at the serum gentamicin concentrations of 0, 2, 4, 8, 12, and 16 microg/mL in quadruplicate. The polynominal equation of gentamicin assay error was found to be SD (microg/mL) = 0.0246 - (0.0495C) + (0.00203C2). There were differences in the influence of weight with gentamicin assay error on pharmacokinetic parameters of gentamicin using the nonlinear least squares regression analysis but there were no differences on the Bayesian analysis. This polynominal equation can be used to improve the precision of fitting of pharmacokinetic models to optimize the process of model simulation both for population and for individualized pharmacokinetic models. The result would be improved dosage regimens and better, safer care of patients receiving gentamicin.

Influence of Fluid Therapy on Gentamicin Pharmacokinetics in Colic Horses

The aminoglycoside antibiotic gentamicin is commonly used in equine medicine for the prevention and treatment of Gram-negative and staphylococcal bacteria in surgically treated colic patients. The pharmacokinetics of gentamicin in these patients might be altered by the disease status, and/or under the influence of fluid therapy. The purpose of this study was to investigate the effect of intravenous fluid treatment on gentamicin kinetics in colic patients. Colic patients subjected to laparotomy were given fluid infusions according to clinical status. Following gentamicin administration, blood samples were taken for gentamicin analysis at different time points, and the main pharmacokinetic parameters including Vc, Vss, t(1/2) and MRT were calculated. Horses undergoing fluid therapy showed a significantly different t(1/2), clearance and MRT as compared to non-infused patients. However, taking into account the clinical status of the patients receiving fluid support, the data suggest that endotoxaemia, rather than fluid therapy, influence gentamicin pharmacokinetics following laparotomy.

Chronopharmacokinetic Study of Gentamicin in Dogs

The purpose of this experiment was to determine whether the time of day of single intravenous doses of gentamicin affects the drug's pharmacokinetics in dogs maintained under a 12 h light (08:00 to 20:00 h), 12 h dark (20:00 to 08:00 h) cycle. Using a crossover design, 6 mixed‐breed male dogs received a single dose of 2 mg/kg of gentamicin at 8:00 or 20:00 h. Serial blood samples were collected and pharmacokinetic parameters were calculated following each timed dose. The concentration of the antibiotic was lower following the 08:00 h compared to the 20:00 h administration. When gentamicin was administered at 20:00 h, the initial concentration, mean residence time, and area under the disposition curve were significantly higher (p<0.05) and the apparent volume of distribution of the central compartment, apparent volume of distribution, apparent volume of distribution at steady‐state, and total body clearance (1.73±0.55 at 20:00 h versus 3.31±0.67 L/min/kg at 08:00 h) were significantly lower than for the 08:00 h administration (p<0.05). Our results show that the pharmacokinetics of gentamicin exhibits significant temporal variation when administered to dogs at different times of day.

Pharmacokinetics of gentamicin and apramycin in turkeys roosters and hens in the context of pharmacokinetic–pharmacodynamic relationships

Aminoglycoside antibiotics are widely used in veterinary practice because of their activity against many gram-negative microorganisms, including poultry pathogens. The pharmacokinetics (PK) of gentamicin has been investigated in a number of avian species, including male and female chickens (Pedersoli et al., 1990; Itoh & Okada, 1993; Ramsay & Vulliet, 1993). Investigations in turkeys are very limited (Pedersoli et al., 1989). Like other aminoglycosides, gentamicin is a highly polar drug with poor tissue penetration and low values of volume of distribution. The degree of binding to plasma proteins is low (approximately 10%). The absorption is rapid and the absolute bioavailability after i.m. dose is between 70 and 100%. The PKs of apramycin, an aminocyclitol drug, has been investigated in chickens but only limited data exist for other bird species, including turkeys (Freidlin et al., 1985; Shiha, 1987; Lashev et al., 1992; Lashev, 1998). Apramycin has low values of volume of distribution, but higher than gentamicin, significantly different values of ClB and therefore differences in t1/2b have been reported. The antibiotic is rapidly absorbed after i.m. administration. One approach to optimizing antimicrobial dosage is through PK–pharmacodynamic (PD) relationships (McKellar, 2002). These have received increased emphasis leading to optimization of dosage regimen to improve the outcome and reduce the selection of resistant mutants. There are studies, particularly in human medicine, for aminoglycosides demonstrating that the ratio of 24-h area under the curve to MIC is an important predictor of therapeutic outcomes as well as the ratio of peak serum concentration to MIC (Smith et al., 2001; Scaglione, 2002). Information on PK–PD parameters and their validation is based on clinical experience in humans and the data in domestic animals are limited (Toutain, 2002, 2003). Apramycin is used for treatment of infections of chickens and turkeys. Therefore, comparison of its efficacy with that of gentamicin would be of value. There have been no previous reports on PK–PD integration of data for gentamicin and apramycin in poultry. Therefore, the present investigation was carried out to study the PKs of gentamicin and apramycin after i.v. and i.m. administration in turkeys, roosters and hens and PK–PD parameters AUC0)24 h/ MIC90 and Cmax/MIC90 for pathogenic strains of Escherichia coli and Salmonella spp. isolated from poultry. Gentamicin sulfate (activity 649 IU, provided by Balkanfarma Ltd, Sofia, Bulgaria 3 ) was used as a 3% (w/v) aqueous solution. Apramycin sulfate (substance, activity 618 IU, provided by Balkanfarma Ltd) was used as a 6% (w/v) aqueous solution. The sterile solutions were prepared immediately before use. The doses [in mg/kg body weight (bw) according to the drug activity in IU/ mg] and the injected volumes of gentamicin and apramycin were calculated for each animal. Six healthy roosters and six hens (breed Erebati), 6 months old, weighing from 2.27 to 3.63 kg were used. Six animals were included in experiments with gentamicin and six animals with apramycin. Eleven healthy male turkeys (breed BUT 9), six for gentamicin and five for apramycin, 4 months old, weighing from 5.5 to 8.4 kg were used. All birds were collected from an experimental poultry farm – Stara Zagora, Institute of Animal Husbandry. The birds were allowed a 7-day acclimatization period prior to the study. They were housed in identical conditions (at room temperature, 20 C), according to the requirements of the species. Food (without antibiotics and coccidiostats) and water were supplied ad libitum. All treatments commenced between 07.30 and 8.30 hours. Each treatment was followed by a 30-day washout period in turkeys. A two-way crossover design was used. The turkeys received drugs i.v. in the v. brachialis. For i.m. administration, the J. vet. Pharmacol. Therap. 27, 381–384, 2004. SHORT COMMUNICATION

Pharmacokinetic basis for the use of extended interval dosage regimens of gentamicin in neonates.

To analyse the pharmacokinetic basis for the use of extended-interval dosage regimens of gentamicin in neonates using population pharmacokinetics. The population pharmacokinetics of gentamicin was studied retrospectively in a population of 113 neonates divided into two groups: one for computing the population model (n=97) and another for validation (n=36). A one-compartment pharmacokinetic model and non-linear mixed-effects modelling were used to assess the population pharmacokinetic model. Weight (W) and postnatal age (PA) were the covariates that influenced the pharmacokinetic parameters of gentamicin. The final population model obtained was: distribution volume, V (L)=0.636 x W (kg)0.852; clearance, Cl (L/h)=0.032 x W (kg)1.482+0.0024 x PA (days). The predictive performance of the model in the population validation was adequate for clinical purposes. The optimized population model allowed us to simulate gentamicin serum levels and their variability, in this kind of patient, when extended-interval dosage administration regimens were implemented. According to our pharmacokinetic population model, initial doses of gentamicin of 10 mg/kg, and dosage intervals between 36-48 h, appear to be appropriate to achieve target peak and trough serum levels of 15-20 and <0.5 mg/L, respectively, when extended-interval dosage regimens are implemented in newborns. The half-life of gentamicin in premature babies of very low weight and gestational age <31 weeks is long. Thus, to achieve serum concentrations in the 1-10 mg/L range, the use of dosage regimens of 5 mg/kg at 36-48 h dosage intervals seems suitable.

Gentamicin pharmacokinetics in the chicken inner ear.

Avians have the unique ability to regenerate cochlear hair cells that are lost due to ototoxins or excessive noise. Many methodological techniques are available to damage the hair cells for subsequent scientific study. A recent method utilizes topical application of an ototoxic drug to the round window membrane. The current study examines the pharmacokinetics of gentamicin in the inner ear of chickens following topical application to the round window membrane or a single systemic high dose given intraperitoneally. Chickens were given gentamicin topically or systemically and survived for 1, 4, 12, 24, or 120 h (controls at 4 and 120 h). Serum and perilymph samples were obtained prior to sacrifice and measured for gentamicin levels. Results revealed higher levels of gentamicin in the perilymph of topically treated chickens than systemically treated chickens, with significant amounts of gentamicin still present in both at the latest survival time of 5 days. As expected, systemically treated chickens had much higher levels of gentamicin in the serum than topically treated chickens. Advantages and disadvantages to each method of drug administration are discussed.

Population pharmacokinetics of gentamicin in hospitalized patients receiving once-daily dosing

The purpose of this study was to describe the population pharmacokinetics of gentamicin in a group of 939 adult hospitalized patients receiving once-daily administration of gentamicin and to evaluate the potential influence of patient covariates on gentamicin disposition. Data comprising 1294 serum concentrations from 939 patients, were analyzed using a nonlinear mixed-effect model (NONMEM). The patients had an average age of 55 and an average weight of 70 kg, 431 of the patients were female. The patient covariates including body weight, gender, age, and creatinine clearance (CL CR) were analyzed in a stepwise fashion to identify their potential influences on gentamicin pharmacokinetics. The data were best described with a two-compartment model. NONMEM analyses showed that gentamicin clearance (CL, l/h) was linearly correlated with CL CR with proportionality constant: 0.047 (S.E.: 0.0035) × CL CR (ml/min). Volume of the central compartment ( V 1, l) was linearly related to body weight with proportionality constant: 0.28 (S.E.: 0.021) × body weight (kg). The mean population estimates of CL and V 1 were 4.32 l/h and 19.6 l, respectively. The inter-individual variability in CL and V 1 were 29.6 and 5.8%, respectively. Residual errors were 0.23 mg/l and 23.7%. The mean population values of CL and V 1 of gentamicin dosed once daily are in agreement with those described by others. This analysis indicates that once-daily dosing (7 mg/kg) of gentamicin should achieve satisfactory concentration in patients with normal renal function although serum concentration monitoring is required to confirm the optimal dosing interval in patients with impaired renal function.

Bayesian Pharmacokinetics of Gentamicin in a Haemodialysis Population

Aminoglycosides are commonly used in the haemodialysis population. Standard pharmacokinetic approaches require multiple sampling to describe the parameters of drug distribution and elimination in the intra- and interdialytic periods. To characterise the pharmacokinetics of gentamicin in a haemodialysis population by using Bayesian pharmacokinetic methods and only two plasma concentrations. Prospective case series of 13 adult (aged 36-70 years) haemodialysis patients (Fresenius F80 dialysers were used) receiving gentamicin. Patients with suspected or confirmed Gram-negative infections were given gentamicin. At 48 hours after receiving the dose (at the next haemodialysis session), patients provided two blood samples, one immediately before the dialysis session and another 1 hour after haemodialysis. Data on dosage, timing and plasma concentrations for all subjects were analysed with PASTRX version 10.6 and Bayesian pharmacokinetic analysis. Volume of distribution (Vd), interdialytic elimination rate constant (k(inter)), interdialytic elimination half-life (t1/2beta, inter)) and interdialytic clearance (CL(inter)) were determined from a single predialysis plasma concentration. Elimination rate constant (k(dial)), elimination half-life (t1/2beta, dial)) and clearance (CL(dial)) during 3.5-4 hours of dialysis were also determined from the pre- and post-plasma concentrations. Pharmacokinetic parameters (mean +/- SD) were: Vd 0.288 +/- 0.002 L/kg, k(inter) 0.015 +/- 0.004h(-1), t1/2beta, inter) 48 +/- 11h, CL(inter) 5.9 +/- 2.4 mL/min, k(dial) 0.25 +/- 0.05 h(-1), t1/2beta, dial) 3.0 +/- 1.0h and CL(dial) 91 +/- 24 mL/min. The rate of elimination of gentamicin was 17-fold greater (95% CI 13.7-20.7) on haemodialysis with a Fresenius F80 than off haemodialysis. All of the pharmacokinetic parameters of interest were determined using Bayesian pharmacokinetic procedures and only two plasma gentamicin concentrations.

The effect of postnatal age on gentamicin pharmacokinetics in neonates.

To determine if gentamicin serum concentrations obtained from newborns on day 2 of life versus days 3-4 yield significantly different pharmacokinetic parameter values. Retrospective chart review. Neonatal intensive care unit. Two hundred and sixty-seven infants who had peak and trough gentamicin serum concentrations determined on days 2, 3, or 4 of life. Determination of peak and trough serum gentamicin concentrations on days 2, 3, or 4 of life. The elimination rate constant, serum half-life, volume of distribution, and clearance of gentamicin were calculated using a one-compartment pharmacokinetic model. Gestational age, birthweight, gentamicin dosage, peak and trough gentamicin concentrations, and hours after birth at which serum concentrations were drawn were recorded for all infants. Infants were stratified into three groups based on gestational age: 28 weeks or younger, older than 28 weeks but younger than 37 weeks, and 37 weeks or older. Birthweight and calculated pharmacokinetic parameters were compared by 2-tailed Student t test to determine if significant differences existed between pharmacokinetics parameters determined on day 2 of life versus days 3 or 4 within each of the gestational age groups. These analyses revealed only one significant difference between parameters assessed on day 2 versus days 3 or 4: at day 2, the mean trough concentration of gentamicin in infants of gestational age between 28 and 37 weeks was 1.63 +/- 0.44 mg/L, whereas at days 3 or 4, the same parameter for patients of the same gestational age was 1.4 +/- 0.48 mg/L (p=0.005). With one exception--elevated trough concentrations in infants in the gestational age group between 28 and 37 weeks--pharmacokinetic parameters calculated using gentamicin serum concentrations determined on day 2 of life are not significantly different from those derived from gentamicin serum concentrations determined on days 3 or 4. This suggests that gentamicin serum concentrations and subsequent dosage adjustments can be determined on day 2 of life.

Population pharmacokinetics of intramuscular gentamicin administered to young infants with suspected severe sepsis in Kenya.

To determine the population pharmacokinetics of intramuscular (i.m.) gentamicin in African infants with suspected severe sepsis. Samples were withdrawn 1 h after a single i.m. injection of 8 mg x kg(-1) gentamicin and the next morning prior to any further dosing. Concentration-time data were analysed with the population pharmacokinetic package NONMEM. Data were fitted using a one-compartment model with a log-normal model for interindividual variability and an additive residual error model. The influence of a range of clinical characteristics was tested on the pharmacokinetics of intramuscular gentamicin and the effect of incorporating interindividual variability on bioavailability was examined. The data set comprised 107 patients and 203 concentrations. Peak concentrations ranged from 3.0 mg x L(-1) to 19.8 mg x L(-1) (median 10.6 mg x L(-1)) and 'next day' samples from 0.3 mg x L(-1) to 6.2 mg x L(-1). The best models were clearance/bioavailability (CL) (L x h(-1)) = 0.0913 x weight (kg) x (age (days) + 1)/11)0.130 and volume of distribution/bioavailability (V) = 2.02 x (1 + 0.277 x (weight -3)). Therefore, an infant with the median weight of 3 kg and age 10 days would have a predicted CL of 0.274 L x h(-1) and V of 2.02 L. Interindividual variability in CL was 40% and in V was 42%. This model required a term for covariance between CL and V. When variability in bioavailability was introduced as an alternative model, interindividual variability in CL was 22%, in V 18% and in relative bioavailability 36%. Intramuscular administration of 8 mg x kg(-1) gentamicin daily to infants gives mean 1 h peak concentration of 10.6 mg x L(-1) and a trough concentration of less than 2 mg x L(-1). Wide variability in the peak concentration may reflect variable absorption rate or bioavailability.

Comparative disposition kinetics and plasma protein binding of gentamicin sulphate in three juvenile animal species.

The pharmacokinetics of gentamicin was studied in lambs, calves and foals, respectively after single intravenous (i.v.) injections of 5 mg kg(-1) body weight. The plasma concentration-time curves of gentamicin sulphate were best fitted to follow a two-compartment open model in calves and foals and a three-compartment open model in lambs. Gentamicin showed high plasma level at 5 min post-injection. Then its concentration decreased gradually until its minimum detectable level at 10 and 12 h post-injection in foals and calves, respectively, was reached. In contrast, the plasma concentrations were much higher in lambs and persisted up to 48 h from the onset of injection. Values of pharmacokinetic parameters for gentamicin sulphate in different animals after i.v. injections were calculated. Pharmacokinetic data in lambs demonstrated a triphasic decline in plasma gentamicin concentration with slow terminal elimination phase (washout phase) with (t(1/2y)) of 7.7 h. Gentamicin showed a small volume of distribution Vd(ss) (80.3 ml kg(-1)) in lambs indicating that the drug is slightly distributed in extra-vascular tissues. The overall rate of total body clearance ClB in lambs was (0.46 ml kg(-1)) slower than in calves (1.5 ml kg(-1)) and foals (2.7 ml kg(-1)). In vitro protein binding per cent of gentamicin sulphate in plasma were 16.80, 11.03 and 7.98% in lambs, calves and foals. The results of this study emphasize the importance of determining the pharmacokinetics of gentamicin in each species of young animals separately.

Gentamicin pharmacokinetics during slow daily home hemodialysis

Gentamicin is commonly used in hemodialysis patients. Gentamicin pharmacokinetics during traditional hemodialysis have been described. Slow daily home (SDH) hemodialysis (7 to 9 hours a day/6 days a week) use is increasing due to benefits observed with increased hemodialysis. We determined gentamicin pharmacokinetics for SDH hemodialysis patients. Eight patients (four male and four female) received a single intravenous dose of 0.6 mg/kg gentamicin post-hemodialysis. Blood samples were collected at 5, 10, 15, 30, and 60 minutes after dose. The next day patients underwent a typical SDH hemodialysis (high-flux F50NR dialyzer) session. Blood samples were taken at 0, 5, 15, 60, 120, 240, 360, 480 minutes during and 15, 30 and 60 minutes post-hemodialysis. Baseline and 24-hour urine samples were collected. Pharmacokinetic parameters were calculated assuming a one-compartment model. Patients were 42.5 +/- 13.1 years old (mean +/- SD). Inter-, intra-, and post-hemodialysis collection periods were 17.0 +/- 2.1 hours, 8.1 +/- 0.4 hours, and 1.1 +/- 0.1 hours, respectively. Intra-, and interdialytic gentamicin half-lives were different (intradialytic, 3.7 +/- 0.8 hours; interdialytic, 20.4 +/- 4.7 hours; P < 0.0001). Hemodialysis clearance accounted for 70.5% gentamicin total clearance. Renal clearance correlated with glomerular filtration rate (GFR) (renal clearance=1.2 GFR; r2=0.98; P < 0.001). Mean peak and trough of hemodialysis concentrations were 1.8 +/- 0.6 microg/mL and 0.5 +/- 0.2 microg/mL, respectively. Post-hemodialysis rebound was 3.1 +/- 8.8% at 1 hour. Pharmacokinetic model predicts 2.0 to 2.5 mg/kg dose gentamicin post-hemodialysis would provide peak (1 hour post-dose) and trough (end of SDH hemodialysis session) concentrations of 6.0 to 7.5 microg/mL and 0.7 to 0.8 microg/mL, respectively. This would provide adequate coverage for most gram-negative organisms in SDH hemodialysis patients.