Steady-state Peak Concentrations Research Articles

A Review of the Pharmacokinetics of Abacavir

Abacavir is a carbocyclic 2'-deoxyguanosine nucleoside reverse transcriptase inhibitor that is used as either a 600-mg once-daily or 300-mg twice-daily regimen exclusively in the treatment of HIV infection. Abacavir is rapidly absorbed after oral administration, with peak concentrations occurring 0.63-1 hour after dosing. The absolute bioavailability of abacavir is approximately 83%. Abacavir pharmacokinetics are linear and dose-proportional over the range of 300-1200 mg/day. To date, one study has assessed the steady-state pharmacokinetics of abacavir following a 600-mg once-daily regimen, and reported a geometric mean steady-state abacavir peak concentration of 3.85 microg/mL. Although this concentration is higher than the steady-state abacavir peak concentration reported following a 300-mg twice-daily regimen (0.88-3.19 microg/mL, depending on the study), the geometric mean steady-state abacavir exposure over 24 hours was similar following these regimens. Coadministration with food has no significant effect on abacavir exposure; therefore, abacavir may be administered with or without food.The apparent volume of distribution of abacavir after intravenous administration is approximately 0.86 +/- 0.15 L/kg, suggesting that abacavir is distributed to extravascular spaces. Binding to plasma proteins is about 50% and is independent of the plasma abacavir concentration. Abacavir is extensively metabolized by the liver; less than 2% is excreted as unchanged drug in the urine. Abacavir is primarily metabolized via two pathways, uridine diphosphate glucuronyltransferase and alcohol dehydrogenase, resulting in the inactive glucuronide metabolite (361W94, ~36% of the dose recovered in the urine) and the inactive carboxylate metabolite (2269W93, approximately 30% of the dose recovered in the urine). The remaining 15% of abacavir equivalents found in the urine are minor metabolites, each less than 2% of the total dose. Faecal elimination accounts for about 16% of the dose. The terminal elimination half-life of abacavir is approximately 1.5 hours. The antiviral effect of abacavir is due to its intracellular anabolite, carbovir-triphosphate (CBV-TP). When assessed by validated high-performance liquid chromatography electrospray ionization tandem mass spectrometry, CBV-TP has been shown to have a long elimination half-life (>20 hours), supporting once-daily dosing. The mean CBV-TP trough concentrations do not differ following abacavir 600-mg once-daily and 300-mg twice-daily regimens. Limited data are available for abacavir in subjects with renal dysfunction or hepatic impairment. Abacavir pharmacokinetics in HIV-infected subjects with end-stage renal disease were found to be no different from those observed in healthy adults; this finding was consistent with the kidney being a minor route of abacavir elimination. A study of abacavir pharmacokinetics in hepatically impaired adults (Child-Pugh score of 5-6) showed that the abacavir area under the plasma concentration-time curve and elimination half-life were 89% and 58% greater, respectively, suggesting that the daily dose of abacavir should be reduced in patients with mild hepatic impairment (Child-Pugh score of 5-6). Abacavir pharmacokinetics have not been studied in patients with higher Child-Pugh scores. Abacavir is not significantly metabolized by cytochrome P450 (CYP) enzymes, nor does it inhibit these enzymes. Therefore, clinically significant drug interactions between abacavir and drugs metabolized by CYP enzymes are unlikely. The potential for drug interactions is no different when abacavir is used as a once-daily regimen versus a twice-daily regimen. No clinically significant drug interactions have been observed between recommended doses of abacavir and lamivudine, zidovudine, alcohol (ethanol) or methadone.

Glucosamine oral bioavailability and plasma pharmacokinetics after increasing doses of crystalline glucosamine sulfate in man

Pharmacokinetic data on glucosamine are scant, limiting the understanding of glucosamine sulfate mechanism of action in support of its treatment effects in osteoarthritis. This study investigated the oral pharmacokinetics and dose-proportionality of glucosamine after administration of the patented crystalline glucosamine sulfate in man. Twelve healthy volunteers received three consecutive once-daily oral administrations of glucosamine sulfate soluble powder at the doses of 750, 1,500, and 3,000 mg, in an open, randomised, cross-over fashion. Glucosamine was determined in plasma collected up to 48 h after the last dose by a validated Liquid Chromatography method with Mass Spectrometry detection. Pharmacokinetic parameters were calculated at steady state. Endogenous plasma levels of glucosamine were detected (10.4-204 ng/ml, with low intra-subject variability). Glucosamine was rapidly absorbed after oral administration and its pharmacokinetics were linear in the dose range 750-1,500 mg, but not at 3,000 mg, where the plasma concentration-time profiles were less than expected based on dose-proportionality. Plasma levels increased over 30-folds from baseline and peaked at about 10 microM with the standard 1,500 mg once-daily dosage. Glucosamine distributed to extravascular compartments and its plasma concentrations were still above baseline up to the last collection time. Glucosamine elimination half-life was only tentatively estimated to average 15 h. Glucosamine is bioavailable after oral administration of crystalline glucosamine sulfate, persists in circulation, and its pharmacokinetics support once-daily dosage. Steady state peak concentrations at the therapeutic dose of 1,500 mg were in line with those found to be effective in selected in vitro mechanistic studies. This is the only glucosamine formulation for which pharmacokinetic, efficacy and safety data are now available.

Steady-state plasma and intrapulmonary concentrations of piperacillin/tazobactam 4 g/0.5 g administered to critically ill patients with severe nosocomial pneumonia.

To determine the steady-state plasma and epithelial lining fluid (ELF) concentrations of piperacillin/tazobactam (P/T) administered to critically ill patients with severe bacterial pneumonia. Prospective, open-label study. An intensive care unit and research ward in a university hospital. Ten adult patients with severe nosocomial bacterial pneumonia on mechanical ventilation. All subjects received a 30-min intravenous infusion of P/T 4 g/0.5 g every 8 h. The steady-state plasma and ELF concentrations of P/T were determined by high-performance liquid chromatography. The mean+/-SD steady-state plasma trough, peak, and intermediate concentrations were 8.5+/-4.6 microg/ml, 55.9+/-21.6 microg/ml, and 24.0+/-13.8 microg/ml for piperacillin, and 2.1+/-1.0 microg/ml, 4.8+/-2.1 microg/ml, and 2.4+/-1.2 microg/ml for tazobactam, respectively. The mean+/-SD steady-state intermediate ELF concentrations were 13.6+/-9.4 microg/ml for piperacillin and 2.1+/-1.1 microg/ml for tazobactam, respectively, showing a mean percentage penetration of piperacillin and tazobactam into ELF of 56.8% and 91.3 %, respectively, with a P/T ratio of 6.5:1. Our results show that during the treatment of severe nosocomial pneumonia, a regimen of P/T 4 g/0.5 g every 8 h might provide insufficient concentrations into lung tissue to exceed the MIC of many causative pathogens. This suggests that higher doses of P/T should be administered in order to maximize the antibiotic concentration at the site of infection, or that a second antimicrobial agent should be used in association.

Pharmacokinetics and tolerability of long-acting risperidone in schizophrenia

The pharmacokinetics and tolerability of long-acting risperidone (Risperdal Consta™) were evaluated in a multicenter, prospective, open-label, 15-week study of 86 patients with schizophrenia. Subjects stabilized on 2, 4 or 6 mg of oral risperidone once daily for at least 4 weeks were assigned to receive i.m. injections of 25, 50 or 75 mg of risperidone, respectively, every 2 weeks for 10 weeks. The 90% confidence intervals for the i.m./oral ratios of the mean steady-state plasma-AUC, corrected for dosing interval, and of the average plasma concentration of the active moiety (risperidone plus 9-hydroxyrisperidone) were within the range of 80–125%, indicating bioequivalence of the i.m. and oral formulations. However, mean steady-state peak concentrations of the active moiety were 25–32% lower with i.m. than oral dosing ( P<0.05) and fluctuations in plasma active-moiety levels were 32–42% lower with the i.m. than oral regimen. Symptoms of schizophrenia continued to improve after switching from oral to i.m. dosing. Long-acting risperidone was well tolerated locally and systematically. Although overall bioequivalence of the two formulations was established, the differences in pharmacokinetic profiles between the two formulations indicate potential benefits for long-acting risperidone.

Clinical pharmacokinetics of everolimus.

Everolimus is an immunosuppressive macrolide bearing a stable 2-hydroxyethyl chain substitution at position 40 on the sirolimus (rapamycin) structure. Everolimus, which has greater polarity than sirolimus, was developed in an attempt to improve the pharmacokinetic characteristics of sirolimus, particularly to increase its oral bioavailability. Everolimus has a mechanism of action similar to that of sirolimus. It blocks growth-driven transduction signals in the T-cell response to alloantigen and thus acts at a later stage than the calcineurin inhibitors ciclosporin and tacrolimus. Everolimus and ciclosporin show synergism in immunosuppression both in vitro and in vivo and therefore the drugs are intended to be given in combination after solid organ transplantation. The synergistic effect allows a dosage reduction that decreases adverse effects. For the quantification of the pharmacokinetics of everolimus, nine different assays using high performance liquid chromatography coupled to an electrospray mass spectrometer, and one enzyme-linked immunosorbent assay, have been developed. Oral everolimus is absorbed rapidly, and reaches peak concentration after 1.3-1.8 hours. Steady state is reached within 7 days, and steady-state peak and trough concentrations, and area under the concentration-time curve (AUC), are proportional to dosage. In adults, everolimus pharmacokinetic characteristics do not differ according to age, weight or sex, but bodyweight-adjusted dosages are necessary in children. The interindividual pharmacokinetic variability of everolimus can be explained by different activities of the drug efflux pump P-glycoprotein and of metabolism by cytochrome P450 (CYP) 3A4, 3A5 and 2C8. The critical role of the CYP3A4 system for everolimus biotransformation leads to drug-drug interactions with other drugs metabolised by this cytochrome system. In patients with hepatic impairment, the apparent clearance of everolimus is significantly lower than in healthy volunteers, and therefore the dosage of everolimus should be reduced by half in these patients. The advantage of everolimus seems to be its lower nephrotoxicity in comparison with the standard immunosuppressants ciclosporin and tacrolimus. Observed adverse effects with everolimus include hypertriglyceridaemia, hypercholesterolaemia, opportunistic infections, thrombocytopenia and leucocytopenia. Because of the variable oral bioavailability and narrow therapeutic index of everolimus, blood concentration monitoring seems to be important. The excellent correlation between steady-state trough concentration and AUC makes the former a simple and reliable index for monitoring everolimus exposure. The target trough concentration of everolimus should range between 3 and 15 microg/L in combination therapy with ciclosporin (trough concentration 100-300 microg/L) and prednisone.

Vancomycin dosing in morbidly obese patients.

Vancomycin hydrochloride dosing requirements in morbidly obese patients with normal renal function were computed to determine the dose of vancomycin necessary to achieve target steady-state peak and trough concentrations and compared with a normal weight population. Morbidly obese patients [total body weight (TBW) 165 kg, ideal body weight (IBW) 63 kg] required 31.2 mg x kg(-1) x d(-1) TBW or 81.9 mg x kg(-1) x d(-1) IBW to achieve the target concentrations. Normal weight patients (TBW 68.6 kg) required 27.8 mg x kg(-1) x d(-1) to achieve the same concentrations. Because of altered kinetic parameters in the morbidly obese patients (obese: t1/2 = 3.3 h, V = 52 L, CL = 197 ml x min(-1); normal: t1/2=7.2 h, V=46 L, CL=77 ml x min(-1), 20 of 24 patients required q8h dosing (1938 mg q8h) compared with q12h dosing (954 mg q12h) in all normal weight patients in order to avoid trough concentrations that were too low for prolonged periods. There was a good correlation between TBW and CL, but only fair correlation between TBW and V. Doses required to achieve desired vancomycin concentrations are similar in morbidly obese and normal weight patients when TBW is used as a dosing weight for the obese (approximately 30 mg x kg(-1) x d(-1)). Shorter dosage intervals may be needed when dosing morbidly obese patients so that steady-state trough concentrations remain above 5 microg x ml(-1) in this population. Because of the large amount of variation in required doses, vancomycin serum concentrations should be obtained in morbidly obese patients to ensure that adequate doses are being administered. Dosage requirements for morbidly obese patients with renal dysfunction require further study.

Pharmacokinetics of once-daily dosing of gentamicin in neonates

In a prospective, randomized trial of once-daily versus twice-daily intravenous or intramuscular dosing with gentamicin, 11 neonates received 5.0 mg/kg once daily and 15 received 2.5 mg/kg twice daily for 2 or 3 days. The once-daily intravenous dosing group and the twice-daily intravenous or intramuscular dosing group, respectively, had mean steady-state gentamicin peak concentrations of 10.7 versus 6.6 μg/ml ( p < 0.05), 6-hour postdosing concentrations of 4.7 versus 2.8 μg/ml ( p < 0.05), trough concentrations of 1.7 versus 1.7 μg/ml, elimination half-life of 8.8 versus 5.4 hours ( p < 0.05), and volume of distribution at steady state of 0.57 versus 0.46 L/kg. No nephrotoxic effects were identified in any group. Once-daily gentamicin therapy with 5.0 mg/kg in neonates achieves peak serum levels that are more suitable for optimal bacterial killing than those which traditional regimens achieve. Similar trough levels suggest that even larger doses and longer dosing intervals may be ideal in term neonates. (J Pediatr 1997;131:76-80)

Falsely elevated serum vancomycin concentrations in hemodialysis patients

Fluorescence polarization immunoassay (FPIA) is the most widely used clinical vancomycin assay in the United States. Questions exist regarding the accuracy of this polyclonal assay in patients with end-stage renal disease (ESRD). While several studies have reported discrepancies in vancomycin serum concentrations determined by FPIA compared with other vancomycin assays, no study has investigated the accuracy of vancomycin serum concentrations determined by FPIA in patients with ESRD undergoing maintenance hemodialysis. Therefore, we compared the assay performance of FPIA and enzyme multiplied immunoassay technique (EMIT) in six subjects with ESRD receiving high-efficiency hemodialysis. Subjects underwent 6 consecutive weeks of hemodialysis treatment with a cellulose acetate dialyzer (CA210) and received 1 g vancomycin intravenously once weekly during the last hour of dialysis. Vancomycin serum concentrations were determined by both EMIT and FPIA methodologies. From the serum concentration results of both assays, vancomycin dosing recommendations were calculated to achieve a desired steady-state peak concentration of 35 mg/L and trough concentration of 10 mg/L. Overall, vancomycin serum concentrations reported by FPIA were significantly higher than those reported by EMIT. The mean difference between assays in the peak serum concentrations at weeks 1, 4, and 6 was 7.5, 11.5, and 11.2 mg/L, respectively. The mean difference in trough serum concentrations at weeks 1, 4, and 6 was 4.2, 6.2, and 5.2 mg/L, respectively. The FPIA overestimation of the EMIT values (calculated as FPIA — EMIT) varied widely among study subjects with a range of 0.0 mg/L to 27.0 mg/L for peak serum concentrations and 0.0 mg/L to 12.8 mg/L for trough serum concentrations. The mean doses calculated based on FPIA results were significantly lower than the EMIT-derived doses. No significant difference was observed in the calculated dosing intervals. These results demonstrate that FPIA significantly overestimates vancomycin serum concentrations compared with EMIT in patients with ESRD undergoing high-efficiency hemodialysis. The overestimation by FPIA may result in significantly different vancomycin dosing recommendations, leading to underdosing and the potential for therapeutic failures. Due to the unpredictability of the overestimation by FPIA, we were unable to formulate vancomycin dosing guidelines for institutions that use FPIA. Therefore, we recommend that the EMIT vancomycin assay be used in patients with ESRD to ensure appropriate dosing.

CYCLOSPORINE PHARMACOKINETICS AND VARIABILITY FROM A MICROEMULSION FORMULATION—A MULTICENTER INVESTIGATION IN KIDNEY TRANSPLANT PATIENTS

The steady-state pharmacokinetics and tolerability of a microemulsion formulation of cyclosporine (Sandimmune Neoral) were compared with the commercial formulation (Sandimmune) in 55 clinically stable renal allograft recipients. In study period I (2 weeks' duration), patients entered the study on a stable, individualized twice-daily dosage regimen of the commercial formulation. In period II (2 weeks), they were changed over to the microemulsion formulation at the same dose as at study entry. In period III (2 weeks), dose titration was subsequently allowed if necessary to provide comparable steady-state trough concentrations as at study entry. The commercial formulation was reinstituted during period IV (2 weeks). Safety and tolerability were assessed at weekly clinic visits, and the steady-state pharmacokinetics of cyclosporine in whole blood were characterized at the end of each study period. A milligram-to-milligram dose conversion was adequate when making the initial change between formulations in order to maintain steady-state trough concentrations in the target therapeutic range. Concomitant with this conversion, the steady-state peak concentration and area under the curve increased on average by 59% and 30%, respectively, due to absorption-related differences between the formulations. These increases were not associated with an increase in adverse experiences or changes in blood pressure or clinical laboratory parameters over the first four weeks after the change-over. Trough concentrations were more stable and were more strongly correlated with systemic exposure (area under the curve) during treatment with the microemulsion formulation. Intraindividual coefficients of variation in steady-state peak concentration, time to attain the peak, area under the curve, and percent peak-trough fluctuation ranged from 18% to 74% from the commercial formulation. Variability from the microemulsion formulation was significantly less, ranging from 10% to 22%.

Bayesian forecasting of serum vancomycin concentrations with non-steady-state sampling strategies.

The application of three non-steady-state sampling strategies and the fitting of either three or five pharmacokinetic parameter estimates by a two-compartment Bayesian forecasting program was evaluated retrospectively in 27 adult patients with stable renal function. Sampling strategies included a single midpoint concentration, a set of peak and trough concentrations, and three serial vancomycin concentrations. The most precise and least-bias predictions of steady-state peak vancomycin concentrations were observed by using population-based parameter estimates [mean prediction error (ME) = -0.40 and mean absolute error = 5.77]. The addition of non-steady-state feedback concentration(s) did not provide additional information for predictions of future steady-state peak concentrations. The least-bias prediction of steady-state trough vancomycin concentrations was seen when a single midpoint non-steady-state concentration was used (ME = 0.92 and -0.17 for five and three fitted parameter estimates, respectively). The MEs of serial and peak and trough feedback strategies were similar in magnitude to those obtained using population parameters, but in opposite directions (underprediction vs. overprediction, respectively). The fitting of only three parameters produced results similar to those using five parameters. The results from this study confirm our previous evaluation that non-steady-state concentrations provide very minimal information to Bayesian forecasting of future steady-state concentrations.

Aminoglycoside Pharmacokinetics in Patients with AIDS

Objective To determine the pharmacokinetic parameters of aminoglycosides in patients with AIDS and to compare these parameters with those of a control group of patients not infected with HIV. Design Retrospective, chart-review study. Patients Nineteen AIDS patients and 19 non-HIV-infected patients (control) were identified through a review of pharmacokinetic monitoring cards. Methods Patients’ charts were reviewed for demographic data, aminoglycoside (gentamicin, tobramycin, and amikacin) dosing schedule, and steady-state peak and trough concentrations. Pharmacokinetic parameters were calculated using a one-compartment open model. Results Significant differences were found in the elimination rate constant (Ke) between the two groups (mean ± SD, 0.20 ± 0.084/h in the AIDS group and 0.26 ± 0.095/h in the control group). Half-life was significantly longer in the AIDS group versus controls (4.3 ± 2.5 and 2.99 ± 1.15/h, respectively). The volume of distribution (Vd), expressed in terms of liters and liters per kilogram total body weight (TBW), was significantly larger in the AIDS group than in the control group (28.3 ± 14 L [0.43 ± 0.21 L/kg TBW] and 19.2 ± 4.95 L [0.28 ± 0.07 L/kg TBW], respectively). Clearance in terms of liters per hour and Vd in terms of L/kg ideal body weight were not significantly different between the two groups. Albumin was similar in both groups (34 ± 7 g/L, control group; 28 ± 7 g/L, AIDS group). Conclusions Aminoglycoside pharmacokinetics were found to be altered in the patients with AIDS. When calculating an initial dose of an aminoglycoside in AIDS patients, use of estimated normal population parameters may result in lower peaks in these individuals. Pharmacokinetic parameters may need to be adjusted in AIDS patients because of their large Vd and slower Ke.

Gentamicin Pharmacokinetics in Postpartum Women with Endomyometritis

The pharmacokinetics of gentamicin in postpartum women with endomyometritis were characterized and models for predicting patient pharmacokinetic parameters were developed using multiple regression analysis. Fifty-one women 13-34 years of age received gentamicin in combination with either ampicillin or clindamycin to treat endomyometritis. Forty-three women delivered by cesarean section and 8 women had vaginal deliveries. Gentamicin serum concentrations were determined at steady-state to compute the elimination rate constant (Kc), half-life (t1/2), apparent volume of distribution (Vd), and total body clearance (Cl). Gentamicin dosages were individualized using a one-compartment intermittent infusion model to achieve steady-state peak and trough concentrations of 6.5 and less than 2 micrograms/mL, respectively. The mean gentamicin t1/2 was 2.8 +/- 0.9 h; the mean apparent Vd was 21 +/- 8 L; and the mean total body Cl was 89.5 +/- 31.7 mL/min. Multiple regression analysis revealed that total body weight (TBW) was the best predictor for the apparent Vd, described by the equation Vd = 0.146 TBW + 8.153 (r = 0.56, p = 0.00005). Total body weight and creatinine clearance (Clcr) were included as predictors for total body Cl, described by the equation Cl = 0.264 TBW + 0.337 Clcr + 3.416 (r = 0.68, p = 0.00005). Age and serum creatinine (SCr) were included in the models for the Ke, described by the equation Ke = -3.770 x 10(-3) age -0.115 SCr + 0.449 (r = 0.42, p less than 0.004). Additional patient factors need to be identified to explain the variance in these pharmacokinetic parameters.

AN ASSESSMENT OF POPULATION-BASED AND BAYESIAN METHODS TO INDIVIDUALIZE DIGOXIN DOSES SHORTLY AFTER THE START OF THERAPY FOR ATRIAL FIBRILLATION

The accuracy of population-based methods and of Bayesian analysis to predict individual digoxin pharmacokinetic variables have been evaluated by their ability to predict a measured peak and trough serum digoxin concentration. We studied 13 digitalized patients (three women) whose mean (range) age and weight was 65.8 (60-78) years and 76.6 (68-101.6) kg and who had stable renal function. The population-based methods (using a clearance of 48.87 + 0.87 x creatinine clearance in ml/h/kg and volume of distribution, in litres, of either 7.3 x weight (kg) or 269 + 3.12 x creatinine clearance) were more than adequate for clinical purposes. The mean prediction errors of a measured steady-state peak concentration from these two population methods were -0.074 and 0.013 microgram/l respectively, whilst those of a measured trough concentration were -0.058 and 0.005 microgram/l. Bayesian analysis, using a sample drawn 11 h after the dose on day five of therapy, gave overall the least biased and most precise of the revised estimates. The mean prediction errors of peak and trough values using this sample were 0.069 and -0.005 microgram/l respectively. As expected, the closer the sample was drawn to the time of the trough concentration the more precise were the Bayesian-derived predictions. The value of the Bayesian technique to individualize digoxin doses could not be validated because it was not possible to distinguish between this and the population methods.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of non-kinetic and kinetic approaches to individualization of gentamicin dosage

A prospective study was carried out in 40 acutely ill patients to compare the non-kinetic and kinetic approaches to individualization of the dosage regimen of gentamicin. The patients were divided into two equal groups. For the non-kinetic group, the doses were derived from the physician's personal experience, on a mg/kg basis, and by use of nomograms. The total daily dose ranged from 1.43 to 4.5 mg/kg. Based on serum concentration measurements, the dosage regimen for individual patient was calculated by Sawchuk-Zaske's method. The calculated doses were compared to the prescribed doses in each patient. Of the patients on empirically prescribed doses 65% received 36% more drug than the calculated dose and 20% received 36% less than the calculated dose. The calculated dosing intervals were greater than the recommended intervals in 60% of the patients. The gentamicin trough concentration was greater than 2 micrograms/ml in 70% of the patients. There was a significant tendency to overdosage of the patients. For the kinetic group, following administration of the calculated dose, the steady-state peak and trough concentrations in each patient were measured. The correlation of measured to predicted steady-state serum concentrations was excellent (r = 0.9968, p less than 0.05). About 85% of the served trough concentrations and 90% of the peak values fell within the therapeutic range. The mean of the prediction error (ME), mean absolute error (MAE), mean squared error (MSE), and root mean squared error (RMSE) of the trough and peak concentrations were calculated. The 95% confidence interval of the ME for the trough and peak concentrations included zero, which shows that the prediction was not significantly biased.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of Six Gentamicin Nomograms Using a Bayesian Parameter Estimation Program

A new set of guidelines for the administration of gentamicin was developed by estimating steady-state peak and trough gentamicin concentrations for simulated patients with known weights and creatinine clearances. The most appropriate doses to achieve target peak concentrations of 5-10 mg/L and troughs of less than 2 mg/L were then tabulated. The performance of these new guidelines was assessed using data collected from 60 patients who had received gentamicin and had at least two serum concentration measurements. Individual estimates of clearance and volume of distribution were obtained using a Bayesian parameter estimation program and these estimates were used to predict the steady-state peak and trough concentrations that would arise from the new guidelines and five other previously published nomograms (Mawer, Chan, Hull-Sarubbi, Rule of Eight, and Dettli). The new guidelines, the Dettli nomogram, and the Hull-Sarubbi table achieved similar percentages (52-57%) of patients within the target ranges (5-10 mg/L for peak and less than 2 mg/L for trough), although 28% of patients had predicted peak concentrations below 5 mg/L with the new method compared to 15% with the other two. Only 38% of patients were within both ranges when the Mawer nomogram and the Rule of Eight methods were used. Since a large percentage of patients would have achieved concentrations outside of the target ranges no matter which nomogram was used, serum concentration monitoring is still recommended to confirm dose requirements.

Evaluation of a two-compartment Bayesian forecasting program for predicting vancomycin concentrations.

The application of a two-compartment Bayesian forecasting program for vancomycin was tested retrospectively in 45 adult patients with stable renal function. Serial blood samples from 25 of these patients were used to determine population-based parameter estimates. The predictive performance of the Bayesian program was assessed by using both non-steady-state and steady-state vancomycin concentrations as feedback information. Overall, the program tended to underpredict peak and trough steady-state vancomycin serum concentrations. A larger mean prediction error (ME) was seen when non-steady-state feedback serum concentrations were used compared with using population-based parameter estimates (no feedback). In contrast, a marked improvement in ME (peaks: -1.03 versus -2.61; troughs: -1.60 versus -2.07) was seen when steady-state feedback serum concentrations were used compared with no feedback data. Precision improved when either feedback serum concentrations were used to predict steady-state peak and trough vancomycin concentrations. The results from this clinical evaluation demonstrate that the initial pharmacokinetic parameter estimates for a two-compartment Bayesian model provided accurate prediction of steady-state vancomycin concentrations. Prediction bias and precision were improved when steady-state vancomycin concentrations were used to determine individualized pharmacokinetic parameters.

An approach to forecast aminoglycoside-related nephrotoxicity from routinely collected clinical data.

Routinely collected clinical data on 104 critically ill patients who had received an aminoglycoside (gentamicin or tobramycin) were evaluated using a proposed approach to forecast aminoglycoside-related nephrotoxicity. Observed steady-state peak and trough concentrations were greater than the respective predicted values when one-compartment model was assumed. This difference was particularly eminent for trough concentrations. The bias (difference between predicted and observed values) for trough concentrations was analyzed assuming tissue accumulation by an extended least-squares method to estimate population pharmacokinetics. The mean values for terminal half-life of gentamicin and tobramycin in patients who did not develop nephrotoxicity were estimated to be approximately 50 and 116 h, respectively. By using these values, the bias of trough concentration was found to be greater in patients who developed nephrotoxicity during or within 60 days after the therapy than in those who did not. Our results suggest that assessing the bias of steady-state trough concentrations of aminoglycosides can provide a useful index to forecast an aminoglycoside-induced nephrotoxicity.

The influence of food on the bioavailability of a slow release theophylline preparation.

Food-induced changes in the absorption of Theostat 300, a controlled release formulation of theophylline, have been studied in healthy volunteers. This open, randomised, 3-way, single-dose study involved 12 volunteers who received the drug either while fasting, or with a standardised low-fat (10g), or high-fat (60g) breakfast. Each subject was studied over a 3-week period, with 3 separate days of oral treatment and a 7-day washout period between treatments. The results showed no differences in AUC0-24 and tmax values between the 3 kinds of diet. The only differences observed concerned absorption. Food intake increased Cmax values by 20%. The steady-state peak concentration obtained by means of simulated plasma levels was not influenced by food intake. This slight food-drug interaction of Theostat 300 seemed to be of no clinical significance.

Pharmacokinetics of bisoprolol during repeated oral administration to healthy volunteers and patients with kidney or liver disease.

The pharmacokinetics of bisoprolol were investigated following oral administration of 10mg once daily for 7 days in 8 healthy subjects, in 14 patients with different degrees of renal impairment and in 18 patients with liver disease. In healthy subjects peak and trough steady-state concentrations of 52 micrograms/L and 11 micrograms/L, respectively, an elimination half-life of 10.0 hours and total body clearance of 14.2 L/h were observed. 5.21 mg/24 hours of unchanged bisoprolol were recovered following urinary excretion during the dosage interval. In 11 patients with renal impairment (mean CLCR = 28 +/- 5 ml/min/1.72m2) half-life was prolonged to 18.5 hours, and peak and trough concentrations were 74 and 32 micrograms/L, respectively. Correspondingly, urinary excretion decreased to 3.35 mg/24 hours and total body clearance to 7.8 L/h. In uraemic patients (CLCR less than 5 ml/min/1.73m2) the total clearance of bisoprolol was 5.0 L/h and the elimination half-life was 24.2 hours. In patients with liver cirrhosis half-life increased to 13.5 hours, steady-state peak and trough concentrations increased to 62 and 22 micrograms/L, respectively, and total body clearance decreased to 10.8 L/h. The present study indicates that in patients with impairment of kidney or liver function accumulation of bisoprolol above a factor of 2 did not occur. However, in the terminal stages of insufficiency of kidney or liver function bisoprolol dosage should not exceed 10mg.

Pharmacokinetics of netilmicin in premature infants.

The pharmacokinetics of netilmicin were studied in 12 premature infants with proven or presumed sepsis during the first month of life. Eleven of 12 patients received netilmicin 2.5 mg/kg intravenously every 12 h while one 770-gram birth weight infant received 2.5 mg/kg every 18 h. Mean steady-state peak and trough concentrations were 8.9 micrograms/ml and 2.8 micrograms/ml, respectively. Of twelve patients, 11 had trough serum concentration above 2 micrograms/ml and four had trough serum concentrations above 3 micrograms/ml. Mean total body clearance of netilmicin was 0.84 ml/min/kg. The mean clearance of 0.72 ml/min/kg was substantially lower in patients with a mean postnatal age of 2.7 days than the clearance of 1.10 ml/min/kg in patients with a mean postnatal age of 23 days. The mean apparent volume of distribution was 0.63 l/kg; and the mean elimination halflife was 8.6 h. A three-fold interpatient variation in pharmacokinetic parameters was seen. These data suggest the need for careful monitoring of netilmicin serum concentration in premature infants.