Single Dosing Interval Research Articles

Clearance of Piperacillin-Tazobactam and Vancomycin During Continuous Renal Replacement With Regional Citrate Anticoagulation.

The use of regional citrate anticoagulation during continuous venovenous hemodiafiltration (CVVHDF) has increased worldwide. However, data on its effect on the pharmacokinetics of antibiotics are limited. In this study, the authors aimed to measure the clearance of piperacillin-tazobactam and vancomycin in patients receiving CVVHDF with regional citrate anticoagulation. This study measured piperacillin-tazobactam and vancomycin concentrations in patients receiving CVVHDF with regional citrate anticoagulation. Dosing regimens were independently selected by intensivists. Arterial blood and effluent fluid samples were obtained over a single dosing interval and analyzed using ultra-high-performance liquid chromatography with tandem mass spectrometry. Seventeen sampling intervals in 15 patients (9 receiving piperacillin-tazobactam only, 4 receiving vancomycin only, and 2 receiving both) were used. The median overall clearance for piperacillin was 35.2 mL/min [interquartile range (IQR): 32.2-38.6], 70 mL/min (IQR: 62.7-76.2) for tazobactam, and 29.5 mL/min (IQR: 26.2-32) for vancomycin. This is the first study to quantify the pharmacokinetics of vancomycin and piperacillin-tazobactam in patients receiving CVVHDF with regional citrate anticoagulation. These results indicate high clearance and provide key information to guide optimal dosing.

Antimicrobial Exposures in Critically Ill Patients Receiving Extracorporeal Membrane Oxygenation.

Rationale: Data suggest that altered antimicrobial concentrations are likely during extracorporeal membrane oxygenation (ECMO). Objectives: The primary aim of this analysis was to describe the pharmacokinetics (PKs) of antimicrobials in critically ill adult patients receiving ECMO. Our secondary aim was to determine whether current antimicrobial dosing regimens achieve effective and safe exposure. Methods: This study was a prospective, open-labeled, PK study in six ICUs in Australia, New Zealand, South Korea, and Switzerland. Serial blood samples were collected over a single dosing interval during ECMO for 11 antimicrobials. PK parameters were estimated using noncompartmental methods. Adequacy of antimicrobial dosing regimens were evaluated using predefined concentration exposures associated with maximal clinical outcomes and minimal toxicity risks. Measurements and Main Results: We included 993 blood samples from 85 patients. The mean age was 44.7 ± 14.4 years, and 61.2% were male. Thirty-eight patients (44.7%) were receiving renal replacement therapy during the first PK sampling. Large variations (coefficient of variation of ⩾30%) in antimicrobial concentrations were seen leading to more than fivefold variations in all PK parameters across all study antimicrobials. Overall, 70 (56.5%) concentration profiles achieved the predefined target concentration and exposure range. Target attainment rates were not significantly different between modes of ECMO and renal replacement therapy. Poor target attainment was observed across the most frequently used antimicrobials for ECMO recipients, including for oseltamivir (33.3%), piperacillin (44.4%), and vancomycin (27.3%). Conclusions: Antimicrobial PKs were highly variable in critically ill patients receiving ECMO, leading to poor target attainment rates. Clinical trial registered with the Australian New Zealand Clinical Trials Registry (ACTRN12612000559819).

Should patients skip late doses of medication? A pharmacokinetic perspective.

Missed doses, late doses, and other dosing irregularities are major barriers to effective pharmacotherapy, especially for the treatment of chronic conditions. What should a patient do if they did not take their last dose at the prescribed time? Should they take it late or skip it? In this paper, we investigate the pharmacokinetic effects of taking a late dose. We consider a single compartment model with linear absorption and elimination for a patient instructed to take doses at regular time intervals. We suppose that the patient forgets to take a dose and then realizes some time later and must decide what remedial steps to take. Using mathematical analysis, we derive several metrics which quantify the effects of taking the dose late. The metrics involve the difference between the drug concentration time courses for the case that the dose is taken late and the case that the dose is taken on time. In particular, the metrics are the integral of the absolute difference over all time, the maximum of the difference, and the maximum of the integral of the difference over any single dosing interval. We apply these general mathematical formulas to levothyroxine, atorvastatin, and immediate release and extended release formulations of lamotrigine. We further show how population variability can be immediately incorporated into these results. Finally, we use this analysis to propose general principles and strategies for dealing with dosing irregularities.

1107. Vancomycin AUC Dosing: Is One Concentration in the Hand Worth Two in the Bush?

BackgroundRecent guidelines recommend a transition from trough-based to area-under the curve-based (AUC) monitoring for vancomycin for serious invasive methicillin-resistant Staphylococcus aureus infections. Due to the challenges of performing AUC monitoring in clinical practice, this study sought to compare the accuracy of an AUC calculated from two points using trapezoidal calculations and from a single steady-state trough combined with population assumptions.MethodsThis prospective cohort analysis included hospitalized patients with stable renal function from 10.2020 to 12.2020 with two vancomycin concentrations obtained at steady-state during a single dosing interval. For each patient, AUC was calculated via trapezoidal equations utilizing peak and trough concentrations (P/T) and using the trough concentration (T) combined with population volume of distribution. Appropriate concentrations were defined as a peak at least 2 hours after the end of the infusion and a trough within one hour of the next dose. The percent and actual differences were calculated between the P/T and T AUC assessments for each patient. A patient level review was independently conducted by two clinical pharmacists to evaluate if a change in dosing would have been made according to AUC estimation methodology.ResultsThirty-one patients had appropriate steady-state P/T obtained. Baseline demographics are shown in Table 1 with the majority of patients being overweight with normal renal function. The mean calculated AUC for both groups was similar, P/T 544.8 and T 549.8. The mean and median percent differences were 1.85% and 0.65%, with a standard deviation of 7.3% and an apparent normal distribution (Figure 1, p = 0.94 by Shapiro’s test). The median absolute difference in AUC was 25.82 mg*h/L between methodologies. Both methods would have resulted in the same modification to the vancomycin regimen based on patient level chart review. ConclusionThe single-trough method performed similarly to the more laborious P/T method. No patient would have received a dose adjustment based on the two different AUC estimation methods. The single-trough method may represent a resource and workflow conscious AUC estimation method for patients meeting population assumptions.Disclosures All Authors: No reported disclosures

64. Novel Biomarkers Improve Estimation of Vancomycin Clearance in Critically Ill Children

BackgroundThere are a paucity of robust population PK (popPK) models to inform vancomycin (VAN) dosing in critically ill children. The majority of published models incorporate peak/trough data and rely on flawed estimates of renal function. We sought to develop a popPK model for IV VAN in critically ill children utilizing novel plasma and urinary biomarkers.MethodsWe conducted a prospective observational study of critically ill children prescribed VAN for a suspected infection in the CHOP pediatric ICU. Children < 1 year of age and those receiving ECMO or CRRT were excluded. Five VAN samples were collected from a single dosing interval for each subject. Plasma biomarkers (creatinine [Cr], cystatin C [CysC], NGAL) and urinary biomarkers (CysC, NGAL, KIM-1, osteopontin) were collected the morning of PK sampling; urinary biomarkers were corrected for urine creatinine. Nonparametric popPK modeling was performed using Pmetrics. The impact of renal function (GFR) on VAN clearance (CL) was estimated first, comparing model performance with each biomarker (Cr and plasma CysC). The influence of age, sex, additional biomarkers, PIM3 score, and receipt of vasopressors as covariates was then assessed for relevant PK parameters.Results30 subjects completed the study. Median age was 10 years (range 1-17); 76% were male. The majority (90%) of children received VAN for suspected sepsis. PK sampling occurred at a median of 37.7 hours (range 24.6-94.8) into VAN treatment; 136 VAN samples were included. A 2-compartment model with fixed allometric scaling of 0.75 on clearances and 1 on volumes best described the data. CysC-based GFR as a covariate on VAN CL using the HOEK formula (GFR = -4.32 + (80.35/CysC)) resulted in the best model fit. Age and plasma NGAL were also informative on VAN CL in the final model (Figure 1). During model building, urinary NGAL was also associated with VAN CL (comparable to plasma NGAL) and outperformed Cr, although it was not retained in the final model.Figure 1. Final population PK model and parameter estimates. ConclusionPlasma CysC is a better renal function estimate than Cr to inform VAN clearance in critically ill children. Urinary and plasma NGAL also improved estimation of VAN CL during popPK modeling. Novel biomarkers can better describe VAN exposures in critically ill children than reliance on Cr alone.Disclosures Kevin J. Downes, MD, Merck (Individual(s) Involved: Self): Grant/Research Support Stuart L. Goldstein, MD, Bioporto (Consultant, Grant/Research Support)

Effect of Cystatin C on Vancomycin Clearance Estimation in Critically Ill Children Using a Population Pharmacokinetic Modeling Approach.

Vancomycin is eliminated by glomerular filtration, but current approaches to estimate kidney function in children are unreliable. The authors sought to compare the suitability of cystatin C (CysC)-based glomerular filtration rate equations with the most commonly used creatinine-based equation, bedside Schwartz, to estimate vancomycin clearance (CL). This prospective observational study enrolled critically ill patients (2-18 years) receiving intravenous vancomycin at the Children's Hospital of Philadelphia during December 2015-November 2017. Vancomycin levels were collected during clinical care and at 3 times during a single dosing interval. Plasma CysC was measured within 24 hours before intravenous vancomycin (baseline) initiation or immediately after enrollment and along with the third pharmacokinetic sample. Nonlinear mixed effects modeling was performed using NONMEM software. Covariate selection was used to test model fit with inclusion of the estimated glomerular filtration rate (eGFR) on CL using bedside Schwartz versus various published CysC-based equations. In total, 83 vancomycin levels were obtained from 20 children. The median age was 12.7 years; 6 patients were women. A 1-compartment model best described the data; CL was allometrically scaled to 0.75. During covariate selection, inclusion of the eGFR calculated using a CysC-based equation significantly improved model fit [reduction in objective function value (OFV) range: -17.191 to -18.704] than bedside Schwartz ([INCREMENT]OFV -12.820). Including the full age spectrum equation, an eGFR equation based on both creatinine and CysC, led to the largest OFV reduction (-22.913); female sex was also a significant covariate of CL in the model. Final model pharmacokinetic indices were CL = 0.29 L/h/kg and volume of distribution = 0.48 L/kg. CysC-based equations help better estimate vancomycin CL than bedside Schwartz in critically ill children.

Population pharmacokinetics and pharmacodynamics of fosfomycin in non–critically ill patients with bacteremic urinary infection caused by multidrug-resistant Escherichia coli

ObjectivesTo describe the population pharmacokinetics of fosfomycin for patients with bacteraemic urinary tract infection (BUTI). The analysis identified optimal regimens on the basis of pharmacodynamic targets and assessed the adequacy of Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) susceptibility breakpoints for Escherichia coli. MethodsData of 16 patients with BUTI caused by multidrug-resistant E. coli (FOREST clinical trial) received intravenous fosfomycin (4 g every 6 hours) were analysed. A population pharmacokinetic analysis was performed, and Monte Carlo simulations were undertaken using 4 g every 6 hours and 8 g every 8 hours. The probability of pharmacodynamic target attainment was assessed using pharmacodynamic targets for E. coli for static effect, 1-log drop in bacterial burden and resistance suppression. ResultsSixty-four plasma samples were collected over a single dosing interval (day 2 or 3 after starting fosfomycin treatment). Fosfomycin concentrations were highly variable. Pharmacodynamic target attainment analysis showed mild improvement by increasing fosfomycin dosing (4 g every 6 hours vs. every 8 hours). These dosages showed success for decreasing 1-log bacterial burden in 89% to 96% (EUCAST breakpoints) and 33% to 54% (CLSI breakpoints) of patients, but they were unable to reach bacterial resistance suppression targets. ConclusionsFosfomycin concentrations are highly variable—a fact partially explained by renal impairment. The present work supports the use of 4 g every 6 hours as an effective regimen for the treatment of non–critically ill patients with BUTI caused by multidrug-resistant E. coli, as higher dosages might increase toxicity but may not significantly increase efficacy. The current information may suggest that fosfomycin susceptibility breakpoints need to be reappraised.

Are standard doses of piperacillin sufficient for critically ill patients with augmented creatinine clearance?

IntroductionThe aim of this study was to explore the impact of augmented creatinine clearance and differing minimum inhibitory concentrations (MIC) on piperacillin pharmacokinetic/pharmacodynamic (PK/PD) target attainment (time above MIC (fT>MIC)) in critically ill patients with sepsis receiving intermittent dosing.MethodsTo be eligible for enrolment, critically ill patients with sepsis had to be receiving piperacillin-tazobactam 4.5 g intravenously (IV) by intermittent infusion every 6 hours for presumed or confirmed nosocomial infection without significant renal impairment (defined by a plasma creatinine concentration greater than 171 μmol/L or the need for renal replacement therapy). Over a single dosing interval, blood samples were drawn to determine unbound plasma piperacillin concentrations. Renal function was assessed by measuring creatinine clearance (CLCR). A population PK model was constructed, and the probability of target attainment (PTA) for 50% and 100% fT>MIC was calculated for varying MIC and CLCR values.ResultsIn total, 48 patients provided data. Increasing CLCR values were associated with lower trough plasma piperacillin concentrations (P < 0.01), such that with an MIC of 16 mg/L, 100% fT>MIC would be achieved in only one-third (n = 16) of patients. Mean piperacillin clearance was approximately 1.5-fold higher than in healthy volunteers and correlated with CLCR (r = 0.58, P < 0.01). A reduced PTA for all MIC values, when targeting either 50% or 100% fT>MIC, was noted with increasing CLCR measures.ConclusionsStandard intermittent piperacillin-tazobactam dosing is unlikely to achieve optimal piperacillin exposures in a significant proportion of critically ill patients with sepsis, owing to elevated drug clearance. These data suggest that CLCR can be employed as a useful tool to determine whether piperacillin PK/PD target attainment is likely with a range of MIC values.

Systemic Exposure to the Metabolites of Lesogaberan in Humans and Animals: A Case Study of Metabolites in Safety Testing

During preclinical and early phase clinical studies of drug candidates, exposure to metabolites should be monitored to determine whether safety conclusions drawn from studies in animals can be extrapolated to humans. Metabolites accounting for more than 10% of total exposure to drug-related material (DRM) in humans are of regulatory concern, and for any such metabolites, adequate exposure should be demonstrated in animals before large-scale phase 3 clinical trials are conducted. We have previously identified six metabolites, M1-M6, of the gastroesophageal reflux inhibitor lesogaberan. In this study, we measured exposure in humans, rats, and beagle dogs to lesogaberan and these metabolites. Plasma samples were taken at various time points after lesogaberan dosing in two clinical and three preclinical studies. Concentrations of lesogaberan and its metabolites were measured, and exposures during a single dosing interval were calculated. The parent compound and metabolites M1, M2, M4, and M5 were together shown to constitute all significant exposure to DRM in humans. Only M4 and M5 were present at levels of regulatory concern (10.6% and 18.9% of total exposure to DRM, respectively, at steady state). Absolute exposure to M5 was greater in rats during toxicology studies than the highest absolute exposure observed in humans at steady state (117.0 µmol × h/liter vs. 52.2 µmol × h/liter). In contrast, exposure to M4 in rats was less than 50% of the highest absolute exposure observed in humans. Further safety testing of this metabolite may therefore be required.

DALI: Defining Antibiotic Levels in Intensive Care Unit Patients: Are Current -Lactam Antibiotic Doses Sufficient for Critically Ill Patients?

Morbidity and mortality for critically ill patients with infections remains a global healthcare problem. We aimed to determine whether β-lactam antibiotic dosing in critically ill patients achieves concentrations associated with maximal activity and whether antibiotic concentrations affect patient outcome. This was a prospective, multinational pharmacokinetic point-prevalence study including 8 β-lactam antibiotics. Two blood samples were taken from each patient during a single dosing interval. The primary pharmacokinetic/pharmacodynamic targets were free antibiotic concentrations above the minimum inhibitory concentration (MIC) of the pathogen at both 50% (50% f T>MIC) and 100% (100% f T>MIC) of the dosing interval. We used skewed logistic regression to describe the effect of antibiotic exposure on patient outcome. We included 384 patients (361 evaluable patients) across 68 hospitals. The median age was 61 (interquartile range [IQR], 48-73) years, the median Acute Physiology and Chronic Health Evaluation II score was 18 (IQR, 14-24), and 65% of patients were male. Of the 248 patients treated for infection, 16% did not achieve 50% f T>MIC and these patients were 32% less likely to have a positive clinical outcome (odds ratio [OR], 0.68; P = .009). Positive clinical outcome was associated with increasing 50% f T>MIC and 100% f T>MIC ratios (OR, 1.02 and 1.56, respectively; P < .03), with significant interaction with sickness severity status. Infected critically ill patients may have adverse outcomes as a result of inadeqaute antibiotic exposure; a paradigm change to more personalized antibiotic dosing may be necessary to improve outcomes for these most seriously ill patients.

Sirolimus Pharmacokinetics in Early Postmyeloablative Pediatric Blood and Marrow Transplantation

This study examined the pharmacokinetics of sirolimus in pediatric allogeneic blood and marrow transplantation (BMT) recipients in the presence and absence of concomitant fluconazole. Forty pediatric BMT recipients received a daily oral dose of sirolimus and a continuous i.v. infusion of tacrolimus for graft-versus-host disease prophylaxis. Fluconazole was administered i.v. to 19 patients and orally to 6 patients. Full pharmacokinetic profiles of sirolimus within a single dosing interval were collected. Whole-blood sirolimus concentrations were measured by HPLC/mass spectrometry. Noncompartmental analysis was performed using WinNonlin. Nonlinear mixed-effects pharmacokinetic models were developed using NONMEM following standard procedures. The mean ± SD sirolimus trough level before the dose (C0) was 8.0 ± 4.6 ng/mL (range, 1.8-21.6 ng/mL). The peak concentration was 19.9 ± 11.8 ng/mL (range, 3.9-46.1 ng/mL), and the trough level 24 hours later (C24) was 9.1 ± 5.3 ng/mL (range, 1.0-19.1 ng/mL). The terminal disposition half-life (T1/2) was 24.5 ± 11.2 hours (range, 5.8-53.2 hours), and the area under the concentration-versus-time curve (AUC0-24) was 401.1 ± 316.3 ng·h/mL (range, 20.7-1332.3 ng·h/mL). In patients at steady state, C0 and C24 were closely correlated (R2 = 0.77) with a slope of 0.99, indicating the achievement of steady state. C24 was 1.7-fold greater (P = .036) and AUC0-24 was 2-fold greater (P = .012) in Caucasian patients (n = 22) compared with Hispanic patients (n = 9). The average apparent oral clearance was 3-fold greater (P = .001) and the apparent oral volume of distribution was 2-fold greater (P = .018) in patients age ≤12 years compared with those age >12 years. C24 was significantly lower in patients (n = 10) who developed grade III-IV aGVHD (n = 10) than in those with grade 0-II aGVHD (n = 22) (6.1 ± 2.9 ng/mL versus 9.4 ± 5.5 ng/mL; P = .044). Dose-normalized sirolimus trough concentrations were significantly higher in patients receiving concomitant fluconazole therapy compared with those not receiving fluconazole (C0: 3.9 ± 2.5 versus 2.4 ± 1.5 ng/mL/mg, P = .030; C24: 4.8 ± 3.3 versus 2.5 ± 1.7 ng/mL/mg, P = .018). This pharmacokinetic study of sirolimus in pediatric patients documents a large interindividual variability in the exposure of sirolimus. Steady-state trough blood concentrations were correlated with drug exposure. Trough concentrations were higher with a concomitant use of fluconazole and were higher in Caucasian patients than in Hispanic patients. Oral clearance was greater in children age ≤12 years than in older children and adolescents. With therapeutic drug monitoring, the majority (79%) of sirolimus trough levels could be maintained within the target range (3-12 ng/mL). This study provides a rationale and support for dose adjustments of sirolimus based on steady-state blood concentrations aimed at achieving a target concentration to minimize toxicity and maximize therapeutic benefits in pediatric BMT recipients.

Approaches to handling pharmacodynamic baseline responses

A few approaches for handling baseline responses are available for use in pharmacokinetic (PK)-pharmacodynamic (PD) analysis. They include: (method 1-B1) estimation of the typical value and interindividual variability (IIV) of baseline in the population, (B2) inclusion of the observed baseline response as a covariate acknowledging the residual variability, (B3) a more general version of B2 as it also takes the IIV of the baseline in the population into account, and (B4) normalization of all observations by the baseline value. The aim of this study was to investigate the relative performance of B1-B4. PD responses over a single dosing interval were simulated from an indirect response model in which a drug acts through stimulation or inhibition of the response according to an Emax model. The performance of B1-B4 was investigated under 22 designs, each containing 100 datasets. NONMEM VI beta was used to estimate model parameters with the FO and the FOCE method. The mean error (ME, %) and root mean squared error (RMSE, %) of the population parameter estimates were computed and used as an indicator of bias and imprecision. Absolute ME (|ME|) and RMSE from all methods were ranked within the same design, the lower the rank value the better method performance. Average rank of each method from all designs was reported. The results showed that with B1 and FOCE, the average of |ME| and RMSE across all typical individual parameters and all conditions was 5.9 and 31.8%. The average rank of |ME| for B1, B2, B3, and B4 was 3.7, 3.8, 3.3, and 5.2 for the FOCE method, and 4.6, 4.3, 4.7, and 6.4 for the FO method. The smallest imprecision was noted with the use of B1 (rank of 3.1 for FO, and 2.9 for FOCE) and increased, in order, with B3 (3.9-FO and 3.6-FOCE), B2 (4.8-FO; 4.7-FOCE), and B4 (6.4-FO; 6.5-FOCE). We conclude that when considering both bias and imprecision B1 was slightly better than B3 which in turn was better than B2. Differences between these methods were small. B4 was clearly inferior. The FOCE method led to a smaller bias, but no marked reduction in imprecision of parameter estimates compared to the FO method.

Theophylline absorption in young asthmatic children receiving sustained-release formulations

Theophylline absorption from sustained-release formulations intended for administration every 8 hours and every 12 hours was examined in children ages 2 to 6 years during multiple dosing intervals. By generally applied measurements, including mean serum theophylline concentration, bioavailability over a single daytime dosing interval, and percent change in serum theophylline concentration over a single dosing interval, the preparations did not differ. However, over multiple dosing intervals, the 8-hour preparation varied in rate and extent of absorption, with subsequent large variations in serum theophylline concentrations. The 12-hour preparation, on the other hand, was completely bioavailable during each dosing interval, although the rate of absorption did differ from day to night, and was associated with generally acceptable changes in serum concentrations. Thus, analysis of dose-to-dose absorption was required to reveal the differences between the two study preparations. This indicates that traditional analysis of a single daytime dosing interval may be inadequate in the evaluation of preparations of sustained-release theophylline.

372 SUSTAINED RELEASE THEOPHYLLINE (SRT): ABSORPTION IN YOUNG CHILDREN

Available reports concerning the use of SRT in preschool children are limited to evaluations of single daytime dosing intervals with no data regarding the rate or extent of theophylline absorption. This study was performed to examine SRT absorption over multiple dosing intervals in young children. Eight asthmatic children, ages 2-6 yrs, were selected. After an IV aminophylline study to obtain essential pharmacokinetic parameters, each child received Slo-Bid Gyrocaps (S-B, Rorer) q 12 hrs and Slo-Phyllin Gyrocaps (S-P, Rorer) q 8 hrs for 7 days each. On day 7 of each study period, serurm theophylline concentrations (STC) were obtained every 2 hrs for 24 hrs and absorption over time calculated. By generally applied parameters, including mean STC, total bioavailability, and % change in STC over a single dosing interval, the preparations did not differ. However, a more detailed evaluation of absorption revealed a marked difference between the two preparations. S-B was essentially 100% bioavailable at both the morning (97 ± 9% SEM) and evening (99 ± 10%) doses and showed a consistent rise in STCs to a peak 4-6' hrs after each dose. S-P, on the other hand, showed no consistent peak-trough effect and had considerable dose-to-dose variation in % bioavailability (0800 hrs - 102 ± 14; 1600 hrs - 77 ± 15; and 2400 hrs -141 ± 13). These differences indicate delayed and then overlapping absorption with the 1600 and 2400 hr doses, respectively. In summary, analysis of dose-to-dose absorption was required to reveal the difference between the two study preparations. Comparison of theophylline preparations by standard techniques appears inadequate for evaluation of therapeutic value.

Tocainide kinetics in congestive heart failure.

Our subjects were 20 patients with life-threatening or symptomatic ventricular arrhythmias refractory to standard oral antiarrhythmic drugs but responsive to intravenous lidocaine. After evaluation of arrhythmias and treatment with intravenous lidocaine, oral tocainide dosage regimens were based on age, weight, and clinical status. During initial tocainide treatment, six plasma tocainide concentrations were recorded within a single dosing interval in 17 of 20 patients, by which standard kinetic parameters were calculated. Eventual trough steady-state tocainide plasma concentrations were predicted from the derived patient-specific kinetic parameters. Mean daily tocainide dose was 1800 mg (1200 to 2400). Mean daily tocainide doses (milligram per kilogram) did not differ significantly among responders and nonresponders or among patients with or without congestive heart failure. Mean peak and trough plasma concentrations 48 hr after initiation of therapy were 9.8 and 7.5 mcg/ml. Tocainide plasma concentrations did not correlate with responders and nonresponders or identify patients who were developing adverse reactions to tocainide. There were no significant differences in any of the calculated kinetic parameters as a function of response to tocainide or the presence of congestive heart failure, but there was a trend toward smaller volumes of distribution and higher average plasma concentrations at steady state in patients with congestive heart failure. There were no significant kinetic differences among patients with and without congestive heart failure, but a trend toward higher plasma concentrations in patients with congestive heart failure and the small number of patients suggests that further data collection is necessary before dosage recommendations can be made.

Valproic acid dosage and plasma protein binding and clearance.

Valproic acid clearance was determined in six normal subjects during a single-dose (250-mg) study and multiple-dose experiments of 500, 1,000, and 1,500 mg/day. Eight consecutive oral doses were taken at 12-hr intervals at each dosing level. Valproate levels and protein binding were determined at steady state. Clearance declined 20% from 8.33 +/- 2.44 to 6.67 +/- 1.25 ml/hr/kd between the single-dose and the 500-mg/day steps (p = 0.05). Clearance was unchanged between the 500- and 1,000-mg/day steps despite a 44% increase in mean free fraction (0.0703 +/- 0.0381 vs 0.1011 +/- 0.0438, p < 0.05), implying a balanced opposing decline in intrinsic clearance (from 89.2 +/0 71.0 to 72.0 +/- 20.8 ml/hr/kg; p = 0.025). In four subjects completing the 1,500-mg/day step, clearance increased from 6.76 +/- 1.48 ml/hr/kg (1,000- mg/day) to 8.20 +/- 1.62 ml/hr/kg, corresponding to a further increase in free fraction. Free fraction varied within a single dosing interval (%SD = 11% to 49%). The apparent dose-related decline in intrinsic clearance suggests autoinhibition or saturation of metabolism.